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"count": 334,
"next": "https://mitotox.org/api/papers/list?format=api&page=4",
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"results": [
{
"pap_id": "28",
"title": "Characterization of hepatic mitochondrial injury induced by fatty acid oxidation inhibitors.",
"authors": "Vickers, Alison E M",
"chapter": "",
"pages": "78-88",
"journal": "Toxicologic Pathology",
"pub_date": "2009-01-01",
"pub_year": 2009,
"volume": "37",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1177/0192623308329285",
"doi": "10.1177/0192623308329285",
"pmid": "19234235.0",
"pmcid": "",
"abstract": "Impairment of liver mitochondrial beta-oxidation is an important mechanism of drug-induced liver injury. Four inhibitors of fatty acid oxidation were compared in short-term rat in vivo studies in which the rats were administered one or four doses. The hepatocellular vacuolation represented ultra-structural mitochondrial changes. Urine nuclear magnetic resonance (NMR) spectroscopy revealed that both FOX988 and SDZ51-641 induced a persistent dicarboxylic aciduria, suggesting an inhibition of mitochondrial beta-oxidation and incomplete fatty acid metabolism. Etomoxir caused minimal mitochondrial ultrastructural changes and induced only transient dicarboxylic aciduria. CPI975 served as a negative control, in that there were no significant perturbations to the mitochondrial ultrastructural morphology or in the urine NMR composition; however, compound exposure was confirmed by the up-regulation of liver gene expression compared to vehicle control. The liver gene expression changes that were altered by the compounds were indicative of mitochondria, general and oxidative stress, and peroxisomal enzymes involved in beta-oxidation, suggestive of a compensatory response to the inhibition in the mitochondria. In addition, both FOX988 and SDZ51-641 up-regulated ribosomal genes associated with apoptosis, as well as p53 pathways linked with apoptosis. In summary, metabonomics and liver gene expression provided mechanistic information on mitochondrial dysfunction and impaired fatty acid oxidation to further define the clinical pathology and histopathology findings of hepatotoxicity.",
"references": [
"RC00914",
"RC00913",
"RC00912",
"RC00911"
]
},
{
"pap_id": "280",
"title": "The specificity and metabolic implications of the inhibition of pyruvate transport in isolated mitochondria and intact tissue preparations by alpha-Cyano-4-hydroxycinnamate and related compounds.",
"authors": "Halestrap, A P; Denton, R M",
"chapter": "",
"pages": "97-106",
"journal": "The Biochemical Journal",
"pub_date": "1975-04-01",
"pub_year": 1975,
"volume": "148",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/bj1480097",
"doi": "10.1042/bj1480097",
"pmid": "1171687.0",
"pmcid": "PMC1165510",
"abstract": "1. Effects of alpha-cyano-4-hydroxycinnamate and alpha-cyanocinnamate on a number of enzymes involved in pyruvate metabolism have been investigated. Little or no inhibition was observed of any enzyme at concentrations that inhibit completely mitochondrial pyruvate transport. At much higher concentrations (1 mM) some inhibition of pyruvate carboxylase was apparent. 2. Alpha-Cyano-4-hydroxycinnamate (1-100 muM) specifically inhibited pyruvate oxidation by mitochondria isolated from rat heart, brain, kidney and from blowfly flight muscle; oxidation of other substrates in the presence or absence of ADP was not affected. Similar concentrations of the compound also inhibited the carboxylation of pyruvate by rat liver mitochondria and the activation by pyruvate of pyruvate dehydrogenase in fat-cell mitochondria. These findings imply that pyruvate dehydrogenase, pyruvate dehydrogenase kinase and pyruvate carboxylase are exposed to mitochondrial matrix concentrations of pyruvate rather than to cytoplasmic concentrations. 3. Studies with whole-cell preparations incubated in vitro indicate that alpha-cyano-4-hydroxycinnamate or alpha-cyanocinnamate (at concentrations below 200 muM) can be used to specifically inhibit mitochondrial pyruvate transport within cells and thus alter the metabolic emphasis of the preparation. In epididymal fat-pads, fatty acid synthesis from glucose and fructose, but not from acetate, was markedly inhibited. No changes in tissue ATP concentrations were observed. The effects on fatty acid synthesis were reversible. In kidney-cortex slices, gluconeogenesis from pyruvate and lactate but not from succinate was inhibited. In the rat heart perfused with medium containing glucose and insulin, addition of alpha-cyanocinnamate (200 muM) greatly increased the output and tissue concentrations of lactate plus pyruvate but decreased the lactate/pyruvate ratio. 4. The inhibition by cyanocinnamate derivatives of pyruvate transport across the cell membrane of human erythrocytes requires much higher concentrations of the derivatives than the inhibition of transport across the mitochondrial membrane. Alpha-Cyano-4-hydroxycinnamate appears to enter erythrocytes on the cell-membrane pyruvate carrier. Entry is not observed in the presence of albumin, which may explain the small effects when these compounds are injected into whole animals.",
"references": [
"RC03771",
"RC03770",
"RC03769",
"RC03768",
"RC03767",
"RC03766",
"RC03765"
]
},
{
"pap_id": "281",
"title": "Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones.",
"authors": "McKee, E E; Ferguson, M; Bentley, A T; Marks, T A",
"chapter": "",
"pages": "2042-2049",
"journal": "Antimicrobial Agents and Chemotherapy",
"pub_date": "2006-06-01",
"pub_year": 2006,
"volume": "50",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1128/AAC.01411-05",
"doi": "10.1128/AAC.01411-05",
"pmid": "16723564.0",
"pmcid": "PMC1479116",
"abstract": "The effects of a variety of oxazolidinones, with different antibacterial potencies, including linezolid, on mitochondrial protein synthesis were determined in intact mitochondria isolated from rat heart and liver and rabbit heart and bone marrow. The results demonstrate that a general feature of the oxazolidinone class of antibiotics is the inhibition of mammalian mitochondrial protein synthesis. Inhibition was similar in mitochondria from all tissues studied. Further, oxazolidinones that were very potent as antibiotics were uniformly potent in inhibiting mitochondrial protein synthesis. These results were compared to the inhibitory profiles of other antibiotics that function by inhibiting bacterial protein synthesis. Of these, chloramphenicol and tetracycline were significant inhibitors of mammalian mitochondrial protein synthesis while the macrolides, lincosamides, and aminoglycosides were not. Development of future antibiotics from the oxazolidinone class will have to evaluate potential mitochondrial toxicity.",
"references": [
"RC03832",
"RC03831",
"RC03830",
"RC03829"
]
},
{
"pap_id": "282",
"title": "Oxazolidinones inhibit cellular proliferation via inhibition of mitochondrial protein synthesis.",
"authors": "Nagiec, Eva E; Wu, Luping; Swaney, Steve M; Chosay, John G; Ross, Daniel E; Brieland, Joan K; Leach, Karen L",
"chapter": "",
"pages": "3896-3902",
"journal": "Antimicrobial Agents and Chemotherapy",
"pub_date": "2005-09-01",
"pub_year": 2005,
"volume": "49",
"issue": "9",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1128/AAC.49.9.3896-3902.2005",
"doi": "10.1128/AAC.49.9.3896-3902.2005",
"pmid": "16127068.0",
"pmcid": "PMC1195406",
"abstract": "The oxazolidinones are a relatively new structural class of antibacterial agents that act by inhibiting bacterial protein synthesis. The oxazolidinones inhibit mitochondrial protein synthesis, as shown by [35S]methionine incorporation into intact rat heart mitochondria. Treatment of K562 human erythroleukemia cells with the oxazolidinone eperezolid resulted in a time- and concentration-dependent inhibition of cell proliferation. The cells remained viable, but an increase in doubling time was observed with eperezolid treatment. Inhibition was reversible, since washing and refeeding of cells in the absence of compound resulted in a resumption of growth. The growth-inhibitory effect of the oxazolidinones did not appear to be cell type specific, and inhibition of CHO and HEK cells also was demonstrated. Treatment of cells resulted in a decrease in mitochondrial cytochrome oxidase subunit I levels, consistent with an inhibition of mitochondrial protein synthesis. Eperezolid caused no growth inhibition of rho zero (rho0) cells, which contain no mitochondrial DNA; however, the growth of the parent 143B cells was inhibited. These results provide a direct demonstration that the inhibitory effect of eperezolid in mammalian cells is the result of mitochondrial protein synthesis inhibition.",
"references": [
"RC03828",
"RC03827"
]
},
{
"pap_id": "283",
"title": "Mitochondrial Aurora kinase A induces mitophagy by interacting with MAP1LC3 and Prohibitin 2",
"authors": "Bertolin, Giulia; Alves-Guerra, Marie-Clotilde; Burel, Agn?s; Prigent, Claude; Le Borgne, Roland; Tramier, Marc",
"chapter": "",
"pages": "",
"journal": "BioRxiv",
"pub_date": "2020-04-01",
"pub_year": 2020,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://biorxiv.org/lookup/doi/10.1101/2020.04.06.027896",
"doi": "10.1101/2020.04.06.027896",
"pmid": "",
"pmcid": "",
"abstract": "Epithelial and haematologic tumours often show the overexpression of the serine/threonine kinase AURKA. Recently, AURKA was shown to localise at mitochondria, where it regulates mitochondrial dynamics and ATP production. Here we define the molecular mechanisms of AURKA in regulating mitochondrial turnover by mitophagy. When overexpressed, AURKA induces the rupture of the Outer Mitochondrial Membrane in a proteasome-dependent manner. Then, AURKA triggers the degradation of Inner Mitochondrial Membrane (IMM)/matrix proteins by interacting with core components of the autophagy pathway. On the IMM, the kinase forms a tripartite complex with MAP1LC3 and the mitophagy receptor PHB2. This complex is necessary to trigger mitophagy in a PARK2/Parkin-independent manner. The formation of the tripartite complex is induced by the phosphorylation of PHB2 on Ser39, which is required for MAP1LC3 to interact with PHB2. Last, treatment with the PHB2 ligand Xanthohumol blocks AURKA-induced mitophagy by destabilising the tripartite complex. This treatment also restores normal ATP production levels. Altogether, these data provide evidence for a previously undetected role of AURKA in promoting mitophagy through the interaction with PHB2 and MAP1LC3. This work paves the way to the use of function-specific pharmacological inhibitors to counteract the effects of the overexpression of AURKA in cancer.",
"references": [
"RC03875"
]
},
{
"pap_id": "284",
"title": "Mechanisms of anti-cancer action and pharmacology of clofarabine.",
"authors": "Zhenchuk, Anna; Lotfi, Koroush; Juliusson, Gunnar; Albertioni, Freidoun",
"chapter": "",
"pages": "1351-1359",
"journal": "Biochemical Pharmacology",
"pub_date": "2009-12-01",
"pub_year": 2009,
"volume": "78",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.bcp.2009.06.094",
"doi": "10.1016/j.bcp.2009.06.094",
"pmid": "19576186.0",
"pmcid": "",
"abstract": "Clofarabine, a next-generation deoxyadenosine analogue, was developed on the basis of experience with cladribine and fludarabine in order to achieve higher efficacy and avoid extramedullary toxicity. During the past decade this is the only drug granted approval for treatment of pediatric acute leukemia. Recent clinical studies have established the efficacy of clofarabine in treating malignancies with a poor prognosis, such as adult, elderly, and relapsed pediatric leukemia. The mechanisms of its anti-cancer activity involve a combination of direct inhibition of DNA synthesis and ribonucleotide reductase and induction of apoptosis. Due to this broad cytotoxicity, this drug is effective against various subtypes of leukemia and is currently being tested as an oral formulation and for combination therapy of both leukemias and solid tumors. In this review we summarize current knowledge pertaining to the molecular mechanisms of action and pharmacological properties of clofarabine, as well as clinical experiences with this drug with the purpose of facilitating the evaluation of its efficacy and the development of future therapies.",
"references": [
"RC03876"
]
},
{
"pap_id": "285",
"title": "Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies.",
"authors": "Ugalde, Cristina; Vogel, Rutger; Huijbens, Richard; Van Den Heuvel, Bert; Smeitink, Jan; Nijtmans, Leo",
"chapter": "",
"pages": "2461-2472",
"journal": "Human Molecular Genetics",
"pub_date": "2004-10-15",
"pub_year": 2004,
"volume": "13",
"issue": "20",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/hmg/ddh262",
"doi": "10.1093/hmg/ddh262",
"pmid": "15317750.0",
"pmcid": "",
"abstract": "With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by two-dimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the complex is formed in distinct steps. The B17 subunit is part of a subcomplex to which ND1, ND6 and PSST are subsequently added. This is bound to a hydrophilic subcomplex containing the 30 and 49 kDa subunits, to which a subcomplex including the 39 kDa subunit is incorporated, and later on the 18 and 24 kDa subunits. At a later stage more subunits, including the 15 kDa, are added and holo-complex I is formed. Our results suggest that human complex I assembly resembles that of Neurospora crassa, in which a membrane arm is formed and assembled to a preformed peripheral arm, and support ideas about modular evolution.",
"references": [
"RC03878",
"RC03877"
]
},
{
"pap_id": "286",
"title": "The assembly pathway of mitochondrial respiratory chain complex I.",
"authors": "Guerrero-Castillo, Sergio; Baertling, Fabian; Kownatzki, Daniel; Wessels, Hans J; Arnold, Susanne; Brandt, Ulrich; Nijtmans, Leo",
"chapter": "",
"pages": "128-139",
"journal": "Cell Metabolism",
"pub_date": "2017-01-10",
"pub_year": 2017,
"volume": "25",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.cmet.2016.09.002",
"doi": "10.1016/j.cmet.2016.09.002",
"pmid": "27720676.0",
"pmcid": "",
"abstract": "Mitochondrial complex I is the largest integral membrane enzyme of the respiratory chain and consists of 44 different subunits encoded in the mitochondrial and nuclear genome. Its biosynthesis is a highly complicated and multifaceted process involving at least 14 additional assembly factors. How these subunits assemble into a functional complex I and where the assembly factors come into play is largely unknown. Here, we applied a dynamic complexome profiling approach to elucidate the assembly of human mitochondrial complex I and its further incorporation into respiratory chain supercomplexes. We delineate the stepwise incorporation of all but one subunit into a series of distinct assembly intermediates and their association with known and putative assembly factors, which had not been implicated in this process before. The resulting detailed and comprehensive model of complex I assembly is fully consistent with recent structural data and the remarkable modular architecture of this multiprotein complex. Copyright ? 2017 Elsevier Inc. All rights reserved.",
"references": [
"RC03879"
]
},
{
"pap_id": "287",
"title": "Dissecting the roles of mitochondrial complex I intermediate assembly complex factors in the biogenesis of complex I.",
"authors": "Formosa, Luke E; Muellner-Wong, Linden; Reljic, Boris; Sharpe, Alice J; Jackson, Thomas D; Beilharz, Traude H; Stojanovski, Diana; Lazarou, Michael; Stroud, David A; Ryan, Michael T",
"chapter": "",
"pages": "107541",
"journal": "Cell reports",
"pub_date": "2020-04-21",
"pub_year": 2020,
"volume": "31",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.celrep.2020.107541",
"doi": "10.1016/j.celrep.2020.107541",
"pmid": "32320651.0",
"pmcid": "",
"abstract": "Mitochondrial complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integration of distinct intermediate modules, mediated by numerous assembly factors. The mitochondrial complex I intermediate assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module. The role of the MCIA complex and the involvement of other proteins in the biogenesis of this module is unclear. Cell knockout studies reveal that while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centered on ACAD9. We also identify TMEM186 and COA1 as bona fide components of the MCIA complex with loss of either resulting in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, and COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly. Copyright ? 2020 The Author(s). Published by Elsevier Inc. All rights reserved.",
"references": [
"RC03880"
]
},
{
"pap_id": "288",
"title": "Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia.",
"authors": "Skrti\u0007\u0001, Marko; Sriskanthadevan, Shrivani; Jhas, Bozhena; Gebbia, Marinella; Wang, Xiaoming; Wang, Zezhou; Hurren, Rose; Jitkova, Yulia; Gronda, Marcela; Maclean, Neil; Lai, Courteney K; Eberhard, Yanina; Bartoszko, Justyna; Spagnuolo, Paul; Rutledge, Angela C; Datti, Alessandro; Ketela, Troy; Moffat, Jason; Robinson, Brian H; Cameron, Jessie H; Wrana, Jeffery; Eaves, Connie J; Minden, Mark D; Wang, Jean C Y; Dick, John E; Humphries, Keith; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D",
"chapter": "",
"pages": "674-688",
"journal": "Cancer Cell",
"pub_date": "2011-11-15",
"pub_year": 2011,
"volume": "20",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.ccr.2011.10.015",
"doi": "10.1016/j.ccr.2011.10.015",
"pmid": "22094260.0",
"pmcid": "PMC3221282",
"abstract": "To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity. 2011 Elsevier Inc. All rights reserved.",
"references": [
"RC03884",
"RC03883",
"RC03882",
"RC03881"
]
},
{
"pap_id": "289",
"title": "Inhibition of MG132-induced mitochondrial dysfunction and cell death in PC12 cells by 3-morpholinosydnonimine.",
"authors": "Lee, Chung Soo; Han, Eun Sook; Park, Eon Sob; Bang, Hyoweon",
"chapter": "",
"pages": "18-26",
"journal": "Brain Research",
"pub_date": "2005-03-02",
"pub_year": 2005,
"volume": "1036",
"issue": "1月2日",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.brainres.2004.12.036",
"doi": "10.1016/j.brainres.2004.12.036",
"pmid": "15725397.0",
"pmcid": "",
"abstract": "The effect of 3-morpholinosydnonimine (SIN-1) against the cytotoxicity of MG132, a proteasome inhibitor, in differentiated PC12 cells was assessed by measuring the effect on the mitochondrial membrane permeability. Treatment of PC12 cells with MG132 resulted in the nuclear damage, decrease in the mitochondrial transmembrane potential, cytosolic accumulation of cytochrome c, activation of caspase-3, increase in the formation of reactive oxygen species (ROS), and depletion of GSH. Addition of SIN-1, a producer of nitric oxide (NO) and superoxide, differentially reduced the MG132-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 150 microM. Carboxy-PTIO, superoxide dismutase, Mn-TBAP, and ascorbate prevented the inhibitory effect of SIN-1 on the cytotoxicity of MG132. SIN-1 inhibited the MG132-induced change in the mitochondrial membrane permeability, ROS formation and decrease in GSH contents in PC12 cells. S-nitroso-N-acetyl-DL-penicillamine reduced the MG132-induced cell death in PC12 cells, whereas peroxynitrite and H2O2 did not affect the cytotoxicity of MG132. The results suggest that NO and superoxide liberated from SIN-1 exert an inhibitory effect against the cytotoxicity of MG132. SIN-1 may inhibit the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability that is associated with oxidative damage.",
"references": [
"RC03890",
"RC03889",
"RC03888",
"RC03887",
"RC03886",
"RC03885"
]
},
{
"pap_id": "29",
"title": "Myxothiazol, a new inhibitor of the cytochrome b-c1 segment of the respiratory chain",
"authors": "Thierbach, Georg; Reichenbach, Hans",
"chapter": "",
"pages": "282-289",
"journal": "Biochimica et Biophysica Acta (BBA) - Bioenergetics",
"pub_date": "1981-12-01",
"pub_year": 1981,
"volume": "638",
"issue": "2",
"Issn": "52728",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0005272881902383",
"doi": "10.1016/0005-2728(81)90238-3",
"pmid": "",
"pmcid": "",
"abstract": "Myxothiazol inhibited oxygen consumption of beef heart mitochondria in the presence and absence of 2,4-dinitrophenol, as well as NADH oxidation by submitochondrial particles. The doses required for 50% inhibition were 0.58 mol myxothiazol/mol cytochrome b for oxygen consumption of beef heart mitochondria, and 0.45 mol/mol cytochrome b for NADH oxidation by submitochondrial particles. Difference spectra with beef heart mitochondria and with cell suspensions of Saccharomyces cerevisiae revealed that myxothiazol blocked the electron transport within the cytochrome b-c1 segment of the respiratory chain. Myxothiazol induced a spectral change in cytochrome b which was different from and independent of the shift induced by antimycin. Myxothiazol did not give the extra reduction of cytochrome b typical for antimycin. Studies on the effect of mixtures of myxothiazol and antimycin on the inhibition of NADH oxidation indicated that the binding sites of the two inhibitors are not identical.",
"references": [
"RC00915"
]
},
{
"pap_id": "290",
"title": "Shutting down the pore: The search for small molecule inhibitors of the mitochondrial permeability transition.",
"authors": "`\u0001ileikyt\u0017\u0001, Justina; Forte, Michael",
"chapter": "",
"pages": "1197-1202",
"journal": "Biochimica et Biophysica Acta",
"pub_date": "2016-08-01",
"pub_year": 2016,
"volume": "1857",
"issue": "8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.bbabio.2016.02.016",
"doi": "10.1016/j.bbabio.2016.02.016",
"pmid": "26924772.0",
"pmcid": "PMC4893955",
"abstract": "The mitochondrial permeability transition pore (PTP) is now recognized as playing a key role in a wide variety of human diseases whose common pathology may be based in mitochondrial dysfunction. Recently, PTP assays have been adapted to high-throughput screening approaches to identify small molecules specifically inhibiting the PTP. Following extensive secondary chemistry, the most potent inhibitors of the PTP described to date have been developed. This review will provide an overview of each of these screening efforts, use of resulting compounds in animal models of PTP-based diseases, and problems that will require further study. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. Copyright ? 2016 Elsevier B.V. All rights reserved.",
"references": [
"RC03896"
]
},
{
"pap_id": "291",
"title": "Inhibition of proteasome reveals basal mitochondrial ubiquitination.",
"authors": "Sulkshane, Prasad; Duek, Inbar; Ram, Jonathan; Thakur, Anita; Reis, Noa; Ziv, Tamar; Glickman, Michael H",
"chapter": "",
"pages": "103949",
"journal": "Journal of Proteomics",
"pub_date": "2020-10-01",
"pub_year": 2020,
"volume": "229",
"issue": "",
"Issn": "18743919",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S1874391920303171",
"doi": "10.1016/j.jprot.2020.103949",
"pmid": "32882436.0",
"pmcid": "",
"abstract": "Strict quality control for mitochondrial proteins is necessary to ensure cell homeostasis. Two cellular pathways-Ubiquitin Proteasome System (UPS) and autophagy-contribute to mitochondrial homeostasis under stressful conditions. Here, we investigate changes to the mitochondria proteome and to the ubiquitin landscape at mitochondria in response to proteasome inhibition. Treatment of HeLa cells devoid of Parkin, the primary E3 ligase responsible for mitophagy, with proteasome inhibitor MG132 for a few hours caused mitochondrial oxidative stress and fragmentation, reduced energy output, and increased mitochondrial ubiquitination without inducing mitophagy. Overexpression of Parkin did not show any induction of mitophagy in response to MG132 treatment. Analysis of ubiquitin chains on isolated mitochondria revealed predominance of K48, K29 and K63-linked polyubiquitin. Interestingly, of all ubiquitinated mitochondrial proteins detected in response to MG132 treatment, a majority (e90%) were intramitochondrial irrespective of Parkin expression. However",
"references": [
"RC03894",
"RC03893",
"RC03892",
"RC03891"
]
},
{
"pap_id": "292",
"title": "Megamitochondria formation - physiology and pathology.",
"authors": "Wakabayashi, T",
"chapter": "",
"pages": "497-538",
"journal": "Journal of Cellular and Molecular Medicine",
"pub_date": "2002-12-01",
"pub_year": 2002,
"volume": "6",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1111/j.1582-4934.2002.tb00452.x",
"doi": "10.1111/j.1582-4934.2002.tb00452.x",
"pmid": "12611638.0",
"pmcid": "PMC6741312",
"abstract": "Mitochondria undergo structural changes simultaneously with their functional changes in both physiological and pathological conditions. These structural changes of mitochondria are classified into two categories: simple swelling and the formation of megamitochondria (MG). Data have been accumulated to indicate that free radicals play a crucial role in the mechanism of the MG formation induced by various experimental conditions which are apparently various. These include ethanol-, chloramphenicol- and hydrazine-induced MG formation. Involvement of free radicals in the mechanism of MG formation is showed by the fact that MG formation is successfully suppressed by free radical scavengers such as alpha-tocopherol, coenzyme Q(10), and 4-OH-TEMPO. Detailed mechanisms and pathophysiological meanings of MG formation still remain to be investigated. However, a body of evidence strongly suggests that enormous changes in physicochemical and biochemical properties of the mitochondrial membranes during MG formation take place and these changes are favorable for membrane fusion. A recent report showed that continous exposure of cells with MG to free radicals induces apoptosis, finding which suggests that MG formation is an adaptative process to unfavorable environments at the level of intracellular organelles. Mitochondria try to decrease intracellular reactive oxygen species (ROS) levels by decreasing the consume of oxygen via MG formation. If mitochondria succeed to suppress intracellular ROS levels, MG return to normal both structurally and functionally, and they restore the ability to actively synthesize ATP. If cells are additionally exposed to excess amounts of free radicals, MG become swollen, membrane potential of mitochondria (DeltaPsim) decreases, cytochrome c is released from mitochondria, leading to activation of caspases and apoptosis is induced.",
"references": [
"RC03904",
"RC03903",
"RC03902",
"RC03901",
"RC03900",
"RC03899",
"RC03898",
"RC03897"
]
},
{
"pap_id": "293",
"title": "Diazepam inhibits cell respiration and induces fragmentation of mitochondrial reticulum.",
"authors": "Vorobjev, I A; Zorov, D B",
"chapter": "",
"pages": "311-314",
"journal": "FEBS Letters",
"pub_date": "1905-06-05",
"pub_year": 1905,
"volume": "163",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0014-5793(83)80842-4",
"doi": "10.1016/0014-5793(83)80842-4",
"pmid": "6641946.0",
"pmcid": "",
"abstract": "Diazepam (70-150 micrograms/ml) significantly inhibits oxygen consumption by pig kidney embryo cells and causes the cellular ATP level to fall. The maximum inhibitory effect develops after 1.5-2.5 h of diazepam treatment. In isolated mitochondria diazepam inhibits respiration in state 2 and 3u with glutamate and in state 3u with succinate. Ethylrhodamine staining and electron microscopic study reveal fragmentation of mitochondria in living cells.",
"references": [
"RC03910",
"RC03909",
"RC03908",
"RC03907"
]
},
{
"pap_id": "294",
"title": "Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death.",
"authors": "Park, So Jung; Shin, Ji Hyun; Kang, Hee; Hwang, Jung Jin; Cho, Dong-Hyung",
"chapter": "",
"pages": "517-522",
"journal": "BMB Reports",
"pub_date": "2011-08-01",
"pub_year": 2011,
"volume": "44",
"issue": "8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.5483/bmbrep.2011.44.8.517",
"doi": "10.5483/bmbrep.2011.44.8.517",
"pmid": "21871175.0",
"pmcid": "",
"abstract": "Mitochondrial dynamics not only involves mitochondrial morphology but also mitochondrial biogenesis, mitochondrial distribution, and cell death. To identify specific regulators to mitochondria dynamics, we screened a chemical library and identified niclosamide as a potent inducer of mitochondria fission. Niclosamide promoted mitochondrial fragmentation but this was blocked by down-regulation of Drp1. Niclosamide treatment resulted in the disruption of mitochondria membrane potential and reduction of ATP levels. Moreover, niclosamide led to apoptotic cell death by caspase-3 activation. Interestingly, niclosamide also increased autophagic activity. Inhibition of autophagy suppressed niclosamide-induced cell death. Therefore, our findings suggest that niclosamide induces mitochondria fragmentation and may contribute to apoptotic and autophagic cell death.",
"references": [
"RC03906",
"RC03905"
]
},
{
"pap_id": "295",
"title": "Identification of New Activators of Mitochondrial Fusion Reveals a Link between Mitochondrial Morphology and Pyrimidine Metabolism.",
"authors": "Miret-Casals, Laia; Sebasti?n, David; Brea, Jos?; Rico-Leo, Eva M; Palac?n, Manuel; Fern?ndez-Salguero, Pedro M; Loza, M Isabel; Albericio, Fernando; Zorzano, Antonio",
"chapter": "",
"pages": "268-278.e4",
"journal": "Cell Chemical Biology",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "25",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.chembiol.2017.12.001",
"doi": "10.1016/j.chembiol.2017.12.001",
"pmid": "29290623.0",
"pmcid": "",
"abstract": "Mitochondria are dynamic organelles that produce most of the cellular ATP, and are involved in many other cellular functions such as Ca2+ signaling, differentiation, apoptosis, cell cycle, and cell growth. One?key process of mitochondrial dynamics is mitochondrial fusion, which is catalyzed by mitofusins (MFN1?and MFN2) and OPA1. The outer mitochondrial membrane protein MFN2 plays a relevant role in the?maintenance of mitochondrial metabolism, insulin signaling, and mutations that cause neurodegenerative disorders. Therefore, modulation of proteins involved in mitochondrial dynamics has emerged as?a potential pharmacological strategy. Here, we report the identification of small molecules by high-throughput screen that promote mitochondrial elongation in an MFN1/MFN2-dependent manner. Detailed analysis of their mode of action reveals a previously unknown connection between pyrimidine metabolism and mitochondrial dynamics. Our data indicate a link between pyrimidine biosynthesis and mitochondrial dynamics, which maintains cell survival under stress conditions characterized by loss of pyrimidine synthesis. Copyright ? 2017 Elsevier Ltd. All rights reserved.",
"references": [
"RC03914",
"RC03913",
"RC03912",
"RC03911"
]
},
{
"pap_id": "296",
"title": "Mitochondrial fission - a drug target for cytoprotection or cytodestruction?",
"authors": "Rosdah, Ayeshah A; K Holien, Jessica; Delbridge, Lea M D; Dusting, Gregory J; Lim, Shiang Y",
"chapter": "",
"pages": "e00235",
"journal": "Pharmacology research & perspectives",
"pub_date": "1905-07-08",
"pub_year": 1905,
"volume": "4",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/prp2.235",
"doi": "10.1002/prp2.235",
"pmid": "27433345.0",
"pmcid": "PMC4876145",
"abstract": "Mitochondria are morphologically dynamic organelles constantly undergoing processes of fission and fusion that maintain integrity and bioenergetics of the organelle: these processes are vital for cell survival. Disruption in the balance of mitochondrial fusion and fission is thought to play a role in several pathological conditions including ischemic heart disease. Proteins involved in regulating the processes of mitochondrial fusion and fission are therefore potential targets for pharmacological therapies. Mdivi-1 is a small molecule inhibitor of the mitochondrial fission protein Drp1. Inhibiting mitochondrial fission with Mdivi-1 has proven cytoprotective benefits in several cell types involved in a wide array of cardiovascular injury models. On the other hand, Mdivi-1 can also exert antiproliferative and cytotoxic effects, particularly in hyperproliferative cells. In this review, we discuss these divergent effects of Mdivi-1 on cell survival, as well as the potential and limitations of Mdivi-1 as a therapeutic agent.",
"references": [
"RC03952"
]
},
{
"pap_id": "297",
"title": "Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases.",
"authors": "Szabo, Aliz; Sumegi, Katalin; Fekete, Katalin; Hocsak, Eniko; Debreceni, Balazs; Setalo, Gyorgy; Kovacs, Krisztina; Deres, Laszlo; Kengyel, Andras; Kovacs, Dominika; Mandl, Jozsef; Nyitrai, Miklos; Febbraio, Mark A; Gallyas, Ferenc; Sumegi, Balazs",
"chapter": "",
"pages": "86-96",
"journal": "Biochemical Pharmacology",
"pub_date": "2018-02-01",
"pub_year": 2018,
"volume": "150",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.bcp.2018.01.038",
"doi": "10.1016/j.bcp.2018.01.038",
"pmid": "29378182.0",
"pmcid": "",
"abstract": "Mitochondria fragmentation destabilizes mitochondrial membranes, promotes oxidative stress and facilitates cell death, thereby contributing to the development and the progression of several mitochondria-related diseases. Accordingly, compounds that reverse mitochondrial fragmentation could have therapeutic potential in treating such diseases. BGP-15, a hydroxylamine derivative, prevents insulin resistance in humans and protects against several oxidative stress-related diseases in animal models. Here we show that BGP-15 promotes mitochondrial fusion by activating optic atrophy 1 (OPA1), a GTPase dynamin protein that assist fusion of the inner mitochondrial membranes. Suppression of Mfn1, Mfn2 or OPA1 prevents BGP-15-induced mitochondrial fusion. BGP-15 activates Akt, S6K, mTOR, ERK1/2 and AS160, and reduces JNK phosphorylation which can contribute to its protective effects. Furthermore, BGP-15 protects lung structure, activates mitochondrial fusion, and stabilizes cristae membranes in vivo determined by electron microscopy in a model of pulmonary arterial hypertension. These data provide the first evidence that a drug promoting mitochondrial fusion in in vitro and in vivo systems can reduce or prevent the progression of mitochondria-related disorders. Copyright ? 2018 The Author(s). Published by Elsevier Inc. All rights reserved.",
"references": [
"RC03917",
"RC03916",
"RC03915"
]
},
{
"pap_id": "298",
"title": "Inhibition of mitochondrial electron transport by peroxynitrite.",
"authors": "Radi, R; Rodriguez, M; Castro, L; Telleri, R",
"chapter": "",
"pages": "89-95",
"journal": "Archives of Biochemistry and Biophysics",
"pub_date": "1994-01-01",
"pub_year": 1994,
"volume": "308",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1006/abbi.1994.1013",
"doi": "10.1006/abbi.1994.1013",
"pmid": "8311480.0",
"pmcid": "",
"abstract": "Mammalian mitochondria are sensitive targets of the cytotoxic effects of superoxide (O.2-) and nitric oxide (.NO). In turn, when superoxide and nitric oxide are simultaneously produced, they rapidly react with each other yielding the highly oxidizing peroxynitrite anion (ONOO-) which may be also toxic to mammalian mitochondria. In this study we report that peroxynitrite exposure to rat heart mitochondria resulted in significant inactivation of electron carriers such as succinate dehydrogenase and NADH dehydrogenase as well as the mitochondrial ATPase. As a result of enzyme inactivation, peroxynitrite lead to a profound inhibition of glutamate/malate- and succinate-supported oxygen consumption but did not cause mitochondrial uncoupling. Secondary to inhibiting mitochondrial electron transport, peroxynitrite induced an enhanced succinate-stimulated hydrogen peroxide formation by heart mitochondria. Most of the damaging effects against mitochondria can be ascribed to peroxynitrite anion itself and not to hydroxyl radical-like oxidant yielded during the proton-catalyzed decomposition of peroxynitrite, as hydroxyl radical scavengers provided a rather modest protection. Our observations indicate that mitochondria may constitute a key intracellular loci for the toxic effects of peroxynitrite under the various pathological conditions in which peroxynitrite appears to play a contributory role.",
"references": [
"RC03921",
"RC03920",
"RC03919",
"RC03918"
]
},
{
"pap_id": "299",
"title": "ROS as a novel indicator to predict anticancer drug efficacy.",
"authors": "Zaidieh, Tarek; Smith, James R; Ball, Karen E; An, Qian",
"chapter": "",
"pages": "1224",
"journal": "BMC Cancer",
"pub_date": "2019-12-16",
"pub_year": 2019,
"volume": "19",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1186/s12885-019-6438-y",
"doi": "10.1186/s12885-019-6438-y",
"pmid": "31842863.0",
"pmcid": "PMC6916036",
"abstract": "BACKGROUND: Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells' response to ROS-stimulating therapy. METHODS: Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. RESULTS: Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. CONCLUSIONS: Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.",
"references": [
"RC03929",
"RC03928",
"RC03927",
"RC03926",
"RC03925",
"RC03924",
"RC03923",
"RC03922"
]
},
{
"pap_id": "3",
"title": "Target identification of drug induced mitochondrial toxicity using immunocapture based OXPHOS activity assays.",
"authors": "Nadanaciva, Sashi; Bernal, Autumn; Aggeler, Robert; Capaldi, Roderick; Will, Yvonne",
"chapter": "",
"pages": "902-911",
"journal": "Toxicology in Vitro",
"pub_date": "2007-08-01",
"pub_year": 2007,
"volume": "21",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2007.01.011",
"doi": "10.1016/j.tiv.2007.01.011",
"pmid": "17346924.0",
"pmcid": "",
"abstract": "Mitochondrial dysfunction has been shown to be a pharmacotoxicological response to a variety of currently-marketed drugs. In order to reduce attrition due to mitochondrial toxicity, high throughput-applicable screens are needed for early stage drug discovery. We describe, here, a set of immunocapture based assays to identify compounds that directly inhibit four of the oxidative phosphorylation (OXPHOS) complexes: I, II, IV, and V. Intra- and inter-assay variation were determined and specificity tested by using classical mitochondrial inhibitors. Twenty drugs, some with known mitochondrial toxicity and others with no known mitochondrial liability, were studied. Direct inhibition of one or more of the OXPHOS complexes was identified for many of the drugs. Novel information was obtained for several drugs including ones with previously unknown effects on oxidative phosphorylation. A major advantage of the immunocapture approach is that it can be used throughout drug screening from early compound evaluation to clinical trials.",
"references": [
"RC00110",
"RC00111",
"RC00112",
"RC00113",
"RC00114",
"RC00115",
"RC00116",
"RC00117",
"RC00118",
"RC00119",
"RC00120",
"RC00121",
"RC00122",
"RC00123",
"RC00124",
"RC00125",
"RC00126",
"RC00127",
"RC00128",
"RC00129",
"RC00130",
"RC00131",
"RC00132",
"RC00133",
"RC00134",
"RC00135",
"RC00136",
"RC00137",
"RC00138",
"RC00139",
"RC00140",
"RC00141",
"RC00142",
"RC00143",
"RC00144",
"RC00145",
"RC00146",
"RC00147",
"RC00148",
"RC00149",
"RC00150",
"RC00151",
"RC00152",
"RC00153",
"RC00154",
"RC00155",
"RC00156",
"RC00157",
"RC00158",
"RC00159",
"RC00160",
"RC00161",
"RC00162",
"RC00163",
"RC00164",
"RC00165",
"RC00166",
"RC00167",
"RC00168",
"RC00169",
"RC00170",
"RC00171",
"RC00172",
"RC00173",
"RC00174",
"RC00175",
"RC00176",
"RC00177",
"RC00178",
"RC00179",
"RC00180",
"RC00181",
"RC00182",
"RC00183",
"RC00184",
"RC00185",
"RC00186",
"RC00187",
"RC00188",
"RC00189",
"RC00190",
"RC00191",
"RC00192",
"RC00193",
"RC00194",
"RC00195",
"RC00196",
"RC00197",
"RC00198",
"RC00199",
"RC00200",
"RC00201",
"RC00202",
"RC00203",
"RC00204",
"RC00205",
"RC00206",
"RC00207",
"RC00208",
"RC00209",
"RC00210",
"RC00211",
"RC00212",
"RC00213",
"RC00214",
"RC00215",
"RC00216",
"RC00217",
"RC00218",
"RC00219",
"RC00220",
"RC00221"
]
},
{
"pap_id": "30",
"title": "Effect of dopamine, dimethoxyphenylethylamine, papaverine, and related compounds on mitochondrial respiration and complex I activity.",
"authors": "Morikawa, N; Nakagawa-Hattori, Y; Mizuno, Y",
"chapter": "",
"pages": "1174-1181",
"journal": "Journal of Neurochemistry",
"pub_date": "1996-03-01",
"pub_year": 1996,
"volume": "66",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1046/j.1471-4159.1996.66031174.x",
"doi": "10.1046/j.1471-4159.1996.66031174.x",
"pmid": "8769881.0",
"pmcid": "",
"abstract": "We report the effect of papaverine, tetrahydro-papaverine, laudanosine, dimethoxyphenylethylamine, dopamine, and its metabolites on mitochondrial respiration and activities of the enzymes in the electron transfer complexes, as mitochondrial toxins may be implicated in the etiology and the pathogenesis of Parkinson's disease. Papaverine was the most potent inhibitor of complex I and NADH-linked mitochondrial respiration among the compounds tested next to rotenone. Tetrahydropapaverine, dimethoxyphenylethylamine, and laudanosine also inhibited NADH-linked mitochondrial respiration and complex I activity in this order. Dopamine and its metabolites showed either no inhibition or only very week inhibition. Compounds with dimethoxy residues in the phenyl ring were associated with more potent inhibition of complex I than those without. Our results warrant further studies on these and some related compounds as candidate neurotoxins causing Parkinson's disease.",
"references": [
"RC01371",
"RC00916"
]
},
{
"pap_id": "300",
"title": "Mitochondrial electron transport chain in heavy metal-induced neurotoxicity: effects of cadmium, mercury, and copper.",
"authors": "Belyaeva, Elena A; Sokolova, Tatyana V; Emelyanova, Larisa V; Zakharova, Irina O",
"chapter": "",
"pages": "136063",
"journal": "Thescientificworldjournal",
"pub_date": "2012-04-24",
"pub_year": 2012,
"volume": "2012",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1100/2012/136063",
"doi": "10.1100/2012/136063",
"pmid": "22619586.0",
"pmcid": "PMC3349094",
"abstract": "To clarify the role of mitochondrial electron transport chain (mtETC) in heavy-metal-induced neurotoxicity, we studied action of Cd(2+), Hg(2+), and Cu(2+) on cell viability, intracellular reactive oxygen species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd(2+) beginning from 10 [mu]M and already at short incubation time (3 h) significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 [mu]M Hg(2+) or 500 [mu]M Cd(2+), whereas even after 48 h exposure with 500 [mu]M Cu(2+), only a 50% inhibition of the respiration occurred. Against the Cd(2+)-induced cell injury, not only different antioxidants and mitochondrial permeability transition pore inhibitors were protective but also such mtETC effectors as FCCP and stigmatellin (complex III inhibitor). However, all mtETC effectors used did not protect against the Hg(2+)- or Cu(2+)-induced cell damage. Notably, stigmatellin was shown to be one of the strongest protectors against the Cd(2+)-induced cell damage, producing a 15-20% increase in the cell viability. The mechanisms of the mtETC involvement in the heavy-metal-induced mitochondrial membrane permeabilization and cell death are discussed.",
"references": [
"RC03940",
"RC03939",
"RC03938",
"RC03937",
"RC03936",
"RC03935",
"RC03934",
"RC03933",
"RC03932",
"RC03931",
"RC03930"
]
},
{
"pap_id": "301",
"title": "A High-Throughput Screening Identifies MICU1 Targeting Compounds.",
"authors": "Di Marco, Giulia; Vallese, Francesca; Jourde, Benjamin; Bergsdorf, Christian; Sturlese, Mattia; De Mario, Agnese; Techer-Etienne, Valerie; Haasen, Dorothea; Oberhauser, Berndt; Schleeger, Simone; Minetti, Giulia; Moro, Stefano; Rizzuto, Rosario; De Stefani, Diego; Fornaro, Mara; Mammucari, Cristina",
"chapter": "",
"pages": "2321-2331.e6",
"journal": "Cell reports",
"pub_date": "2020-02-18",
"pub_year": 2020,
"volume": "30",
"issue": "7",
"Issn": "22111247",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S2211124720301157",
"doi": "10.1016/j.celrep.2020.01.081",
"pmid": "32075766.0",
"pmcid": "PMC7034061",
"abstract": "Mitochondrial Ca2+ uptake depends on the mitochondrial calcium uniporter (MCU) complex, a highly selective channel of the inner mitochondrial membrane (IMM). Here, we screen a library of 44,000 non-proprietary compounds for their ability to modulate mitochondrial Ca2+ uptake. Two of them, named MCU-i4 and MCU-i11, are confirmed to reliably decrease mitochondrial Ca2+ influx. Docking simulations reveal that these molecules directly bind a specific cleft in MICU1, a key element of the MCU complex that controls channel gating. Accordingly, in MICU1-silenced or deleted cells, the inhibitory effect of the two compounds is lost. Moreover, MCU-i4 and MCU-i11 fail to inhibit mitochondrial Ca2+ uptake in cells expressing a MICU1 mutated in the critical amino acids that forge the predicted binding cleft. Finally, these compounds are tested ex?vivo, revealing a primary role for mitochondrial Ca2+ uptake in muscle growth. Overall, MCU-i4 and MCU-i11 represent leading molecules for the development of MICU1-targeting drugs. Copyright ? 2020 The Author(s). Published by Elsevier Inc. All rights reserved.",
"references": [
"RC03950",
"RC03949",
"RC03948",
"RC03947",
"RC03946",
"RC03945",
"RC03944",
"RC03943",
"RC03942",
"RC03941"
]
},
{
"pap_id": "302",
"title": "DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter.",
"authors": "Kon, Naohiro; Murakoshi, Michiko; Isobe, Aya; Kagechika, Katsuji; Miyoshi, Naoki; Nagayama, Takahiro",
"chapter": "",
"pages": "17045",
"journal": "Cell death discovery",
"pub_date": "2017-07-17",
"pub_year": 2017,
"volume": "3",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/cddiscovery.2017.45",
"doi": "10.1038/cddiscovery.2017.45",
"pmid": "28725491.0",
"pmcid": "PMC5511861",
"abstract": "In cardiac myocytes, regulation of mitochondrial Ca2+ is important for cellular signaling and cardiac contraction. Ca2+ entry into the mitochondria is mediated by a highly selective Ca2+ channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulatory subunits such as MICU1. Although pharmacological regulation of the mitochondrial Ca2+ influx is a promising approach to controlling the cellular functions, a cell-permeable and specific inhibitor of the mitochondrial calcium uniporter has not yet been developed. Here, we identify a novel cell-permeable inhibitor of the uniporter by a high-throughput screening of 120 000 small-molecule compounds. In our study, DS16570511 dose-dependently inhibited serum-induced mitochondrial Ca2+ influx in HEK293A cells with an IC50 of 7 ?M. DS16570511 inhibited Ca2+ uptake of isolated mitochondria from human cells, rat heart and pig heart. Overexpression of hMCU or hMICU1 in HEK293A cells increased mitochondrial Ca2+ influx, and the increases were completely suppressed by the pretreatment with DS16570511. DS16570511 also blocks mitochondrial Ca2+ overload in a Langendorff perfused beating rat heart. Interestingly, DS16570511 increased cardiac contractility without affecting heart rate in the perfused heart. These results show that DS16570511 is a novel cell-permeable inhibitor of the mitochondrial calcium uniporter and applicable for control of the cardiac functions.",
"references": [
"RC03951"
]
},
{
"pap_id": "303",
"title": "Inhibition of mitochondrial function in isolated rat liver mitochondria by azole antifungals",
"authors": "Rodriguez, Rosita J.; Acosta, Daniel",
"chapter": "",
"pages": "127-131",
"journal": "Journal of biochemical toxicology",
"pub_date": "1905-06-18",
"pub_year": 1905,
"volume": "11",
"issue": "3",
"Issn": "0887-2082",
"Isbn": "",
"url": "http://doi.wiley.com/10.1002/%28SICI%291522-7146%281996%2911%3A3%3C127%3A%3AAID-JBT4%3E3.0.CO%3B2-M",
"doi": "10.1002/(SICI)1522-7146(1996)11:3<127::AID-JBT4>3.0.CO;2-M",
"pmid": "9029271.0",
"pmcid": "",
"abstract": "Ketoconazole is an imidazole oral antifungal agent with a broad spectrum of activity. Ketoconazole has been reported to cause liver damage, but the mechanism is unknown. However, ketoconazole and a related rug, miconazole, have been shown to have inhibitory effects on oxidative phosphorylation in fungi. Fluconazole, another orally administered antifungal azole, has also been reported to cause liver damage despite its supposedly low toxicity profile. The primary objective of this study was to evaluate the metabolic integrity of adult rat liver mitochondria after exposure to ketoconazole, miconazole, fluconazole, and the deacetylated metabolite of ketoconazole by measuring ADP-dependent oxygen uptake polarographically and succinate dehydrogenase activity spectrophotometrically. Ketoconazole, N-deacetyl ketoconazole, and miconazole inhibited glutamate-malate oxidation in a dose-dependent manner such that the 50% inhibitory concentration (I50) was 32,300, and 110 microM, respectively. In addition, the effect of ketoconazole, miconazole, and fluconazole on phosphorylation coupled to the oxidation of pyruvate/malate, ornithine/malate, arginine/malate, and succinate was evaluated. The results demonstrated that ketoconazole and miconazole produced a dose-dependent inhibition of NADH oxidase in which ketoconazole was the most potent inhibitor. Fluconazole had minimal inhibitory effects on NADH oxidase and succinate dehydrogenase, whereas higher concentrations of ketoconazole were required to inhibit the activity of succinate dehydrogenase. N-deacetylated ketoconazole inhibited succinate dehydrogenase with an I50 of 350 microM. In addition, the reduction of ferricyanide by succinate catalyzed by succinate dehydrogenase demonstrated that ketoconazole caused a dose-dependent inhibition of succinate activity (I50 of 74 microM). In summary, ketoconazole appears to be the more potent mitochondrial inhibitor of the azoles studied; complex I of the respiratory chain is the apparent target of the drug's action.",
"references": [
"RC03958",
"RC03957",
"RC03956",
"RC03955",
"RC03954"
]
},
{
"pap_id": "304",
"title": "Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus.",
"authors": "Shekhova, Elena; Kniemeyer, Olaf; Brakhage, Axel A",
"chapter": "",
"pages": "",
"journal": "Antimicrobial Agents and Chemotherapy",
"pub_date": "2017-11-01",
"pub_year": 2017,
"volume": "61",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1128/AAC.00978-17",
"doi": "10.1128/AAC.00978-17",
"pmid": "28848005.0",
"pmcid": "PMC5655112",
"abstract": "Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of Aspergillus fumigatus with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds. Copyright ? 2017 American Society for Microbiology.",
"references": [
"RC03970",
"RC03969",
"RC03968",
"RC03967",
"RC03966",
"RC03965",
"RC03964",
"RC03963",
"RC03962",
"RC03961",
"RC03960",
"RC03959"
]
},
{
"pap_id": "305",
"title": "Toxicity and Loss of Mitochondrial Membrane Potential Induced by Alkyl Gallates in Trypanosoma cruzi.",
"authors": "Andr?o, Rog?rio; Regasini, Lu?s Oct?vio; Petr?nio, Maicon Segalla; Chiari-Andr?o, Bruna Galdorfini; Tansini, Aline; Silva, Dulce Helena Siqueira; Cicarelli, Regina Maria Barretto",
"chapter": "",
"pages": "924670",
"journal": "International scholarly research notices",
"pub_date": "2015-01-01",
"pub_year": 2015,
"volume": "2015",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1155/2015/924670",
"doi": "10.1155/2015/924670",
"pmid": "27347554.0",
"pmcid": "PMC4897139",
"abstract": "American trypanosomiasis or Chagas disease is a debilitating disease representing an important social problem that affects, approximately, 10 million people in the world. The main aggravating factor of this situation is the lack of an effective drug to treat the different stages of this disease. In this context, the search for trypanocidal substances isolated from plants, synthetic or semi synthetic molecules, is an important strategy. Here, the trypanocidal potential of gallates was assayed in epimastigotes forms of T. cruzi and also, the interference of these substances on the mitochondrial membrane potential of the parasites was assessed, allowing the study of the mechanism of action of the gallates in the T. cruzi organisms. Regarding the preliminary structure-activity relationships, the side chain length of gallates plays crucial role for activity. Nonyl, decyl, undecyl, and dodecyl gallates showed potent antitrypanosomal effect (IC50 from 1.46 to 2.90 ?M) in contrast with benznidazole (IC50 = 34.0 ?M). Heptyl gallate showed a strong synergistic activity with benznidazole, reducing by 10(5)-fold the IC50 of benznidazole. Loss of mitochondrial membrane potential induced by these esters was revealed. Tetradecyl gallate induced a loss of 53% of the mitochondrial membrane potential, at IC50 value.",
"references": [
"RC03973",
"RC03972",
"RC03971"
]
},
{
"pap_id": "306",
"title": "High-content screening of drug-induced mitochondrial impairment in hepatic cells: effects of statins.",
"authors": "Tolosa, Laia; Carmona, Antonio; Castell, Jos? V; G?mez-Lech?n, M Jos?; Donato, M Teresa",
"chapter": "",
"pages": "1847-1860",
"journal": "Archives of Toxicology",
"pub_date": "2015-10-01",
"pub_year": 2015,
"volume": "89",
"issue": "10",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s00204-014-1334-3",
"doi": "10.1007/s00204-014-1334-3",
"pmid": "25160661.0",
"pmcid": "",
"abstract": "A frequent mechanism for drug-induced liver injury (DILI) is mitochondrial impairment, and early evaluation of new drugs for their potential to cause mitochondrial dysfunction is becoming an important task for drug development. To this end, we designed a high-content screening assay to study mitochondrial-induced hepatotoxicity in HepG2 cells in detail. Simultaneous assessment of mitochondrial mass and cell viability in cells exposed for 24?h to compounds provides preliminary information on the mitochondrial- or nonmitochondrial-related hepatotoxic potential of compounds. To fully address the mechanisms implicated in mitochondrial impairment, prelethal changes in mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial permeability transition, intracellular calcium concentration and apoptotic cell death were studied in cells incubated for 1?h with compounds. The assay correctly classified a set of well-known mitochondrial toxicants and negative controls and revealed high sensitivity for the detection of mitochondrial DILI and the establishment of different mitochondrial toxicity risks (low to high). This procedure was used for analysing the potential mitochondrial impairment of six statins to determine their clinical risk. All the tested statins produced mitochondrial impairment, although they showed different levels of toxicity (low-medium toxicity risk). The results suggest that this cell-based assay is a promising in vitro approach to predict the potential of drug candidates to induce mitochondrial-associated hepatotoxicity.",
"references": [
"RC04663",
"RC04664",
"RC04652",
"RC04653",
"RC04654",
"RC04655",
"RC04656",
"RC04657",
"RC04658",
"RC04659",
"RC04660",
"RC04661",
"RC04662",
"RC04641",
"RC04642",
"RC04643",
"RC04644",
"RC04645",
"RC04646",
"RC04647",
"RC04648",
"RC04649",
"RC04650",
"RC04651",
"RC04665",
"RC04666",
"RC04667",
"RC04668",
"RC04669",
"RC04670",
"RC04671",
"RC04672",
"RC04673",
"RC04674",
"RC04675",
"RC04676",
"RC04677",
"RC04678",
"RC04679",
"RC04680",
"RC04681",
"RC04682",
"RC04683",
"RC04684",
"RC04685",
"RC04686",
"RC04687",
"RC04688",
"RC04689",
"RC04690",
"RC04691",
"RC04692"
]
},
{
"pap_id": "307",
"title": "Impact of pharmacological agents on mitochondrial function: a growing opportunity?",
"authors": "Stoker, Megan L; Newport, Emma; Hulit, James C; West, A Phillip; Morten, Karl J",
"chapter": "",
"pages": "1757-1772",
"journal": "Biochemical Society Transactions",
"pub_date": "2019-12-20",
"pub_year": 2019,
"volume": "47",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/BST20190280",
"doi": "10.1042/BST20190280",
"pmid": "31696924.0",
"pmcid": "PMC6925523",
"abstract": "Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation. ? 2019 The Author(s).",
"references": [
"RC04735",
"RC04736",
"RC04693",
"RC04694",
"RC04695",
"RC04696",
"RC04697",
"RC04698",
"RC04699",
"RC04700",
"RC04701",
"RC04702",
"RC04703",
"RC04704",
"RC04705",
"RC04706",
"RC04707",
"RC04708",
"RC04709",
"RC04710",
"RC04711",
"RC04712",
"RC04713",
"RC04714",
"RC04715",
"RC04716",
"RC04717",
"RC04718",
"RC04719",
"RC04720",
"RC04721",
"RC04722",
"RC04723",
"RC04724",
"RC04725",
"RC04726",
"RC04727",
"RC04728",
"RC04729",
"RC04730",
"RC04731",
"RC04732",
"RC04733",
"RC04734",
"RC04737",
"RC04738",
"RC04739",
"RC04740",
"RC04741",
"RC04742",
"RC04743",
"RC04744",
"RC04745",
"RC04747",
"RC04748",
"RC04749",
"RC04750",
"RC04751",
"RC04752",
"RC04753",
"RC04754",
"RC04755",
"RC04756",
"RC04757",
"RC04758",
"RC04759",
"RC04760",
"RC04761",
"RC04762",
"RC04763",
"RC04764"
]
},
{
"pap_id": "308",
"title": "Mitochondrial dynamics: biogenesis, fission, fusion, and mitophagy in the regulation of stem cell behaviors.",
"authors": "Fu, Wenyan; Liu, Yang; Yin, Hang",
"chapter": "",
"pages": "9757201",
"journal": "Stem cells international",
"pub_date": "2019-04-07",
"pub_year": 2019,
"volume": "2019",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1155/2019/9757201",
"doi": "10.1155/2019/9757201",
"pmid": "31089338.0",
"pmcid": "PMC6476046",
"abstract": "Stem cells have the unique capacity to differentiate into many cell types during embryonic development and postnatal growth. Through coordinated cellular behaviors (self-renewal, proliferation, and differentiation), stem cells are also pivotal to the homeostasis, repair, and regeneration of many adult tissues/organs and thus of great importance in regenerative medicine. Emerging evidence indicates that mitochondria are actively involved in the regulation of stem cell behaviors. Mitochondria undergo specific dynamics (biogenesis, fission, fusion, and mitophagy) during stem cell self-renewal, proliferation, and differentiation. The alteration of mitochondrial dynamics, fine-tuned by stem cell niche factors and stress signaling, has considerable impacts on stem cell behaviors. Here, we summarize the recent research progress on (1) how mitochondrial dynamics controls stem cell behaviors, (2) intrinsic and extrinsic factors that regulate mitochondrial dynamics, and (3) pharmacological regulators of mitochondrial dynamics and their therapeutic potential. This review emphasizes the metabolic control of stemness and differentiation and may shed light on potential new applications in stem cell-based therapy.",
"references": [
"RC03974"
]
},
{
"pap_id": "309",
"title": "Bottom-line mechanism of organochlorine pesticides on mitochondria dysfunction linked with type 2 diabetes.",
"authors": "Ko, Eun; Choi, Moonsung; Shin, Sooim",
"chapter": "",
"pages": "122400",
"journal": "Journal of hazardous materials",
"pub_date": "2020-07-05",
"pub_year": 2020,
"volume": "393",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.jhazmat.2020.122400",
"doi": "10.1016/j.jhazmat.2020.122400",
"pmid": "32135367.0",
"pmcid": "",
"abstract": "Environmental pollution by anthropogenic chemicals has become a considerable problem. Organochlorine pesticides (OCPs), a subclass of persistent organic pollutants, are used as insecticides and industrial chemicals. They are lipophilic and minimally degradable, and they easily accumulate in the environment and human body. Epidemiological studies have demonstrated that exposure to OCPs strongly correlates with the development of type 2 diabetes, which involves mitochondrial dysfunction. To clarify their effects, OCP mixtures (?-hexachlorocyclohexane, heptachlor, hexachlorobenzene, 4,4'-DDT, and chlordane) were used to treat mitochondria from zebrafish livers. Results showed that as OCP concentrations increased, Ca2+ intake into the mitochondria rose, which increased the activity of mitochondrial complexes I, II, IV, and citrate synthase. Complex III yielded the opposite result because the OCP mixture mimicked decylubiquinol, a natural substrate of complex III. Our results reflect the actual state of toxins, non-monotonic, in the environment, which is important for determining the consequences of OCPs on mitochondrial dysfunction. Copyright ? 2020 Elsevier B.V. All rights reserved.",
"references": [
"RC03977",
"RC03976"
]
},
{
"pap_id": "31",
"title": "The effects of salicylic acid on the respiratory activity of mitochondria",
"authors": "Penniall, Ralph",
"chapter": "",
"pages": "247-251",
"journal": "Biochimica et biophysica acta",
"pub_date": "1958-11-01",
"pub_year": 1958,
"volume": "30",
"issue": "2",
"Issn": "63002",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0006300258900477",
"doi": "10.1016/0006-3002(58)90047-7",
"pmid": "",
"pmcid": "",
"abstract": "Salicylic acid was found capable of uncoupling phosphorylation from the oxidation of β-hydroxybutyrate, glutamate and Fe++-cytochrome c at concentrations in the range of 10−4M. In an acceptor-free system it stimulated oxygen uptake and acetoacetate formation from β-hydroxybutyrate. It is also inhibitory to the phosphorylations accompanying K3Fe(CN)6 reduction with both β-hydroxybutyrate and glutamate; oxidation of the latter substrate appears to be the more susceptible process. Salicylic acid influenced the following processes in a manner consistent with other known uncoupling agents: latent ATPase activity; 32Pi:ATP exchange; and mitochondrial swelling in hypotonic media. The data indicate that the compound is capable of an uncoupling activity qualitatively similar to that of DNP.",
"references": [
"RC00917"
]
},
{
"pap_id": "310",
"title": "A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity.",
"authors": "Qi, Xin; Qvit, Nir; Su, Yu-Chin; Mochly-Rosen, Daria",
"chapter": "",
"pages": "789-802",
"journal": "Journal of Cell Science",
"pub_date": "2013-02-01",
"pub_year": 2013,
"volume": "126",
"issue": "Pt 3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1242/jcs.114439",
"doi": "10.1242/jcs.114439",
"pmid": "23239023.0",
"pmcid": "PMC3619809",
"abstract": "Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and reactive oxygen species (ROS) production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. Taken together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for the treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur.",
"references": [
"RC03980",
"RC03979",
"RC03978"
]
},
{
"pap_id": "311",
"title": "Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson's disease model induced by MPTP.",
"authors": "Filichia, Emily; Hoffer, Barry; Qi, Xin; Luo, Yu",
"chapter": "",
"pages": "32656",
"journal": "Scientific Reports",
"pub_date": "2016-09-13",
"pub_year": 2016,
"volume": "6",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/srep32656",
"doi": "10.1038/srep32656",
"pmid": "27619562.0",
"pmcid": "PMC5020318",
"abstract": "Accumulating evidence suggest mitochondria-mediated pathways play an important role in dopaminergic neuronal cell death in Parkinson's disease (PD). Drp1, a key regulator of mitochondrial fission, has been shown to be activated and translocated to mitochondria under stress, leading to excessive mitochondria fission and dopaminergic neuronal death in vitro. However, whether Drp1 inhibition can lead to long term stable preservation of dopaminergic neurons in PD-related mouse models remains unknown. In this study, using a classical MPTP animal PD model, we showed for the first time Drp1 activation and mitochondrial translocation in vivo after MPTP administration. Inhibition of Drp1 activation by a selective peptide inhibitor P110, blocked MPTP-induced Drp1 mitochondrial translocation and attenuated dopaminergic neuronal loss, dopaminergic nerve terminal damage and behavioral deficits caused by MPTP. MPTP-induced microglial activation and astrogliosis were not affected by P110 treatment. Instead, inhibition of Drp1 mitochondrial translocation diminished MPTP-induced p53, BAX and PUMA mitochondrial translocation. This study demonstrates that inhibition of Drp1 hyperactivation by a Drp1 peptide inhibitor P110 is neuroprotective in a MPTP animal model. Our data also suggest that the protective effects of P110 treatment might be mediated by inhibiting the p53 mediated apoptotic pathways in neurons through inhibition of Drp1-dependent p53 mitochondrial translocation.",
"references": []
},
{
"pap_id": "312",
"title": "Gentamicin rapidly inhibits mitochondrial metabolism in high-frequency cochlear outer hair cells.",
"authors": "Jensen-Smith, Heather C; Hallworth, Richard; Nichols, Michael G",
"chapter": "",
"pages": "e38471",
"journal": "Plos One",
"pub_date": "2012-06-08",
"pub_year": 2012,
"volume": "7",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1371/journal.pone.0038471",
"doi": "10.1371/journal.pone.0038471",
"pmid": "22715386.0",
"pmcid": "PMC3371036",
"abstract": "Aminoglycosides (AG), including gentamicin (GM), are the most frequently used antibiotics in the world and are proposed to cause irreversible cochlear damage and hearing loss (HL) in 1/4 of the patients receiving these life-saving drugs. Akin to the results of AG ototoxicity studies, high-frequency, basal turn outer hair cells (OHCs) preferentially succumb to multiple HL pathologies while inner hair cells (IHCs) are much more resilient. To determine if endogenous differences in IHC and OHC mitochondrial metabolism dictate differential sensitivities to AG-induced HL, IHC- and OHC-specific changes in mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence during acute (1 h) GM treatment were compared. GM-mediated decreases in NADH fluorescence and succinate dehydrogenase activity were observed shortly after GM application. High-frequency basal turn OHCs were found to be metabolically biased to rapidly respond to alterations in their microenvironment including GM and elevated glucose exposures. These metabolic biases may predispose high-frequency OHCs to preferentially produce cell-damaging reactive oxygen species during traumatic challenge. Noise-induced and age-related HL pathologies share key characteristics with AG ototoxicity, including preferential OHC loss and reactive oxygen species production. Data from this report highlight the need to address the role of mitochondrial metabolism in regulating AG ototoxicity and the need to illuminate how fundamental differences in IHC and OHC metabolism may dictate differences in HC fate during multiple HL pathologies.",
"references": [
"RC03990",
"RC03989",
"RC03988",
"RC03987",
"RC03986",
"RC03985",
"RC03984",
"RC03983"
]
},
{
"pap_id": "313",
"title": "A high-throughput real-time in vitro assay using mitochondrial targeted roGFP for screening of drugs targeting mitochondria.",
"authors": "Chandrasekharan, Aneesh; Varadarajan, Shankara Narayanan; Lekshmi, Asha; Lupitha, Santhik Subhasingh; Darvin, Pramod; Chandrasekhar, Leena; Pillai, Prakash Rajappan; Santhoshkumar, T R; Pillai, M Radhakrishna",
"chapter": "",
"pages": "379-389",
"journal": "Redox biology",
"pub_date": "1905-07-11",
"pub_year": 1905,
"volume": "20",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.redox.2018.10.013",
"doi": "10.1016/j.redox.2018.10.013",
"pmid": "30408753.0",
"pmcid": "PMC6222140",
"abstract": "Most toxic compounds including cancer drugs target mitochondria culminating in its permeabilization. Cancer drug-screening and toxicological testing of compounds require cost-effective and sensitive high-throughput methods to detect mitochondrial damage. Real-time methods for detection of mitochondrial damage are less toxic, allow kinetic measurements with good spatial resolution and are preferred over end-stage assays. Cancer cell lines stably expressing genetically encoded mitochondrial-targeted redox-GFP2 (mt-roGFP) were developed and validated for its suitability as a mitochondrial damage sensor. Diverse imaging platforms and flow-cytometry were utilized for ratiometric analysis of redox changes with known toxic and cancer drugs. Key events of cell death and mitochondrial damage were studied at single-cell level coupled with mt-roGFP. Cells stably expressing mt-roGFP and H2B-mCherry were developed for high-throughput screening (HTS) application. Most cancer drugs while inducing mitochondrial permeabilization trigger mitochondrial-oxidation that can be detected at single-cell level with mt-roGFP. The image-based assay using mt-roGFP outperformed other quantitative methods of apoptosis in ease of screening. Incorporation of H2B-mCherry ensures accurate and complete automated segmentation with excellent Z value. The results substantiate that most cancer drugs and known plant-derived antioxidants trigger cell-death through mitochondrial redox alterations with pronounced ratio change in the mt-roGFP probe. Real-time analysis of mitochondrial oxidation and mitochondrial permeabilization reveal a biphasic ratio change in dying cells, with an initial redox surge before mitochondrial permeabilization followed by a drastic increase in ratio after complete mitochondrial permeabilization. Overall, the results prove that mitochondrial oxidation is a reliable indicator of mitochondrial damage, which can be readily determined in live cells using mt-roGFP employing diverse imaging techniques. The assay described is highly sensitive, easy to adapt to HTS platforms and is a valuable resource for identifying cytotoxic agents that target mitochondria and also for dissecting cell signaling events relevant to redox biology. Copyright ? 2018 The Authors. Published by Elsevier B.V. All rights reserved.",
"references": [
"RC03997",
"RC03996",
"RC03995",
"RC03994",
"RC03993",
"RC03992",
"RC03991"
]
},
{
"pap_id": "314",
"title": "Small-molecule inhibitors of human mitochondrial DNA transcription.",
"authors": "Bonekamp, Nina A; Peter, Bradley; Hillen, Hauke S; Felser, Andrea; Bergbrede, Tim; Choidas, Axel; Horn, Moritz; Unger, Anke; Di Lucrezia, Raffaella; Atanassov, Ilian; Li, Xinping; Koch, Uwe; Menninger, Sascha; Boros, Joanna; Habenberger, Peter; Giavalisco, Patrick; Cramer, Patrick; Denzel, Martin S; Nussbaumer, Peter; Klebl, Bert; Falkenberg, Maria; Gustafsson, Claes M; Larsson, Nils-G?ran",
"chapter": "",
"pages": "",
"journal": "Nature",
"pub_date": "2020-12-16",
"pub_year": 2020,
"volume": "",
"issue": "",
"Issn": "0028-0836",
"Isbn": "",
"url": "http://www.nature.com/articles/s41586-020-03048-z",
"doi": "10.1038/s41586-020-03048-z",
"pmid": "33328633.0",
"pmcid": "",
"abstract": "Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1-6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.",
"references": [
"RC04000",
"RC03999",
"RC03998"
]
},
{
"pap_id": "315",
"title": "Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death.",
"authors": "Esterberg, Robert; Linbo, Tor; Pickett, Sarah B; Wu, Patricia; Ou, Henry C; Rubel, Edwin W; Raible, David W",
"chapter": "",
"pages": "3556-3566",
"journal": "The Journal of Clinical Investigation",
"pub_date": "2016-09-01",
"pub_year": 2016,
"volume": "126",
"issue": "9",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1172/JCI84939",
"doi": "10.1172/JCI84939",
"pmid": "27500493.0",
"pmcid": "PMC5004972",
"abstract": "Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure.",
"references": [
"RC03982",
"RC03981"
]
},
{
"pap_id": "316",
"title": "Gentamicin affects the bioenergetics of isolated mitochondria and collapses the mitochondrial membrane potential in cochlear sensory hair cells.",
"authors": "O'Reilly, Molly; Young, Luke; Kirkwood, Nerissa K; Richardson, Guy P; Kros, Corn? J; Moore, Anthony L",
"chapter": "",
"pages": "416",
"journal": "Frontiers in Cellular Neuroscience",
"pub_date": "2019-09-13",
"pub_year": 2019,
"volume": "13",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.3389/fncel.2019.00416",
"doi": "10.3389/fncel.2019.00416",
"pmid": "31572129.0",
"pmcid": "PMC6753894",
"abstract": "Aminoglycoside antibiotics are widely prescribed to treat a variety of serious bacterial infections. They are extremely useful clinical tools, but have adverse side effects such as oto- and nephrotoxicity. Once inside a cell they are thought to cause mitochondrial dysfunction, subsequently leading to apoptotic cell death due to an increase in reactive oxygen species (ROS) production. Here we present evidence of a direct effect of gentamicin (the most commonly prescribed aminoglycoside) on the respiratory activities of isolated rat liver and kidney mitochondria. We show that gentamicin stimulates state 4 and inhibits state 3u respiratory rates, thereby reducing the respiratory control ratio (RCR) whilst simultaneously causing a collapse of the mitochondrial membrane potential (MtMP). We propose that gentamicin behaves as an uncoupler of the electron transport chain (ETC) - a hypothesis supported by our evidence that it reduces the production of mitochondrial ROS (MtROS). We also show that gentamicin collapses the MtMP in the sensory hair cells (HCs) of organotypic mouse cochlear cultures. Copyright ? 2019 O\u0019 Reilly, Young, Kirkwood, Richardson, Kros and Moore.",
"references": [
"RC04010",
"RC04009",
"RC04008",
"RC04007",
"RC04006",
"RC04005",
"RC04004",
"RC04003",
"RC04002",
"RC04001"
]
},
{
"pap_id": "317",
"title": "In vitro toxicity of alternative oxidase inhibitors salicylhydroxamic acid and propyl gallate on Fusicladium effusum",
"authors": "Seyran, Murat; Brenneman, Timothy B.; Stevenson, Katherine L.",
"chapter": "",
"pages": "421-427",
"journal": "Journal of pest science",
"pub_date": "2010-12-01",
"pub_year": 2010,
"volume": "83",
"issue": "4",
"Issn": "1612-4758",
"Isbn": "",
"url": "http://link.springer.com/10.1007/s10340-010-0312-7",
"doi": "10.1007/s10340-010-0312-7",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03836"
]
},
{
"pap_id": "318",
"title": "Control of the citric acid cycle by glyoxylate. Mechanism of the inhibition by oxalomalate and gamma-hydroxy-alpha-oxoglutarate.",
"authors": "Ruffo, A; Testa, E; Adinolfi, A; Pelizza, G; Moratti, R",
"chapter": "",
"pages": "19-23",
"journal": "The Biochemical Journal",
"pub_date": "1967-04-01",
"pub_year": 1967,
"volume": "103",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/bj1030019",
"doi": "10.1042/bj1030019",
"pmid": "6033757.0",
"pmcid": "PMC1270362",
"abstract": "1. Hydroxyoxoglutarate was obtained by three methods: decarboxylation of oxalomalic acid, and synthesis from glyoxylate and pyruvate by using either Mg(2+) or an enzyme from rat liver as catalysts. 2. The inhibitory effects of oxalomalate and hydroxyoxoglutarate upon aconitate hydratase, isocitrate dehydrogenase (NADP) and oxoglutarate dehydrogenase were investigated. 3. Oxalomalate at low concentrations (1mm) inhibited almost completely both aconitate hydratase and isocitrate dehydrogenase. Hydroxyoxoglutarate also inhibited these enzymes, but at concentrations approximately tenfold that of oxalomalate. 4. Oxalomalate and hydroxyoxoglutarate, at the higher concentrations, inhibited oxoglutarate dehydrogenase to approximately the same extent. 5. It is suggested that the ability of glyoxylate to control reaction rates in the tricarboxylic acid cycle must in some degree be due to its condensation with oxaloacetate and pyruvate to form enzyme inhibitors.",
"references": [
"RC03835",
"RC03834"
]
},
{
"pap_id": "319",
"title": "1-Chloro-2,4-dinitrobenzene is an irreversible inhibitor of human thioredoxin reductase. Loss of thioredoxin disulfide reductase activity is accompanied by a large increase in NADPH oxidase activity.",
"authors": "Arn?r, E S; Bj?rnstedt, M; Holmgren, A",
"chapter": "",
"pages": "3479-3482",
"journal": "The Journal of Biological Chemistry",
"pub_date": "1995-02-24",
"pub_year": 1995,
"volume": "270",
"issue": "8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.270.8.3479",
"doi": "10.1074/jbc.270.8.3479",
"pmid": "7876079.0",
"pmcid": "",
"abstract": "Human thioredoxin reductase is a dimeric enzyme that catalyzes reduction of the disulfide in oxidized thioredoxin by a mechanism involving transfer of electrons from NADPH via FAD to a redox-active disulfide. 1-Chloro-2,4-dinitrobenzene (DNCB) is an alkylating agent used for depleting intracellular GSH and also showing distinct immunomodulatory properties. We have discovered that low concentrations of DNCB completely inactivated human or bovine thioredoxin reductase, with a second order rate constant in excess of 200 M-1 s-1, which is almost 10,000-fold faster than alkylation of GSH. Total inactivation of 50 nM reduced thioredoxin reductase was obtained by 100 microM DNCB after 5 reductase was obtained by 100 microM DNCB after 5 min of incubation at 20 degrees C also in the presence of 1 mM GSH. The inhibition occurred with enzyme only in the presence of NADPH and persisted after removal of DNCB, suggesting alkylation of the active site nascent thiols as the mechanism of inactivation. Thioredoxin reductase modified by DNCB lacked reducing activity with oxidized thioredoxin, 5,5'-dithiobis-(2-nitrobenzoic acid), or sodium selenite. However, the DNCB-modified enzyme oxidized NADPH at a rate of 4.7 nmol/min/nmol of enzyme in the presence of atmospheric oxygen. This activity was not dependent on the presence of DNCB in solution and constituted a 34-fold increase of the inherent low NADPH oxidase activity of the native enzyme. DNCB is a specific inhibitor of mammalian thioredoxin reductase, which reacted 100-fold faster than glutathione reductase. The inactivation of the disulfide reducing activity of thioredoxin reductase and thioredoxin with a concomitant large increase of the NADPH oxidase activity producing reactive oxygen intermediates may mediate effects of DNCB on cells in vivo.",
"references": [
"RC03837"
]
},
{
"pap_id": "32",
"title": "Effect of salicylic acid on mitochondrial-peroxisomal fatty acid catabolism.",
"authors": "Yoshida, Y; Fujii, M; Brown, F R; Singh, I",
"chapter": "",
"pages": "338-341",
"journal": "Pediatric Research",
"pub_date": "1988-03-01",
"pub_year": 1988,
"volume": "23",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1203/00006450-198803000-00021",
"doi": "10.1203/00006450-198803000-00021",
"pmid": "3353181.0",
"pmcid": "",
"abstract": "To understand the possible role of salicylic acid in the pathogenesis of Reye's syndrome, we examined its effect on the oxidative metabolism of fatty acids in the rat liver mitochondrial-peroxisomal fraction. Fatty acids of different chain lengths are oxidized in different organelles. Octanoic acid is oxidized in mitochondria, lignoceric acid in peroxisomes, and palmitic acid in both mitochondria and peroxisomes. Salicylic acid (up to 1 mM concentration) had no effect on the oxidation of [1-14C]lignoceric acid. However, at the same concentration it inhibited the oxidation of [1-14C]palmitic acid by 26% and [1-14C] octanoic acid by 42%. The apparent Ki for the oxidation of [1-14C] octanoic acid, [1-14C]palmitic acid and [1-14C]lignoceric acid were 0.27, 6.0, and 14.8 mM, respectively. This selective inhibition of mitochondrial oxidation of medium-chain (octanoic acid) and long-chain (palmitic acid) fatty acids by salicylic acid may potentiate the accumulation of fatty acids in plasma in Reye's syndrome patients.",
"references": [
"RC00918"
]
},
{
"pap_id": "320",
"title": "Selective disruption of mitochondrial thiol redox state in cells and in?vivo.",
"authors": "Booty, Lee M; Gawel, Justyna M; Cvetko, Filip; Caldwell, Stuart T; Hall, Andrew R; Mulvey, John F; James, Andrew M; Hinchy, Elizabeth C; Prime, Tracy A; Arndt, Sabine; Beninca, Cristiane; Bright, Thomas P; Clatworthy, Menna R; Ferdinand, John R; Prag, Hiran A; Logan, Angela; Prudent, Julien; Krieg, Thomas; Hartley, Richard C; Murphy, Michael P",
"chapter": "",
"pages": "449-461.e8",
"journal": "Cell Chemical Biology",
"pub_date": "2019-03-21",
"pub_year": 2019,
"volume": "26",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.chembiol.2018.12.002",
"doi": "10.1016/j.chembiol.2018.12.002",
"pmid": "30713096.0",
"pmcid": "PMC6436940",
"abstract": "Mitochondrial glutathione (GSH) and thioredoxin (Trx) systems function independently of the rest of the cell. While maintenance of mitochondrial thiol redox state is thought vital for cell survival, this was not testable due to the difficulty of manipulating the organelle's thiol systems independently of those in other cell compartments. To overcome this constraint we modified the glutathione S-transferase substrate and Trx reductase (TrxR) inhibitor, 1-chloro-2,4-dinitrobenzene (CDNB) by conjugation to the mitochondria-targeting triphenylphosphonium cation. The result, MitoCDNB, is taken up by mitochondria where it selectively depletes the mitochondrial GSH pool, catalyzed by glutathione S-transferases, and directly inhibits mitochondrial TrxR2 and peroxiredoxin 3, a peroxidase. Importantly, MitoCDNB inactivates mitochondrial thiol redox homeostasis in isolated cells and in?vivo, without affecting that of the cytosol. Consequently, MitoCDNB enables assessment of the biomedical importance of mitochondrial thiol homeostasis in reactive oxygen species production, organelle dynamics, redox signaling, and cell death in cells and in?vivo. Copyright ? 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.",
"references": [
"RC03838"
]
},
{
"pap_id": "321",
"title": "Does an inhibitor of mitochondrial adenylate kinase also affect oxidative phosphorylation?",
"authors": "L?storff, J; Schlimme, E",
"chapter": "",
"pages": "298-299",
"journal": "Experientia",
"pub_date": "1976-03-15",
"pub_year": 1976,
"volume": "32",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/BF01940801",
"doi": "10.1007/BF01940801",
"pmid": "176055.0",
"pmcid": "",
"abstract": "Adenylate kinase activity of intact mitochondria is strongly inhibited by Ap5A, i.e. p1,p5-Di (adenosine-5') pentaphosphate, whereas oxidative phosphorylation is not affected. Therefore, Ap5A is a useful tool to distinguish between oxidative and non oxidative ATP generating reactions.",
"references": [
"RC03839"
]
},
{
"pap_id": "322",
"title": "Therapeutic potential of coenzyme Q10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury.",
"authors": "Luo, Kang; Yu, Ji Hyun; Quan, Yi; Shin, Yoo Jin; Lee, Kyung Eun; Kim, Hong Lim; Ko, Eun Jeong; Chung, Byung Ha; Lim, Sun Woo; Yang, Chul Woo",
"chapter": "",
"pages": "7995",
"journal": "Scientific Reports",
"pub_date": "2019-05-29",
"pub_year": 2019,
"volume": "9",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/s41598-019-44475-x",
"doi": "10.1038/s41598-019-44475-x",
"pmid": "31142763.0",
"pmcid": "PMC6541596",
"abstract": "We previously reported that oxidative stress induced by long-term tacrolimus treatment impairs mitochondrial function in pancreatic beta cells. In this study, we aimed to investigate the therapeutic potential of coenzyme Q10, which is known to be a powerful antioxidant, in mitochondrial dysfunction in tacrolimus-induced diabetic rats. In a rat model of tacrolimus-induced diabetes mellitus, coenzyme Q10 treatment improved pancreatic beta cell function. The administration of coenzyme Q10 improved insulin immunoreactivity within islets, which was accompanied by reductions in oxidative stress and apoptosis. Assessment of the mitochondrial ultrastructure by electron microscopy revealed that coenzyme Q10 treatment increased the size, number, and volume of mitochondria, as well as the number of insulin granules compared with that induced by tacrolimus treatment alone. An in vitro study using a pancreatic beta cell line showed that tacrolimus treatment increased apoptosis and the production of mitochondrial reactive oxygen species, while cotreatment with coenzyme Q10 effectively attenuated these alterations. At the subcellular level, tacrolimus-induced impairment of mitochondrial respiration was significantly improved by coenzyme Q10, as evidenced by the increased mitochondrial oxygen consumption and ATP production. Our data indicate that coenzyme Q10 plays an important role in reducing tacrolimus-induced oxidative stress and protects the mitochondria in pancreatic beta cells. These findings suggest that supplementation with coenzyme Q10 has beneficial effects in tacrolimus-induced diabetes mellitus.",
"references": [
"RC03845",
"RC03844",
"RC03843",
"RC03842",
"RC03841",
"RC03840"
]
},
{
"pap_id": "323",
"title": "Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.",
"authors": "Simon, Nicolas; Morin, Christophe; Urien, Sa?k; Tillement, Jean-Paul; Bruguerolle, Bernard",
"chapter": "",
"pages": "369-376",
"journal": "British Journal of Pharmacology",
"pub_date": "2003-06-01",
"pub_year": 2003,
"volume": "138",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/sj.bjp.0705038",
"doi": "10.1038/sj.bjp.0705038",
"pmid": "12540528.0",
"pmcid": "PMC1573667",
"abstract": "1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.",
"references": [
"RC03859",
"RC03858",
"RC03857",
"RC03856",
"RC03855",
"RC03854",
"RC03853",
"RC03852",
"RC03851",
"RC03850",
"RC03849",
"RC03848",
"RC03847",
"RC03846"
]
},
{
"pap_id": "324",
"title": "Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.",
"authors": "Warne, Justin; Pryce, Gareth; Hill, Julia M; Shi, Xiao; Lenner?s, Felicia; Puentes, Fabiola; Kip, Maarten; Hilditch, Laura; Walker, Paul; Simone, Michela I; Chan, A W Edith; Towers, Greg J; Coker, Alun R; Duchen, Michael R; Szabadkai, Gyorgy; Baker, David; Selwood, David L",
"chapter": "",
"pages": "4356-4373",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2016-02-26",
"pub_year": 2016,
"volume": "291",
"issue": "9",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.M115.700385",
"doi": "10.1074/jbc.M115.700385",
"pmid": "26679998.0",
"pmcid": "PMC4813465",
"abstract": "The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use. ? 2016 by The American Society for Biochemistry and Molecular Biology, Inc.",
"references": [
"RC03870",
"RC03869",
"RC03868",
"RC03867",
"RC03866",
"RC03865",
"RC03864",
"RC03863",
"RC03862",
"RC03861",
"RC03860"
]
},
{
"pap_id": "325",
"title": "Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity.",
"authors": "Dott, William; Mistry, Pratibha; Wright, Jayne; Cain, Kelvin; Herbert, Karl E",
"chapter": "",
"pages": "224-233",
"journal": "Redox biology",
"pub_date": "2014-01-10",
"pub_year": 2014,
"volume": "2",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.redox.2013.12.028",
"doi": "10.1016/j.redox.2013.12.028",
"pmid": "24494197.0",
"pmcid": "PMC3909783",
"abstract": "Mitochondrial toxicity is increasingly being implicated as a contributing factor to many xenobiotic-induced organ toxicities, including skeletal muscle toxicity. This has necessitated the need for predictive in vitro models that are able to sensitively detect mitochondrial toxicity of chemical entities early in the research and development process. One such cell model involves substituting galactose for glucose in the culture media. Since cells cultured in galactose are unable to generate sufficient ATP from glycolysis they are forced to rely on mitochondrial oxidative phosphorylation for ATP generation and consequently are more sensitive to mitochondrial perturbation than cells grown in glucose. The aim of this study was to characterise cellular growth, bioenergetics and mitochondrial toxicity of the L6 rat skeletal muscle cell line cultured in either high glucose or galactose media. L6 myoblasts proliferated more slowly when cultured in galactose media, although they maintained similar levels of ATP. Galactose cultured L6 cells were significantly more sensitive to classical mitochondrial toxicants than glucose-cultured cells, confirming the cells had adapted to galactose media. Analysis of bioenergetic function with the XF Seahorse extracellular flux analyser demonstrated that oxygen consumption rate (OCR) was significantly increased whereas extracellular acidification rate (ECAR), a measure of glycolysis, was decreased in cells grown in galactose. Mitochondria operated closer to state 3 respiration and had a lower mitochondrial membrane potential and basal mitochondrial O2 ( -) level compared to cells in the glucose model. An antimycin A (AA) dose response revealed that there was no difference in the sensitivity of OCR to AA inhibition between glucose and galactose cells. Importantly",
"references": [
"RC04903",
"RC04902",
"RC04901"
]
},
{
"pap_id": "326",
"title": "Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants.",
"authors": "Delp, Johannes; Funke, Melina; Rudolf, Franziska; Cediel, Andrea; Bennekou, Susanne Hougaard; van der Stel, Wanda; Carta, Giada; Jennings, Paul; Toma, Cosimo; Gardner, Iain; van de Water, Bob; Forsby, Anna; Leist, Marcel",
"chapter": "",
"pages": "1585-1608",
"journal": "Archives of Toxicology",
"pub_date": "2019-06-12",
"pub_year": 2019,
"volume": "93",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s00204-019-02473-y",
"doi": "10.1007/s00204-019-02473-y",
"pmid": "31190196.0",
"pmcid": "",
"abstract": "Many neurotoxicants affect energy metabolism in man, but currently available test methods may still fail to predict mito- and neurotoxicity. We addressed this issue using LUHMES cells, i.e., human neuronal precursors that easily differentiate into mature neurons. Within the NeuriTox assay, they have been used to screen for neurotoxicants. Our new approach is based on culturing the cells in either glucose or galactose (Glc-Gal-NeuriTox) as the main carbohydrate source during toxicity testing. Using this Glc-Gal-NeuriTox assay, 52 mitochondrial and non-mitochondrial toxicants were tested. The panel of chemicals comprised 11 inhibitors of mitochondrial respiratory chain complex I (cI), 4 inhibitors of cII, 8 of cIII, and 2 of cIV; 8 toxicants were included as they are assumed to be mitochondrial uncouplers. In galactose, cells became more dependent on mitochondrial function, which made them 2-3 orders of magnitude more sensitive to various mitotoxicants. Moreover, galactose enhanced the specific neurotoxicity (destruction of neurites) compared to a general cytotoxicity (plasma membrane lysis) of the toxicants. The Glc-Gal-NeuriTox assay worked particularly well for inhibitors of cI and cIII, while the toxicity of uncouplers and non-mitochondrial toxicants did not differ significantly upon glucose ? galactose exchange. As a secondary assay, we developed a method to quantify the inhibition of all mitochondrial respiratory chain functions/complexes in LUHMES cells. The combination of the Glc-Gal-NeuriTox neurotoxicity screening assay with the mechanistic follow up of target site identification allowed both, a more sensitive detection of neurotoxicants and a sharper definition of the mode of action of mitochondrial toxicants.",
"references": [
"RC04904",
"RC04905",
"RC04906",
"RC04907",
"RC04908",
"RC04909",
"RC04910",
"RC04911",
"RC04912",
"RC04913",
"RC04914",
"RC04915",
"RC04916",
"RC04917",
"RC04918",
"RC04919",
"RC04920",
"RC04921",
"RC04922",
"RC04923",
"RC04924",
"RC04926",
"RC04927",
"RC04928",
"RC04929",
"RC04930",
"RC04932",
"RC04933",
"RC04934",
"RC04937",
"RC04938",
"RC04939",
"RC04940",
"RC04941",
"RC04942",
"RC04943",
"RC04944",
"RC04945",
"RC04946",
"RC04947",
"RC04948",
"RC04949",
"RC04950",
"RC04951",
"RC04952",
"RC04953",
"RC04954",
"RC04955",
"RC04956",
"RC04957",
"RC04958",
"RC04959",
"RC04961",
"RC04962",
"RC04963"
]
},
{
"pap_id": "327",
"title": "Mitochondrially targeted effects of berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions.",
"authors": "Pereira, Gon?alo C; Branco, Ana F; Matos, J?lio A C; Pereira, Sandro L; Parke, Donna; Perkins, Edward L; Serafim, Teresa L; Sard?o, Vilma A; Santos, Maria S; Moreno, Antonio J M; Holy, Jon; Oliveira, Paulo J",
"chapter": "",
"pages": "636-649",
"journal": "The Journal of Pharmacology and Experimental Therapeutics",
"pub_date": "2007-11-01",
"pub_year": 2007,
"volume": "323",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1124/jpet.107.128017",
"doi": "10.1124/jpet.107.128017",
"pmid": "17704354.0",
"pmcid": "",
"abstract": "Berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a)quinolizinium] is an alkaloid present in plant extracts and has a history of use in traditional Chinese and Native American medicine. Because of its ability to arrest the cell cycle and cause apoptosis of several malignant cell lines, it has received attention as a potential anticancer therapeutic agent. Previous studies suggest that mitochondria may be an important target of berberine, but relatively little is known about the extent or molecular mechanisms of berberine-mitochondrial interactions. The objective of the present work was to investigate the interaction of berberine with mitochondria, both in situ and in isolated mitochondrial fractions. The data show that berberine is selectively accumulated by mitochondria, which is accompanied by arrest of cell proliferation, mitochondrial fragmentation and depolarization, oxidative stress, and a decrease in ATP levels. Electron microscopy of berberine-treated cells shows a reduction in mitochondria-like structures, accompanied by a decrease in mitochondrial DNA copy number. Isolated mitochondrial fractions treated with berberine had slower mitochondrial respiration, especially when complex I substrates were used, and increased complex I-dependent oxidative stress. It is also demonstrated for the first time that berberine stimulates the mitochondrial permeability transition. Direct effects on ATPase activity were not detected. The present work demonstrates a number of previously unknown alterations of mitochondrial physiology induced by berberine, a potential chemotherapeutic agent, although it also suggests that high doses of berberine should not be used without a proper toxicology assessment.",
"references": [
"RC04019",
"RC04018",
"RC04017",
"RC04016",
"RC04015",
"RC04014",
"RC04013"
]
},
{
"pap_id": "328",
"title": "Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action.",
"authors": "Turner, Nigel; Li, Jing-Ya; Gosby, Alison; To, Sabrina W C; Cheng, Zhe; Miyoshi, Hiroyuki; Taketo, Makoto M; Cooney, Gregory J; Kraegen, Edward W; James, David E; Hu, Li-Hong; Li, Jia; Ye, Ji-Ming",
"chapter": "",
"pages": "1414-1418",
"journal": "Diabetes",
"pub_date": "2008-05-01",
"pub_year": 2008,
"volume": "57",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.2337/db07-1552",
"doi": "10.2337/db07-1552",
"pmid": "18285556.0",
"pmcid": "",
"abstract": "OBJECTIVE: Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy. RESEARCH DESIGN AND METHODS: AMPK phosphorylation was examined in L6 myotubes and LKB1(-/-) cells, with or without the Ca(2+)/calmodulin-dependent protein kinase kinase (CAMKK) inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative, dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet. RESULTS; We have made the following novel observations: 1) BBR dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, similar to that observed with metformin and rosiglitazone; 2) activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKbeta, consistent with major regulation at the level of the AMPK phosphatase; and 3) a novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation, and insulin resistance in high-fat-fed rodents. This effect is likely due to enhanced oral bioavailability. CONCLUSIONS: Complex I of the respiratory chain represents a major target for compounds that improve whole-body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.",
"references": [
"RC04012",
"RC04011"
]
},
{
"pap_id": "329",
"title": "mTOR inhibitors in cancer therapy.",
"authors": "Xie, Jianling; Wang, Xuemin; Proud, Christopher G",
"chapter": "",
"pages": "",
"journal": "F1000Research",
"pub_date": "2016-08-25",
"pub_year": 2016,
"volume": "5",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.12688/f1000research.9207.1",
"doi": "10.12688/f1000research.9207.1",
"pmid": "27635236.0",
"pmcid": "PMC5007757",
"abstract": "The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways and is accordingly hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy. However, progress in using inhibitors of mTOR signaling as therapeutic agents in oncology has been limited by a number of factors, including the fact that the classic mTOR inhibitor, rapamycin, inhibits only some of the effects of mTOR; the existence of several feedback loops; and the crucial importance of mTOR in normal physiology.",
"references": []
},
{
"pap_id": "33",
"title": "Thenoyltrifluoroacetone, a potent inhibitor of carboxylesterase activity.",
"authors": "Zhang, Jin Gang; Fariss, Marc W",
"chapter": "",
"pages": "751-754",
"journal": "Biochemical Pharmacology",
"pub_date": "2002-02-15",
"pub_year": 2002,
"volume": "63",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/s0006-2952(01)00871-1",
"doi": "10.1016/s0006-2952(01)00871-1",
"pmid": "11992644.0",
"pmcid": "",
"abstract": "Thenoyltrifluoroacetone (TTFA), a conventional mitochondrial complex II inhibitor, was found to inhibit purified porcine liver carboxylesterase non-competitively with a K(i) of 0.61x10(-6)M and an IC(50) of 0.54x10(-6)M. Both rat plasma and liver mitochondrial esterases were inhibited in a concentration-dependent fashion. Results indicate that TTFA is a potent inhibitor of carboxylesterase activity, in addition to its ability to inhibit mitochondrial complex II activity. Therefore, caution is warranted in using TTFA as a mitochondrial complex inhibitor in combination with esterase substrates, such as fluorescence probes or vitamin E esters.",
"references": [
"RC00919"
]
},
{
"pap_id": "330",
"title": "Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells.",
"authors": "Bova, Michael P; Tam, Danny; McMahon, Gerald; Mattson, Matthew N",
"chapter": "",
"pages": "41-50",
"journal": "Toxicology Letters",
"pub_date": "2005-01-15",
"pub_year": 2005,
"volume": "155",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.toxlet.2004.08.009",
"doi": "10.1016/j.toxlet.2004.08.009",
"pmid": "15585358.0",
"pmcid": "",
"abstract": "Troglitazone, a thiazolidinedione containing compound, was widely used to treat non-insulin dependent-diabetes. Unfortunately, troglitazone was associated with a sporadic liver toxicity that led to a cessation of its use clinically. Here we show that troglitazone induces a rapid and dose-dependent drop of mitochondrial membrane potential in liver HepG2 cells. The decrease in mitochondrial membrane potential induced by 100 microM troglitazone was completed after 5 min and similar in magnitude to that caused by carbonyl cyanide m-chloro phenylhydrazone. The troglitazone-induced loss of mitochondrial membrane potential preceded changes in cell permeability and cell count. In addition, troglitazone-induced a rise of intracellular calcium, subsequent to the drop in mitochondrial membrane potential, which was blocked by EGTA and the Na+/Ca2+ exchange inhibitor bepridil. Finally, application of 100 microM troglitazone for 24h to HepG2 cells resulted in activation of caspase 3. The results of this study shed light on the molecular mechanisms by which troglitazone can cause cytotoxicity.",
"references": [
"RC04999",
"RC04998",
"RC04997"
]
},
{
"pap_id": "331",
"title": "Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones.",
"authors": "Masubuchi, Yasuhiro; Kano, Satomi; Horie, Toshiharu",
"chapter": "",
"pages": "233-239",
"journal": "Toxicology",
"pub_date": "2006-05-15",
"pub_year": 2006,
"volume": "222",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tox.2006.02.017",
"doi": "10.1016/j.tox.2006.02.017",
"pmid": "16621215.0",
"pmcid": "",
"abstract": "Troglitazone, a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. Troglitazone is metabolized to a reactive metabolite that covalently binds to cellular macromolecules, but the role of the covalent adduct in the hepatotoxicity is controversial. Because troglitazone has been found to cause cytotoxicity to hepatocytes along with mitochondrial dysfunction, we investigated the effects of troglitazone and other thiazolidinediones on mitochondrial function by using liver mitochondria fraction isolated from male CD-1 mice. Incubation of energized mitochondria with succinate in the presence of Ca2+ and troglitazone induced mitochondrial swelling, and the swelling was partially inhibited by cyclosporin A. Troglitazone also induced decreases in mitochondrial membrane potential and mitochondrial Ca2+ accumulation. These results demonstrate that troglitazone induces mitochondrial permeability transition (MPT). Similar results were obtained for ciglitazone, whereas rosiglitazone and pioglitazone, which are less hepatotoxic than troglitazone, had little effect on these mitochondria functions. It is therefore possible that the troglitazone-induced opening of MPT pore, which is not induced by rosiglitazone or pioglitazone, may contribute to the hepatotoxicity induced specifically by troglitazone.",
"references": [
"RC04976",
"RC04975",
"RC04974",
"RC04973",
"RC04972",
"RC04971",
"RC04970",
"RC04969",
"RC04968",
"RC04967",
"RC04966",
"RC04965",
"RC04964"
]
},
{
"pap_id": "332",
"title": "Effects of troglitazone on HepG2 viability and mitochondrial function.",
"authors": "Tirmenstein, Mark A; Hu, Catherine X; Gales, Tracy L; Maleeff, Beverly E; Narayanan, Padma K; Kurali, Edit; Hart, Timothy K; Thomas, Heath C; Schwartz, Lester W",
"chapter": "",
"pages": "131-138",
"journal": "Toxicological Sciences",
"pub_date": "2002-09-01",
"pub_year": 2002,
"volume": "69",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/toxsci/69.1.131",
"doi": "10.1093/toxsci/69.1.131",
"pmid": "12215667.0",
"pmcid": "",
"abstract": "Troglitazone (TRO), a member of the thiazolidinedione class of drugs, has been associated with hepatotoxicity in patients. The following in vitro study was conducted to investigate the effects of TRO on mitochondrial function and viability in a human hepatoma cell line, HepG2. TRO induced a concentration- and time-dependent increase in cell death, as measured by lactate dehydrogenase release. Exposure to 50 or 100 micro M TRO produced total loss of cell viability within 5 h. Preincubation of HepG2 cells with P450 inhibitors did not significantly protect against TRO-induced cell death suggesting that P450 metabolism was not required to induce cell death. Preincubation with the mitochondrial permeability transition inhibitor, cyclosporin A, provided complete protection against TRO-induced cell death. Our results also indicated that TRO produced concentration-dependent decreases in cellular ATP levels and mitochondrial membrane potential (MMP). Ultrastructural analysis demonstrated that TRO induced mitochondrial changes at concentrations of > or =10 micro M after 2 h. Decreased MMP and altered mitochondrial morphology occurred at time points that preceded cell death and at sublethal concentrations of TRO. These observations in HepG2 cells suggest that TRO disrupts mitochondrial function, leading to mitochondrial permeability transition and cell death.",
"references": [
"RC04996",
"RC04995",
"RC04994",
"RC04993"
]
},
{
"pap_id": "333",
"title": "Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research.",
"authors": "Ceccarelli, Simona M; Chomienne, Odile; Gubler, Marcel; Arduini, Arduino",
"chapter": "",
"pages": "3109-3152",
"journal": "Journal of Medicinal Chemistry",
"pub_date": "2011-05-12",
"pub_year": 2011,
"volume": "54",
"issue": "9",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1021/jm100809g",
"doi": "10.1021/jm100809g",
"pmid": "21504156.0",
"pmcid": "",
"abstract": "",
"references": [
"RC05000",
"RC05001",
"RC05002",
"RC05003",
"RC05004",
"RC05005",
"RC05006",
"RC05007",
"RC05008",
"RC05009",
"RC05010",
"RC05011",
"RC05012",
"RC05013",
"RC05014",
"RC05015",
"RC05016",
"RC05017",
"RC05018",
"RC05019",
"RC05020",
"RC05021",
"RC05022",
"RC05023",
"RC05024",
"RC05025",
"RC05026",
"RC05027",
"RC05028",
"RC05029",
"RC05030",
"RC05031",
"RC05032",
"RC05033",
"RC05034",
"RC05035",
"RC05036",
"RC05037",
"RC05038",
"RC05039",
"RC05040",
"RC05041",
"RC05042",
"RC05043",
"RC05044",
"RC05045",
"RC05046",
"RC05047",
"RC05048",
"RC05049",
"RC05050",
"RC05051",
"RC05052",
"RC05053",
"RC05054",
"RC05055",
"RC05056",
"RC05057"
]
},
{
"pap_id": "334",
"title": "Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer.",
"authors": "Wallace, David R; Spandidos, Demetrios A; Tsatsakis, Aristidis; Schweitzer, Amie; Djordjevic, Vladimir; Djordjevic, Aleksandra Buha",
"chapter": "",
"pages": "145-156",
"journal": "International Journal of Molecular Medicine",
"pub_date": "2019-07-01",
"pub_year": 2019,
"volume": "44",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.3892/ijmm.2019.4204",
"doi": "10.3892/ijmm.2019.4204",
"pmid": "31115542.0",
"pmcid": "PMC6559323",
"abstract": "Pancreatic cancer (PC) is insidious with a high mortality rate due to the lack of symptomology prior to diagnosis. Mitochondrial involvement in PC development is becoming accepted, and exposure to cadmium (Cd) is suspected of being a risk factor for the development of PC; however, the mechanisms involved remain unclear. In this study, we examined the role of Cd as a mitochondrial toxicant and whether alterations in mitochondrial function may be an underlying cause for the development of PC. In this study, cadmium chloride (CdCl2)\u0011 mediated toxicity in hTERT\u0011 HPNE and AsPC\u0011 1 pancreatic cell lines was determined by MTT assay. We also investigated the release of LDH and the generation of free radicals. Mitochondrial toxicity assays were performed in media containing glucose (25 mM) or galactose (10 mM) and following exposure to CdCl2 (0\u0011 100 ?M) followed by MTT assay. For the confirmation of mitochondrial toxicity, we measured the release of ATP following exposure to CdCl2. Initial experiments confirmed that exposure to CdCl2 did not reduce the viability of either cell line until a concentration of >10 ?M was used. Non\u0011 linear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 ?M compared to 42 ?M in the AsPC\u0011 1 cells (P< 0.01). The CdCl2\u0011 mediated mitochondrial toxic effects were greater in the HPNE cells, suggesting a heightened sensitivity to the effects of CdCl2, not due to elevated oxidative stress. Increased mitochondrial toxic sensitivity was indicated by a 73.4% reduction in IC50 values in the HPNE cells cultured in galactose compared to culture in glucose media, whereas the AsPC\u0011 1 cells exhibited a 58.8% reduction in IC50 values. In addition, the higher concentration of CdCl2 elicited a significant cell\u0011 dependent effect on ATP release in both cell lines, suggestive of CdCl2 being a mitochondrial toxicant. Cell survival was unaffected following exposure to low concentrations of CdCl2; however, exposure did alter mitochondrial function (control cells > tumor cells). Therefore, the findings of this study indicate that the mitochondria may be a site of action for cadmium in promoting tumor development.",
"references": [
"RC05061",
"RC05060",
"RC05059",
"RC05058"
]
},
{
"pap_id": "34",
"title": "Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier.",
"authors": "Divakaruni, Ajit S; Wiley, Sandra E; Rogers, George W; Andreyev, Alexander Y; Petrosyan, Susanna; Loviscach, Mattias; Wall, Estelle A; Yadava, Nagendra; Heuck, Alejandro P; Ferrick, David A; Henry, Robert R; McDonald, William G; Colca, Jerry R; Simon, Melvin I; Ciaraldi, Theodore P; Murphy, Anne N",
"chapter": "",
"pages": "5422-5427",
"journal": "Proceedings of the National Academy of Sciences of the United States of America",
"pub_date": "2013-04-02",
"pub_year": 2013,
"volume": "110",
"issue": "14",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1073/pnas.1303360110",
"doi": "10.1073/pnas.1303360110",
"pmid": "23513224.0",
"pmcid": "PMC3619368",
"abstract": "Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.",
"references": [
"RC00920"
]
},
{
"pap_id": "35",
"title": "A combined in vitro approach to improve the prediction of mitochondrial toxicants.",
"authors": "Eakins, Julie; Bauch, Caroline; Woodhouse, Heather; Park, Benjamin; Bevan, Samantha; Dilworth, Clive; Walker, Paul",
"chapter": "",
"pages": "161-170",
"journal": "Toxicology in Vitro",
"pub_date": "2016-08-01",
"pub_year": 2016,
"volume": "34",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2016.03.016",
"doi": "10.1016/j.tiv.2016.03.016",
"pmid": "27083147.0",
"pmcid": "",
"abstract": "Drug induced mitochondrial dysfunction has been implicated in organ toxicity and the withdrawal of drugs or black box warnings limiting their use. The development of highly specific and sensitive in vitro assays in early drug development would assist in detecting compounds which affect mitochondrial function. Here we report the combination of two in vitro assays for the detection of drug induced mitochondrial toxicity. The first assay measures cytotoxicity after 24h incubation of test compound in either glucose or galactose conditioned media (Glu/Gal assay). Compounds with a greater than 3-fold toxicity in galactose media compared to glucose media imply mitochondrial toxicity. The second assay measures mitochondrial respiration, glycolysis and a reserve capacity with mechanistic responses observed within one hour following exposure to test compound. In order to assess these assays a total of 72 known drugs and chemicals were used. Dose-response data was normalised to 100× Cmax giving a specificity, sensitivity and accuracy of 100%, 81% and 92% respectively for this combined approach. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.",
"references": [
"RC00921",
"RC00922",
"RC00923",
"RC00924",
"RC00925",
"RC00927",
"RC00928",
"RC00930",
"RC00931",
"RC00932",
"RC00933",
"RC00934",
"RC00935",
"RC00936",
"RC00937",
"RC00938",
"RC00939",
"RC00940",
"RC00941",
"RC00942",
"RC00943",
"RC00944",
"RC00945",
"RC00946",
"RC00947",
"RC00948",
"RC00949",
"RC00950",
"RC00952",
"RC00953",
"RC00954",
"RC00955",
"RC00956",
"RC00957",
"RC00958",
"RC00959",
"RC00960",
"RC00961",
"RC00962",
"RC00963",
"RC00964",
"RC00965",
"RC00966",
"RC00967",
"RC00968",
"RC00969",
"RC00970",
"RC00971",
"RC00972"
]
},
{
"pap_id": "36",
"title": "Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria.",
"authors": "Porceddu, Mathieu; Buron, Nelly; Roussel, Célestin; Labbe, Gilles; Fromenty, Bernard; Borgne-Sanchez, Annie",
"chapter": "",
"pages": "332-345",
"journal": "Toxicological Sciences",
"pub_date": "2012-10-01",
"pub_year": 2012,
"volume": "129",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/toxsci/kfs197",
"doi": "10.1093/toxsci/kfs197",
"pmid": "22987451.0",
"pmcid": "PMC3446843",
"abstract": "Drug-induced liver injury (DILI) in humans is difficult to predict using classical in vitro cytotoxicity screening and regulatory animal studies. This explains why numerous compounds are stopped during clinical trials or withdrawn from the market due to hepatotoxicity. Thus, it is important to improve early prediction of DILI in human. In this study, we hypothesized that this goal could be achieved by investigating drug-induced mitochondrial dysfunction as this toxic effect is a major mechanism of DILI. To this end, we developed a high-throughput screening platform using isolated mouse liver mitochondria. Our broad spectrum multiparametric assay was designed to detect the global mitochondrial membrane permeabilization (swelling), inner membrane permeabilization (transmembrane potential), outer membrane permeabilization (cytochrome c release), and alteration of mitochondrial respiration driven by succinate or malate/glutamate. A pool of 124 chemicals (mainly drugs) was selected, including 87 with documented DILI and 37 without reported clinical hepatotoxicity. Our screening assay revealed an excellent sensitivity for clinical outcome of DILI (94 or 92% depending on cutoff) and a high positive predictive value (89 or 82%). A highly significant relationship between drug-induced mitochondrial toxicity and DILI occurrence in patients was calculated (p < 0.001). Moreover, this multiparametric assay allowed identifying several compounds for which mitochondrial toxicity had never been described before and even helped to clarify mechanisms with some drugs already known to be mitochondriotoxic. Investigation of drug-induced loss of mitochondrial integrity and function with this multiparametric assay should be considered for integration into basic screening processes at early stage to select drug candidates with lower risk of DILI in human. This assay is also a valuable tool for assessing the mitochondrial toxicity profile and investigating the mechanism of action of new compounds and marketed compounds.",
"references": [
"RC00974",
"RC00975",
"RC00976",
"RC00985",
"RC00986",
"RC00987",
"RC00988",
"RC00989",
"RC00990",
"RC01003",
"RC01004",
"RC01005",
"RC01006",
"RC01013",
"RC04020",
"RC04021",
"RC04022",
"RC04023",
"RC04024",
"RC04025",
"RC04026",
"RC04027",
"RC04028",
"RC04029",
"RC04030",
"RC04031",
"RC04032",
"RC04033",
"RC04034",
"RC04035",
"RC04036",
"RC04037",
"RC04038",
"RC04039",
"RC04040",
"RC04041",
"RC04042",
"RC04043",
"RC04044",
"RC04046",
"RC04049",
"RC04050",
"RC04051",
"RC04052",
"RC04053",
"RC04056",
"RC04059",
"RC04063",
"RC04064",
"RC04065",
"RC04067",
"RC04068",
"RC04070",
"RC04071",
"RC04268",
"RC04073",
"RC04074",
"RC04075",
"RC04076",
"RC04077",
"RC04078",
"RC04079",
"RC04080",
"RC04081",
"RC04082",
"RC04083",
"RC04084",
"RC04085",
"RC04087",
"RC04091",
"RC04092",
"RC04097",
"RC04098",
"RC04100",
"RC04101",
"RC04105",
"RC04108",
"RC04109",
"RC04110",
"RC04112",
"RC04269",
"RC04114",
"RC04115",
"RC04116",
"RC04117",
"RC04120",
"RC04122",
"RC04123",
"RC04128",
"RC04131",
"RC04135",
"RC04137",
"RC04138",
"RC04140",
"RC04143",
"RC04144",
"RC04145",
"RC04146",
"RC04147",
"RC04148",
"RC04149",
"RC04150",
"RC04151",
"RC04152",
"RC04153",
"RC04154",
"RC04155",
"RC04156",
"RC04157",
"RC04158",
"RC04159",
"RC04160",
"RC04161",
"RC04162",
"RC04163",
"RC04164",
"RC04165",
"RC04166",
"RC04167",
"RC04168",
"RC04170",
"RC04173",
"RC04174",
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"RC04176",
"RC04177",
"RC04180",
"RC04183",
"RC04187",
"RC04188",
"RC04189",
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"RC04529",
"RC04530",
"RC04531",
"RC04532",
"RC04533",
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"RC04535",
"RC04536",
"RC04537",
"RC04538",
"RC04539",
"RC04540",
"RC04542",
"RC04545",
"RC04546",
"RC04547",
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"RC04559",
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"RC04561",
"RC04563",
"RC04564",
"RC04566",
"RC04567",
"RC04569",
"RC04570",
"RC04571",
"RC04572",
"RC04573",
"RC04574",
"RC04575",
"RC04576",
"RC04577",
"RC04578",
"RC04579",
"RC04580",
"RC04581",
"RC04583",
"RC04587",
"RC04588",
"RC04593",
"RC04594",
"RC04596",
"RC04597",
"RC04601",
"RC04604",
"RC04605",
"RC04606",
"RC04608",
"RC04610",
"RC04611",
"RC04612",
"RC04613",
"RC04616",
"RC04618",
"RC04619",
"RC04624",
"RC04627",
"RC04631",
"RC04633",
"RC04634",
"RC04636",
"RC04639"
]
},
{
"pap_id": "37",
"title": "Hepatocellular toxicity of benzbromarone: effects on mitochondrial function and structure.",
"authors": "Felser, Andrea; Lindinger, Peter W; Schnell, Dominik; Kratschmar, Denise V; Odermatt, Alex; Mies, Suzette; Jenö, Paul; Krähenbühl, Stephan",
"chapter": "",
"pages": "136-146",
"journal": "Toxicology",
"pub_date": "2014-10-03",
"pub_year": 2014,
"volume": "324",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tox.2014.08.002",
"doi": "10.1016/j.tox.2014.08.002",
"pmid": "25108121.0",
"pmcid": "",
"abstract": "Benzbromarone is an uricosuric structurally related to amiodarone and a known mitochondrial toxicant. The aim of the current study was to improve our understanding in the molecular mechanisms of benzbromarone-associated hepatic mitochondrial toxicity. In HepG2 cells and primary human hepatocytes, ATP levels started to decrease in the presence of 25-50μM benzbromarone for 24-48h, whereas cytotoxicity was observed only at 100μM. In HepG2 cells, benzbromarone decreased the mitochondrial membrane potential starting at 50μM following incubation for 24h. Additionally, in HepG2 cells, 50μM benzbromarone for 24h induced mitochondrial uncoupling,and decreased mitochondrial ATP turnover and maximal respiration. This was accompanied by an increased lactate concentration in the cell culture supernatant, reflecting increased glycolysis as a compensatory mechanism to maintain cellular ATP. Investigation of the electron transport chain revealed a decreased activity of all relevant enzyme complexes. Furthermore, treatment with benzbromarone was associated with increased cellular ROS production, which could be located specifically to mitochondria. In HepG2 cells and in isolated mouse liver mitochondria, benzbromarone also reduced palmitic acid metabolism due to an inhibition of the long-chain acyl CoA synthetase. In HepG2 cells, benzbromarone disrupted the mitochondrial network, leading to mitochondrial fragmentation and a decreased mitochondrial volume per cell. Cell death occurred by both apoptosis and necrosis. The study demonstrates that benzbromarone not only affects the function of mitochondria in HepG2 cells and human hepatocytes, but is also associated with profound changes in mitochondrial structure which may be associated with apoptosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.",
"references": [
"RC00977"
]
},
{
"pap_id": "38",
"title": "The in vitro effects of tricyclic drugs and dexamethasone on cellular respiration of malignant glioma.",
"authors": "Higgins, S C; Pilkington, G J",
"chapter": "",
"pages": "391-397",
"journal": "Anticancer Research",
"pub_date": "2010-02-01",
"pub_year": 2010,
"volume": "30",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/20332444",
"doi": "",
"pmid": "20332444.0",
"pmcid": "",
"abstract": "BACKGROUND: In this investigation the effects of tricyclic drugs on cellular respiration were studied using the anaplastic astrocytoma cell line IPSB-18 by use of a Clark-type oxygen electrode which measured changes in cellular respiration rate (oxygen consumption), in a dose-response assay. MATERIALS AND METHODS: The drugs investigated were clomipramine, norclomipramine, amitriptyline and doxepin. In addition, the combined effects of dexamethasone and clomipramine on cellular respiration were investigated. RESULTS: It was established that at lower concentrations (0.14 mM-0.5 mM) amitriptyline was the most potent inhibitor of cellular respiration. Previous studies have indicated that inhibition of cellular respiration is considered an indicator of apoptosis. Overall, it appeared that clomipramine and its metabolite norclomipramine were the most potent inhibitors of cellular respiration in glioma cells over the concentration range 0.5-0.9 mM. Dexamethasone was able to induce inhibition of cellular respiration both alone in glioma cells, and in combination with clomipramine, where it had an additive or synergistic effect, thereby increasing cell death. CONCLUSION: The extensive research currently ongoing and previously reported regarding the use of clomipramine as a potential antineoplastic agent aimed at targeting the mitochondria of gliomas is promising.",
"references": [
"RC00979"
]
},
{
"pap_id": "39",
"title": "Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts.",
"authors": "Ghosh, Rajeshwary; Goswami, Sumanta K; Feitoza, Luis Felipe B B; Hammock, Bruce; Gomes, Aldrin V",
"chapter": "",
"pages": "923-935",
"journal": "International Journal of Cardiology",
"pub_date": "2016-11-15",
"pub_year": 2016,
"volume": "223",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.ijcard.2016.08.233",
"doi": "10.1016/j.ijcard.2016.08.233",
"pmid": "27589040.0",
"pmcid": "PMC5076377",
"abstract": "BACKGROUND: One of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) used worldwide, diclofenac (DIC), has been linked to increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which DIC causes CVD is unknown. METHODS: Proteasome activities were studied in hearts, livers, and kidneys from male Swiss Webster mice treated with either 100mg/kg DIC for 18h (acute treatment) or 10mg/kg DIC for 28days (chronic treatment). Cultured H9c2 cells and neonatal cardiomyocytes were also treated with different concentrations of DIC and proteasome function, cell death and ROS generation studied. Isolated mouse heart mitochondria were utilized to determine the effect of DIC on various electron transport chain complex activities. RESULTS: DIC significantly inhibited the chymotrypsin-like proteasome activity in rat cardiac H9c2 cells, murine neonatal cardiomyocytes, and mouse hearts, but did not affect proteasome subunit expression levels. Proteasome activity was also affected in liver and kidney tissues from DIC treated animals. The levels of polyubiquitinated proteins increased in hearts from DIC treated mice. Importantly, the levels of oxidized proteins increased while the β5i immunoproteasome activity decreased in hearts from DIC treated mice. DIC increased ROS production and cell death in H9c2 cells and neonatal cardiomyocytes while the cardioprotective NSAID, aspirin, had no effect on ROS levels or cell viability. DIC inhibited mitochondrial Complex III, a major source of ROS, and impaired mitochondrial membrane potential suggesting that mitochondria are the major sites of ROS generation. CONCLUSION: These results suggest that DIC induces cardiotoxicity by a ROS dependent mechanism involving mitochondrial and proteasome dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.",
"references": [
"RC00981",
"RC00980"
]
},
{
"pap_id": "4",
"title": "Mechanisms of benzarone and benzbromarone-induced hepatic toxicity.",
"authors": "Kaufmann, Priska; Török, Michael; Hänni, Anya; Roberts, Paul; Gasser, Rodolfo; Krähenbühl, Stephan",
"chapter": "",
"pages": "925-935",
"journal": "Hepatology",
"pub_date": "2005-04-01",
"pub_year": 2005,
"volume": "41",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/hep.20634",
"doi": "10.1002/hep.20634",
"pmid": "15799034.0",
"pmcid": "",
"abstract": "Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, < 1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.",
"references": [
"RC00222",
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"RC00224",
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"RC00246",
"RC00247",
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"RC00249",
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"RC00254",
"RC00255",
"RC00256",
"RC00257",
"RC00258",
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"RC00262",
"RC00263",
"RC00264",
"RC00265",
"RC00266",
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"RC00274",
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"RC00351",
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"RC00353",
"RC00354",
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"RC00356",
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"RC00359",
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"RC00367",
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"RC00370",
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"RC00372",
"RC00373",
"RC00374",
"RC00375",
"RC00376",
"RC00377",
"RC00378",
"RC00379",
"RC00380",
"RC00381",
"RC00382",
"RC00383",
"RC00384",
"RC00385",
"RC00386",
"RC00387",
"RC00388",
"RC00389",
"RC00390",
"RC00391",
"RC00392",
"RC00393",
"RC00394",
"RC00395",
"RC00396",
"RC00397",
"RC00398",
"RC00399",
"RC00400",
"RC00401",
"RC00402",
"RC00403",
"RC00404",
"RC00405",
"RC00406",
"RC00407",
"RC00408",
"RC00409",
"RC00410",
"RC00411",
"RC00412",
"RC00413",
"RC00414",
"RC00415",
"RC00416",
"RC00417",
"RC00418",
"RC00419",
"RC00420",
"RC00421",
"RC00422",
"RC00423",
"RC00424",
"RC00425",
"RC00426",
"RC00427",
"RC00428",
"RC00429",
"RC00430",
"RC00431",
"RC00432",
"RC00433",
"RC00434",
"RC00435",
"RC00436",
"RC00437",
"RC00438",
"RC00439",
"RC00440",
"RC00441",
"RC00442",
"RC00443"
]
},
{
"pap_id": "40",
"title": "Toxicity assessments of nonsteroidal anti-inflammatory drugs in isolated mitochondria, rat hepatocytes, and zebrafish show good concordance across chemical classes.",
"authors": "Nadanaciva, Sashi; Aleo, Michael D; Strock, Christopher J; Stedman, Donald B; Wang, Huijun; Will, Yvonne",
"chapter": "",
"pages": "272-280",
"journal": "Toxicology and Applied Pharmacology",
"pub_date": "2013-10-15",
"pub_year": 2013,
"volume": "272",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.taap.2013.06.019",
"doi": "10.1016/j.taap.2013.06.019",
"pmid": "23811329.0",
"pmcid": "",
"abstract": "To reduce costly late-stage compound attrition, there has been an increased focus on assessing compounds in in vitro assays that predict attributes of human safety liabilities, before preclinical in vivo studies are done. Relevant questions when choosing a panel of assays for predicting toxicity are (a) whether there is general concordance in the data among the assays, and (b) whether, in a retrospective analysis, the rank order of toxicity of compounds in the assays correlates with the known safety profile of the drugs in humans. The aim of our study was to answer these questions using nonsteroidal anti-inflammatory drugs (NSAIDs) as a test set since NSAIDs are generally associated with gastrointestinal injury, hepatotoxicity, and/or cardiovascular risk, with mitochondrial impairment and endoplasmic reticulum stress being possible contributing factors. Eleven NSAIDs, flufenamic acid, tolfenamic acid, mefenamic acid, diclofenac, meloxicam, sudoxicam, piroxicam, diflunisal, acetylsalicylic acid, nimesulide, and sulindac (and its two metabolites, sulindac sulfide and sulindac sulfone), were tested for their effects on (a) the respiration of rat liver mitochondria, (b) a panel of mechanistic endpoints in rat hepatocytes, and (c) the viability and organ morphology of zebrafish. We show good concordance for distinguishing among/between NSAID chemical classes in the observations among the three approaches. Furthermore, the assays were complementary and able to correctly identify \"toxic\" and \"non-toxic\" drugs in accordance with their human safety profile, with emphasis on hepatic and gastrointestinal safety. We recommend implementing our multi-assay approach in the drug discovery process to reduce compound attrition. © 2013.",
"references": [
"RC00982",
"RC04765",
"RC04766",
"RC04767",
"RC04768",
"RC04769",
"RC04770",
"RC04771",
"RC04772",
"RC04773",
"RC04774",
"RC04775",
"RC04776",
"RC04777",
"RC04778",
"RC04779",
"RC04780",
"RC04781",
"RC04782",
"RC04821",
"RC04783",
"RC04784",
"RC04785",
"RC04786",
"RC04787",
"RC04788",
"RC04789",
"RC04790",
"RC04791",
"RC04792",
"RC04793",
"RC04794",
"RC04795",
"RC04796",
"RC04797",
"RC04798",
"RC04799",
"RC04800",
"RC04801",
"RC04802",
"RC04803",
"RC04804",
"RC04805",
"RC04806",
"RC04807",
"RC04808",
"RC04809",
"RC04810",
"RC04811",
"RC04812",
"RC04813",
"RC04814",
"RC04815",
"RC04816",
"RC04817",
"RC04818",
"RC04819",
"RC04820",
"RC04822",
"RC04823",
"RC04824",
"RC04825",
"RC04826",
"RC04827",
"RC04828",
"RC04829",
"RC04830",
"RC04831",
"RC04832",
"RC04833",
"RC04834",
"RC04835",
"RC04836",
"RC04837",
"RC04838",
"RC04839",
"RC04840",
"RC04841",
"RC04842",
"RC04843",
"RC04844",
"RC04845",
"RC04846",
"RC04847",
"RC04848",
"RC04849",
"RC04850",
"RC04851",
"RC04852",
"RC04853",
"RC04854",
"RC04855",
"RC04856",
"RC04857",
"RC04858",
"RC04859",
"RC04860",
"RC04861",
"RC04862",
"RC04863",
"RC04864",
"RC04865",
"RC04866",
"RC04867",
"RC04868"
]
},
{
"pap_id": "41",
"title": "Bioactivation and hepatotoxicity of nitroaromatic drugs.",
"authors": "Boelsterli, Urs A; Ho, Han Kiat; Zhou, Shufeng; Leow, Koon Yeow",
"chapter": "",
"pages": "715-727",
"journal": "Current Drug Metabolism",
"pub_date": "2006-10-01",
"pub_year": 2006,
"volume": "7",
"issue": "7",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.2174/138920006778520606",
"doi": "10.2174/138920006778520606",
"pmid": "17073576.0",
"pmcid": "",
"abstract": "Certain drugs containing a nitroaromatic moiety (e.g., tolcapone, nimesulide, nilutamide, flutamide, nitrofurantoin) have been associated with organ-selective toxicity including rare cases of idiosyncratic liver injury. What they have in common is the potential for multistep nitroreductive bioactivation (6-electron transfer) that produces the potentially hazardous nitroanion radical, nitroso intermediate, and N-hydroxy derivative. These intermediates have been associated with increased oxidant stress and targeting of nucleophilic residues on proteins and nucleic acids. However, other mechanisms including the formation of oxidative metabolites and mitochondrial liability, as well as inherent toxicokinetic properties, also determine the drugs' overall potency. Therefore, structural modification not only of the nitro moiety but also of ring substituents can greatly reduce toxicity. Novel concepts have revealed that, besides the classical microsomal nitroreductases, cytosolic and mitochondrial enzymes including nitric oxide synthase can also bioactivate certain nitroarenes (nilutamide). Furthermore, animal models of silent mitochondrial dysfunction have demonstrated that a mitochondrial oxidant stress posed by certain nitroaromatic drugs (nimesulide) can produce significant mitochondrial injury if superimposed on a genetic mitochondrial abnormality. Finally, there may be mechanisms for all nitroaromatic drugs that do not involve bioactivation of the nitro group, e.g., AHR interactions with flutamide. Taken together, the focus of research on the hepatic toxicity of nitroarene-containing drugs has shifted over the past years from the identification of the reactive intermediates generated during the bioreductive pathway to the underlying biomechanisms of liver injury. Most likely one of the next paradigm shifts will include the identification of determinants of susceptibility to nitroaromatic drug-induced hepatotoxicity.",
"references": [
"RC00983"
]
},
{
"pap_id": "42",
"title": "The effect of hexachlorophene on the respiration of brain and liver mitochondria.",
"authors": "Cammer, W; Moore, C L",
"chapter": "",
"pages": "1887-1894",
"journal": "Biochemical and Biophysical Research Communications",
"pub_date": "1972-03-10",
"pub_year": 1972,
"volume": "46",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0006-291x(72)90066-6",
"doi": "10.1016/0006-291x(72)90066-6",
"pmid": "5015232.0",
"pmcid": "",
"abstract": "",
"references": [
"RC00984"
]
},
{
"pap_id": "43",
"title": "Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria.",
"authors": "Bridges, Hannah R; Jones, Andrew J Y; Pollak, Michael N; Hirst, Judy",
"chapter": "",
"pages": "475-487",
"journal": "The Biochemical Journal",
"pub_date": "2014-09-15",
"pub_year": 2014,
"volume": "462",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/BJ20140620",
"doi": "10.1042/BJ20140620",
"pmid": "25017630.0",
"pmcid": "PMC4148174",
"abstract": "The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.",
"references": [
"RC00991"
]
},
{
"pap_id": "44",
"title": "Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists.",
"authors": "Kenna, J Gerry; Stahl, Simone H; Eakins, Julie A; Foster, Alison J; Andersson, Linda C; Bergare, Jonas; Billger, Martin; Elebring, Marie; Elmore, Charles S; Thompson, Richard A",
"chapter": "",
"pages": "281-290",
"journal": "The Journal of Pharmacology and Experimental Therapeutics",
"pub_date": "2015-02-01",
"pub_year": 2015,
"volume": "352",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1124/jpet.114.220491",
"doi": "10.1124/jpet.114.220491",
"pmid": "25467130.0",
"pmcid": "",
"abstract": "Drug-induced liver injury has been observed in patients treated with the endothelin receptor antagonists sitaxentan and bosentan, but not following treatment with ambrisentan. The aim of our studies was to assess the possible role of multiple contributory mechanisms in this clinically relevant toxicity. Inhibition of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 was quantified using membrane vesicle assays. Inhibition of mitochondrial respiration in human liver-derived HuH-7 cells was determined using a Seahorse XF(e96) analyzer. Cytochrome P450 (P450)-independent and P450-mediated cell toxicity was assessed using transfected SV40-T-antigen-immortalized human liver epithelial (THLE) cell lines. Exposure-adjusted assay ratios were calculated by dividing the maximum human drug plasma concentrations by the IC50 or EC50 values obtained in vitro. Covalent binding (CVB) of radiolabeled drugs to human hepatocytes was quantified, and CVB body burdens were calculated by adjusting CVB values for fractional drug turnover in vitro and daily therapeutic dose. Sitaxentan exhibited positive exposure-adjusted signals in all five in vitro assays and a high CVB body burden. Bosentan exhibited a positive exposure-adjusted signal in one assay (BSEP inhibition) and a moderate CVB body burden. Ambrisentan exhibited no positive exposure-adjusted assay signals and a low CVB body burden. These data indicate that multiple mechanisms contribute to the rare, but potentially severe liver injury caused by sitaxentan in humans; provide a plausible rationale for the markedly lower propensity of bosentan to cause liver injury; and highlight the relative safety of ambrisentan. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.",
"references": [
"RC00996",
"RC00995"
]
},
{
"pap_id": "45",
"title": "Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction.",
"authors": "Seo, Sung-Keum; Lee, Hyung-Chahn; Woo, Sang-Hyeok; Jin, Hyeon-Ok; Yoo, Doo-Hyun; Lee, Su-Jae; An, Sungkwan; Choe, Tae-Boo; Park, Myung-Jin; Hong, Seok-Il; Park, In-Chul; Rhee, Chang-Hun",
"chapter": "",
"pages": "195-209",
"journal": "Apoptosis: An International Journal on Programmed Cell Death",
"pub_date": "2007-01-01",
"pub_year": 2007,
"volume": "12",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s10495-006-0527-5",
"doi": "10.1007/s10495-006-0527-5",
"pmid": "17136320.0",
"pmcid": "",
"abstract": "Non-steroidal anti-inflammatory drugs are well known to induce apoptosis of cancer cells independent of their ability to inhibit cyclooxygenase-2, but the molecular mechanism for this effect has not yet been fully elucidated. The purpose of this study was to elucidate the potential signaling components underlying sulindac-induced apoptosis in human multiple myeloma (MM) cells. We found that sulindac induces apoptosis by promoting ROS generation, accompanied by opening of mitochondrial permeability transition pores, release of cytochrome c and apoptosis inducing factor from mitochondria, followed by caspase activation. Bcl-2 cleavage and down-regulation of the inhibitor of apoptosis proteins (IAPs) family including cIAP-1/2, XIAP, and survivin, occurred downstream of ROS production during sulindac-induced apoptosis. Forced expression of survivin and Bcl-2 blocked sulindac-induced apoptosis. Most importantly, sulindac-derived ROS activated p38 mitogen-activated protein kinase and p53. SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis. Furthermore, p53, Bax, and Bak accumulated in mitochondria during sulindac-induced apoptosis. All of these events were significantly suppressed by SB203580. Our results demonstrate a novel mechanism of sulindac-induced apoptosis in human MM cells, namely, accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production.",
"references": [
"RC00998",
"RC00997"
]
},
{
"pap_id": "46",
"title": "Effects of tamoxifen on the electron transport chain of isolated rat liver mitochondria.",
"authors": "Tuquet, C; Dupont, J; Mesneau, A; Roussaux, J",
"chapter": "",
"pages": "207-219",
"journal": "Cell biology and toxicology",
"pub_date": "1905-06-22",
"pub_year": 1905,
"volume": "16",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1023/a:1007695308257",
"doi": "10.1023/a:1007695308257",
"pmid": "11101003.0",
"pmcid": "",
"abstract": "Tamoxifen (and 4-hydroxytamoxifen), a nonsteroidal triphenylethylene antiestrogenic drug widely used in the treatment of breast cancer, interacts strongly with the respiratory chain of isolated rat liver mitochondria. The drug acts as both an uncoupling agent and a powerful inhibitor of electron transport. Tamoxifen brings about a collapse of the membrane potential. Enzymatic assays and spectroscopic studies indicate that tamoxifen inhibits electron transfer in the respiratory chain at the levels of complex III (ubiquinol-cytochrome-c reductase) and, to a lesser extent, of complex IV (cytochrome-c oxidase). The activities can be restored by the addition of diphosphatidylglycerol, a phospholipid implicated in the functioning of the respiratory chain complexes.",
"references": [
"RC01000",
"RC00999"
]
},
{
"pap_id": "47",
"title": "Measurement of oxygen consumption in mouse aortic endothelial cells using a microparticulate oximetry probe.",
"authors": "Pandian, Ramasamy P; Kutala, Vijay Kumar; Parinandi, Narasimham L; Zweier, Jay L; Kuppusamy, Periannan",
"chapter": "",
"pages": "169-175",
"journal": "Archives of Biochemistry and Biophysics",
"pub_date": "2003-12-01",
"pub_year": 2003,
"volume": "420",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.abb.2003.09.008",
"doi": "10.1016/j.abb.2003.09.008",
"pmid": "14622987.0",
"pmcid": "",
"abstract": "The purpose of this study was to determine the rate of oxygen consumption in mouse aortic endothelial cells (MAECs) and to determine the effect of a variety of inhibitors and stimulators of oxygen consumption measured by electron paramagnetic resonance (EPR) spectroscopy utilizing a new particulate oximetry probe. We have previously demonstrated that the octa-n-butoxy derivative of naphthalocyanine neutral radical (LiNc-BuO) enables accurate, precise, and reproducible measurements of pO(2) in cellular suspensions. In the current study, we carried out measurements to provide an accurate determination of pO(2) in small volume with less number of cells (20,000 cells) that has not been possible with other techniques. To establish the reliability of this method, agents such as menadione, lipopolysaccharide (LPS), potassium cyanide, rotenone, and diphenyleneiodonium chloride (DPI) were used to modulate the oxygen consumption rate in the cells. We observed an increase in oxygen consumption by the cells upon treatment with menadione and LPS, whereas treatment with cyanide, rotenone, and DPI inhibited oxygen consumption. This study clearly demonstrated the utilization of EPR spectrometry with LiNc-BuO probe for determination of oxygen concentration in cultured cells.",
"references": [
"RC01007"
]
},
{
"pap_id": "48",
"title": "Mitochondrial dysfunction induced by sertraline, an antidepressant agent.",
"authors": "Li, Yan; Couch, Letha; Higuchi, Masahiro; Fang, Jia-Long; Guo, Lei",
"chapter": "",
"pages": "582-591",
"journal": "Toxicological Sciences",
"pub_date": "2012-06-01",
"pub_year": 2012,
"volume": "127",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/toxsci/kfs100",
"doi": "10.1093/toxsci/kfs100",
"pmid": "22387747.0",
"pmcid": "PMC5736306",
"abstract": "Sertraline, a selective serotonin reuptake inhibitor, has been used for the treatment of depression. Although it is generally considered safe, cases of sertraline-associated liver injury have been documented; however, the possible mechanism of sertraline-associated hepatotoxicity is entirely unknown. Here, we report that mitochondrial impairment may play an important role in liver injury induced by sertraline. In mitochondria isolated from rat liver, sertraline uncoupled mitochondrial oxidative phosphorylation and inhibited the activities of oxidative phosphorylation complexes I and V. Additionally, sertraline induced Ca(2+)-mediated mitochondrial permeability transition (MPT), and the induction was prevented by bongkrekic acid (BA), a specific MPT inhibitor targeting adenine nucleotide translocator (ANT), implying that the MPT induction is mediated by ANT. In freshly isolated rat primary hepatocytes, sertraline rapidly depleted cellular adenosine triphosphate (ATP) and subsequently induced lactate dehydrogenase leakage; both were attenuated by BA. Our results, including ATP depletion, induction of MPT, inhibition of mitochondrial respiration complexes, and uncoupling oxidative phosphorylation, indicate that sertraline-associated liver toxicity is possibly via mitochondrial dysfunction.",
"references": [
"RC01008"
]
},
{
"pap_id": "49",
"title": "Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: a structure-activity investigation.",
"authors": "de Faria, Priscila A; Bettanin, Fernanda; Cunha, Rodrigo L O R; Paredes-Gamero, Edgar J; Homem-de-Mello, Paula; Nantes, Iseli L; Rodrigues, Tiago",
"chapter": "",
"pages": "44-54",
"journal": "Toxicology",
"pub_date": "2015-04-01",
"pub_year": 2015,
"volume": "330",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tox.2015.02.004",
"doi": "10.1016/j.tox.2015.02.004",
"pmid": "25686698.0",
"pmcid": "",
"abstract": "Phenothiazine derivatives are neuroleptic drugs used in the treatment of schizophrenia and anxiety. Several side effects are described for these drugs, including hepatotoxicity, which may be related to their cytotoxic activity. Working with isolated rat liver mitochondria, we previously showed that phenothiazine derivatives induced the mitochondrial permeability transition associated with cytochrome c release. Since the mitochondrial permeabilization process plays a central role in cell death, the aim of this work was to evaluate the effects of five phenothiazine derivatives (chlorpromazine, fluphenazine, thioridazine, trifluoperazine, and triflupromazine) on the viability of hepatoma tissue culture (HTC) cells to establish the structural requirements for cytotoxicity. All phenothiazine derivatives decreased the viability of the HTC cells in a concentration-dependent manner and exhibited different cytotoxic potencies. The EC50 values ranged from 45 to 125 μM, with the piperidinic derivative thioridazine displaying the most cytotoxicity, followed by the piperazinic and aliphatic derivatives. The addition of the phenothiazine derivatives to cell suspensions resulted in significant morphological changes and plasma membrane permeabilization. Octanol/water partition studies revealed that these drugs partitioned preferentially to the apolar phase, even at low pH values (≤4.5). Also, structural and electronic properties were calculated employing density functional theory. Interestingly, the phenothiazine derivatives promoted an immediate dissipation of the mitochondrial transmembrane potential in HTC cells, and the EC50 values were closely correlated with those obtained in cell viability assays, as well as the EC50 for swelling in isolated mitochondria. These results significantly contribute to improving our understanding of the specific structural requirements of the phenothiazine derivatives to induce cell death and suggest the involvement of the mitochondrial permeability transition in phenothiazine-induced cytotoxicity in HTC cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.",
"references": [
"RC01009"
]
},
{
"pap_id": "5",
"title": "The in vitro and in vivo antitumor effects of clotrimazole on oral squamous cell carcinoma.",
"authors": "Wang, Juan; Jia, Lihua; Kuang, Zirong; Wu, Tong; Hong, Yun; Chen, Xiaobing; Leung, W Keung; Xia, Juan; Cheng, Bin",
"chapter": "",
"pages": "e98885",
"journal": "Plos One",
"pub_date": "2014-06-03",
"pub_year": 2014,
"volume": "9",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1371/journal.pone.0098885",
"doi": "10.1371/journal.pone.0098885",
"pmid": "24892421.0",
"pmcid": "PMC4043897",
"abstract": "BACKGROUND: Clotrimazole is an antifungal imidazole derivative showing anti- neoplastic effect in some tumors, but its anticancer potential is still unclear in oral squamous cell carcinoma (OSCC). The aim of this study was to evaluate the antitumor effect of clotrimazole, and to investigate the possible mechanism of clotrimazole-mediated antitumor activity in OSCC. METHODOLOGY: In vitro experiments, the cell viability and clonogenic ability of three human OSCC cell lines CAL27, SCC25 and UM1 were detected after clotrimazole treatment by CCK8 assay and colony formation assay. Cell cycle progression and apoptosis were assessed by flow cytometry, and the involvement of several mediators of apoptosis was examined by western blot analysis. Then, the in vivo antitumor effect of clotrimazole was investigated in CAL27 xenograft model. Immunohistochemistry and western blot analysis were performed to determine the presence of apoptotic cells and the expression of Bcl-2 and Bax in tumors from mice treated with or without clotrimazole. RESULTS: Clotrimazole inhibited proliferation in all three OSCC cell lines in a dose-and time-dependent manner, and significantly reduced the colony formation of OSCC cells in vitro. Clotrimazole caused cell cycle arrest at the G0/G1 phase. In addition, clotrimazole induced apoptosis in OSCC cells, and significantly down-regulated the anti-apoptotic protein Bcl-2 and up-regulated the pro-apoptotic protein Bax. Notably, clotrimazole treatment inhibited OSCC tumor growth and cell proliferation in CAL27 xenograft model. Clotrimazole also markedly reduced Bcl-2 expression and increased the protein level of Bax in tumor tissues of xenograft model. CONCLUSION: Our findings demonstrated a potent anticancer effect of clotrimazole by inducing cell cycle arrest and cellular apoptosis in OSCC.",
"references": [
"RC00444",
"RC00445",
"RC00446",
"RC00447",
"RC00448",
"RC00449",
"RC00450",
"RC00451",
"RC00452",
"RC00453",
"RC00454",
"RC00455",
"RC00456",
"RC00457",
"RC00458",
"RC00459",
"RC00460",
"RC00461",
"RC00462",
"RC00463",
"RC00464",
"RC00465",
"RC00466",
"RC00467",
"RC00468",
"RC00469"
]
},
{
"pap_id": "50",
"title": "Mitochondrial membrane potential measurement of H9c2 cells grown in high-glucose and galactose-containing media does not provide additional predictivity towards mitochondrial assessment.",
"authors": "Rana, Payal; Nadanaciva, Sashi; Will, Yvonne",
"chapter": "",
"pages": "580-587",
"journal": "Toxicology in Vitro",
"pub_date": "2011-03-01",
"pub_year": 2011,
"volume": "25",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2010.11.016",
"doi": "10.1016/j.tiv.2010.11.016",
"pmid": "21126567.0",
"pmcid": "",
"abstract": "Drug-induced mitochondrial toxicity is a contributing factor to many organ toxicities. The fact that some, but not all members of a particular drug class can induce mitochondrial dysfunction has necessitated the need for predictive screens within the drug development process. One of these screens is a cell viability assay done in two types of media, one containing high-glucose, the other, galactose. Since galactose-grown cells are more susceptible to mitochondrial toxicants than high-glucose-grown cells, this assay distinguishes compounds that cause toxicity primarily through mitochondrial targets from those that cause multifactorial toxicity. However, the assay does not show if compounds that cause multifactorial toxicity cause impairment on mitochondria. To address this problem, we investigated if multiplexing the assay with mitochondrial membrane potential measurements using the fluorescent dye, JC-1, could provide further information. We tested 28 drugs in the multiplexed assay and found that, although mitochondrial toxicants could be detected, no additional information was revealed about compounds that caused multifactorial toxicity. Hence, measurements with JC-1 did not provide additional information beyond what was detected using the cell viability assay. We conclude that even though the multiplexed assay is useful for HTS applications, it provides no additional value over the high-glucose-galactose cell viability assay. Copyright © 2010 Elsevier Ltd. All rights reserved.",
"references": [
"RC01010",
"RC04869",
"RC04870",
"RC04871",
"RC04873",
"RC04874",
"RC04875",
"RC04876",
"RC04877",
"RC04878",
"RC04879",
"RC04880",
"RC04881",
"RC04883",
"RC04884",
"RC04885",
"RC04886",
"RC04888",
"RC04889",
"RC04892",
"RC04893",
"RC04894",
"RC04895",
"RC04896",
"RC04897",
"RC04898",
"RC04899",
"RC04900"
]
},
{
"pap_id": "51",
"title": "Pentamidine is an uncoupler of oxidative phosphorylation in rat liver mitochondria.",
"authors": "Moreno, S N",
"chapter": "",
"pages": "15-20",
"journal": "Archives of Biochemistry and Biophysics",
"pub_date": "1996-02-01",
"pub_year": 1996,
"volume": "326",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1006/abbi.1996.0041",
"doi": "10.1006/abbi.1996.0041",
"pmid": "8579363.0",
"pmcid": "",
"abstract": "Pentamidine is a cationic drug that is used for the treatment of African trypanosomiasis, leishmaniasis, and Pneumocystis carinii pneumonia. When incubated with pharmacological concentrations of pentamidine, some of the etiologic agents of those diseases reach internal concentrations close to 1.0 mM. In this work pentamidine is shown to exhibit characteristics of a cationic uncoupler of oxidative phosphorylation in isolated rat liver mitochondria: it released respiratory control, enhanced the latent ATPase activity, and released the inhibition of State 3 respiration by oligomycin. Maximal stimulation of respiration and ATPase activity was observed at a concentration of pentamidine of 200-300 microM. Higher concentrations had an inhibitory effect on mitochondrial respiration. As it happens with other cationic uncouplers, the uncoupling effect of pentamidine required inorganic phosphate. Pentamidine-induced uncoupling of oxidative phosphorylation was accompanied by an efflux of Ca2+ from the mitochondria and partial collapse of the mitochondrial membrane potential.",
"references": [
"RC01012",
"RC01011"
]
},
{
"pap_id": "52",
"title": "Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity.",
"authors": "Ramamoorthy, Hemalatha; Abraham, Premila; Isaac, Bina",
"chapter": "",
"pages": "246-255",
"journal": "Journal of Biochemical and Molecular Toxicology",
"pub_date": "2014-06-01",
"pub_year": 2014,
"volume": "28",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/jbt.21560",
"doi": "10.1002/jbt.21560",
"pmid": "24615786.0",
"pmcid": "",
"abstract": "The long-term use of tenofovir, a commonly used anti-HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF-treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction. © 2014 Wiley Periodicals, Inc.",
"references": [
"RC01014"
]
},
{
"pap_id": "53",
"title": "Evaluation of in vitro mitochondrial toxicity assays and physicochemical properties for prediction of organ toxicity using 228 pharmaceutical drugs.",
"authors": "Rana, Payal; Aleo, Michael D; Gosink, Mark; Will, Yvonne",
"chapter": "",
"pages": "156-167",
"journal": "Chemical Research in Toxicology",
"pub_date": "2019-01-22",
"pub_year": 2019,
"volume": "32",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1021/acs.chemrestox.8b00246",
"doi": "10.1021/acs.chemrestox.8b00246",
"pmid": "30525499.0",
"pmcid": "",
"abstract": "Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as liver, cardiac, and kidney. In the past decades, two high-throughput applicable screening assays (isolated rat liver mitochondria; glucose-galactose grown HepG2 cells) to assess mitochondrial toxicity have been deployed in many pharmaceutical companies, and numerous publications have demonstrated its usefulness for mechanistic investigations. However, only two publications have demonstrated the utility of these screens as a predictor of human drug-induced liver injury. In the present study, we screened 73 hepatotoxicants, 46 cardiotoxicants, 49 nephrotoxicants, and 60 compounds not known to cause human organ toxicity for their effects on mitochondrial function(s) in the assays mentioned above. Predictive performance was evaluated using specificity and sensitivity of the assays for predicting organ toxicity. Our results show that the predictive performance of the mitochondrial assays are superior for hepatotoxicity as compared to cardiotoxicity and nephrotoxicity (sensitivity 63% vs 33% and 28% with similar specificity of 93%), when the analysis was done at 100* Cmax (drug concentration in human plasma level). We further explored the association of mitochondrial toxicity with physicochemical properties such as calculated log partition coefficient (cLogP), topological polar surface area, ionization status, and molecular weight of the drugs and found that cLogP was most significantly associated mitochondrial toxicity. Since these assays are amenable to higher throughput, we recommend that chemists use these assays to perform structure activity relationship early in the drug discovery process, when chemical matter is abundant. This assures that compounds that lack the propensity to cause mitochondrial dysfunction (and associated organ toxicity) will move forward into animals and humans.",
"references": [
"RC01015",
"RC01016",
"RC01017",
"RC01018",
"RC01019",
"RC01020",
"RC01021",
"RC01022",
"RC01023",
"RC01024",
"RC01025",
"RC01026",
"RC01027",
"RC01028",
"RC01029",
"RC01030",
"RC01031",
"RC01032",
"RC01033",
"RC01034",
"RC01035",
"RC01036",
"RC01037",
"RC01038",
"RC01039",
"RC01066",
"RC01067",
"RC01068",
"RC01069",
"RC01070",
"RC01071",
"RC01072",
"RC01073",
"RC01074",
"RC01075",
"RC01076",
"RC01077",
"RC01078",
"RC01079",
"RC01080",
"RC01081",
"RC01082",
"RC01083",
"RC01084",
"RC01085",
"RC01086",
"RC01087",
"RC01088",
"RC01089",
"RC01090",
"RC01091",
"RC01092",
"RC01093",
"RC01094",
"RC01095",
"RC01096",
"RC01097",
"RC01098",
"RC01099",
"RC01100",
"RC01101",
"RC01102",
"RC01103",
"RC01104",
"RC01105",
"RC01106",
"RC01107",
"RC01108",
"RC01109",
"RC01110",
"RC01111",
"RC01112",
"RC01113",
"RC01114",
"RC01115",
"RC01116",
"RC01117",
"RC01118"
]
},
{
"pap_id": "54",
"title": "Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.",
"authors": "Le Dinh, T; Freneaux, E; Labbe, G; Letteron, P; Degott, C; Geneve, J; Berson, A; Larrey, D; Pessayre, D",
"chapter": "",
"pages": "745-750",
"journal": "The Journal of Pharmacology and Experimental Therapeutics",
"pub_date": "1988-11-01",
"pub_year": 1988,
"volume": "247",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/3183967",
"doi": "",
"pmid": "3183967.0",
"pmcid": "",
"abstract": "Microvesicular steatosis of the liver has been reported in two subjects receiving amineptine (a tricyclic antidepressant metabolized by beta-oxidation of its acyl chain). A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation, or in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of amineptine on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation was inhibited by 27, 33, 46 and 57% respectively, in the presence of 0.25, 0.5, 1 and 2 mM of amineptine. Inhibition was reversible. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetyl coenzyme A by mouse liver mitochondria, was inhibited by 22, 23, 47, 54, 60 and 62%, respectively, in the presence of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mM of amineptine. In vivo, administration of amineptine, 0.5 and 0.75 mmol.kg-1, inhibited by 70 and 84%, respectively, the exhalation of [14C] CO2 during the first 3 hr after the administration of a tracer dose of [U-14C]palmitic acid. Administration of amineptine, 0.0625, 0.25, 0.5 or 1 mmol.kg-1, 6 hr before the measurement, increased hepatic triglycerides by 73, 139, 295 and 320%, respectively. After 1 mmol.kg-1, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 5-fold the control value; liver histology at that time showed microvesicular steatosis.(ABSTRACT TRUNCATED AT 250 WORDS)",
"references": [
"RC01040"
]
},
{
"pap_id": "55",
"title": "Chenodeoxycholate is a potent inducer of the permeability transition pore in rat liver mitochondria.",
"authors": "Rolo, A P; Oliveira, P J; Moreno, A J; Palmeira, C M",
"chapter": "",
"pages": "73-80",
"journal": "Bioscience reports",
"pub_date": "2001-02-01",
"pub_year": 2001,
"volume": "21",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1023/a:1010438202519",
"doi": "10.1023/a:1010438202519",
"pmid": "11508696.0",
"pmcid": "",
"abstract": "Several reports support the concept that bile acids may be cytotoxic during cholestatic disease process by causing mitochondrial dysfunction. Here we report additional data and findings aimed at a better understanding of the involvement of the permeability transition pore (PTP) opening in bile acids toxicity. The mitochondrial PTP is implicated as a mediator of cell injury and death in many situations. In the presence of calcium and phosphate, chenodeoxycholic acid (CDCA) induced a permeability transition in freshly isolated rat liver mitochondria, characterized by membrane depolarization, release of matrix calcium, and osmotic swelling. All these events were blocked by cyclosporine A (CyA) and the calcium uniporter inhibitor ruthenium red (RR). The results suggest that CDCA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the PTP.",
"references": [
"RC01041"
]
},
{
"pap_id": "56",
"title": "Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation.",
"authors": "Mahmud, T; Rafi, S S; Scott, D L; Wrigglesworth, J M; Bjarnason, I",
"chapter": "",
"pages": "1998-2003",
"journal": "Arthritis and Rheumatism",
"pub_date": "1996-12-01",
"pub_year": 1996,
"volume": "39",
"issue": "12",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/art.1780391208",
"doi": "10.1002/art.1780391208",
"pmid": "8961904.0",
"pmcid": "",
"abstract": "OBJECTIVE: There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a \"topical\" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties. METHODS: Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode. RESULTS: Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 microM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimero-flurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling. CONCLUSION: The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.",
"references": [
"RC01042"
]
},
{
"pap_id": "57",
"title": "Release of cytochrome c from isolated mitochondria by etoposide.",
"authors": "Park, Jung-Hee; Kim, Tae-Hyoung",
"chapter": "",
"pages": "619-623",
"journal": "Journal of Biochemistry and Molecular Biology",
"pub_date": "2005-09-30",
"pub_year": 2005,
"volume": "38",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.5483/bmbrep.2005.38.5.619",
"doi": "10.5483/bmbrep.2005.38.5.619",
"pmid": "16202244.0",
"pmcid": "",
"abstract": "The efficacy of chemotherapeutic agents on tumor cells has been shown to be modulated by tumor suppressor gene p53 and its target genes such as Bcl-2 family members (Bax, Noxa, and PUMA). However, various chemotherapeutic agents can induce cell death in tumor cells that do not express the functional p53, suggesting that some chemotherapeutic agents may induce cell death in a p53-independent pathway. Here we showed that etoposide can induce the similar degree of cell death in p53-deficient HCT 116 cells, whereas 5'-FU-mediated cell death is strongly dependent on the existence of functional p53 in HCT 116 cells. Further, we provide the evidence that etoposide can induce the cytochrome c release from isolated mitochondria, and etoposide-induced cytochrome c release is not accompanied with the large amplitude swelling of mitochondria. These data suggest that etoposide can directly induce the mitochondrial dysfunction irrespective of p53 status, and it may, at least in part, account for the p53-independent pathway in cell death induced by chemotherapeutic agents.",
"references": [
"RC01044",
"RC01043"
]
},
{
"pap_id": "58",
"title": "Involvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs.",
"authors": "Santos, N A G; Medina, W S G; Martins, N M; Rodrigues, M A Carvalho; Curti, C; Santos, A C",
"chapter": "",
"pages": "1820-1824",
"journal": "Toxicology in Vitro",
"pub_date": "2008-12-01",
"pub_year": 2008,
"volume": "22",
"issue": "8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2008.08.004",
"doi": "10.1016/j.tiv.2008.08.004",
"pmid": "18783732.0",
"pmcid": "",
"abstract": "The use of the classic aromatic antiepileptic drugs (AAEDs) has recently been expanded to a broad spectrum of psychiatric and neurological disorders. However, the clinical use of these drugs is limited by several adverse effects, mainly idiosyncratic hepatotoxicity. AAED-induced hepatotoxicity has been attributed to a defective detoxification by the epoxide hydrolase and accumulation of arene oxides. The underlying mechanism has been proposed as immune-mediated, but direct toxicity has also been suggested. In general, idiosyncratic drug-induced hepatotoxicity may be mediated, at least in part, by oxidative stress. On the other hand, the oxidative stress induced by the AAED metabolites has not been demonstrated yet. Therefore, in the present study we have evaluated the induction of oxidative stress by three classical AAEDs: carbamazepine, phenytoin and phenobarbital as well as by their metabolites. The toxic effects of the metabolites were evaluated by incubating the drug with rat liver microsomes. The AAED-induced oxidative stress was demonstrated by the increased malondialdehyde levels, oxidation of cardiolipin; oxidation of sulfhydryl proteins and alteration of the cellular redox status. Results suggest that the hepatotoxicity associated with AAED might be mediated by the oxidative stress induced by the drugs metabolites.",
"references": []
},
{
"pap_id": "59",
"title": "Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.",
"authors": "Begriche, Karima; Massart, Julie; Robin, Marie-Anne; Borgne-Sanchez, Annie; Fromenty, Bernard",
"chapter": "",
"pages": "773-794",
"journal": "Journal of Hepatology",
"pub_date": "2011-04-01",
"pub_year": 2011,
"volume": "54",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.jhep.2010.11.006",
"doi": "10.1016/j.jhep.2010.11.006",
"pmid": "21145849.0",
"pmcid": "",
"abstract": "Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis). Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.",
"references": [
"RC01047"
]
},
{
"pap_id": "6",
"title": "Role of mitochondrial permeability transition in diclofenac-induced hepatocyte injury in rats.",
"authors": "Masubuchi, Yasuhiro; Nakayama, Shintaro; Horie, Toshiharu",
"chapter": "",
"pages": "544-551",
"journal": "Hepatology",
"pub_date": "2002-03-01",
"pub_year": 2002,
"volume": "35",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1053/jhep.2002.31871",
"doi": "10.1053/jhep.2002.31871",
"pmid": "11870366.0",
"pmcid": "",
"abstract": "Hepatotoxicity of diclofenac has been known in experimental animals and humans but its mechanism has not been fully understood. The present study examined the role of mitochondrial permeability transition (MPT) in the pathogenesis of diclofenac-induced hepatocyte injury by using isolated mitochondria and primary culture hepatocytes from rats. Incubation of energized mitochondria with succinate in the presence of Ca(2+) and diclofenac resulted in mitochondrial swelling, leakage of accumulated Ca(2+), membrane depolarization, and oxidation of nicotinamide adenine dinucleotide phosphate and protein thiol. All of these phenomena were suppressed by coincubation of the mitochondria with cyclosporin A, a typical inhibitor of MPT, showing that diclofenac opened the MPT pore. It was also suggested that reactive oxygen species probably generated during mitochondrial respiration and/or voltage-dependent mechanism was involved in MPT, which are proposed as mechanisms of MPT by uncouplers of mitochondrial oxidative phosphorylation. Culture of hepatocytes for 24 hours with diclofenac caused a decrease in cellular ATP, leakage of lactate dehydrogenase and membrane depolarization. The hepatocyte toxicity thus observed was attenuated by coincubation of the hepatocytes with cyclosporin A and verapamil, a Ca(2+) channel blocker. In conclusion, these results showed the important role of MPT in pathogenesis of hepatocyte injury induced by diclofenac and its possible contribution to human idiosyncratic hepatotoxicity.",
"references": [
"RC00510",
"RC00506",
"RC00496",
"RC00492",
"RC00486",
"RC00485",
"RC00482",
"RC00481",
"RC00480",
"RC00479",
"RC00478",
"RC00477",
"RC00476",
"RC00475",
"RC00474",
"RC00473",
"RC00472",
"RC00471",
"RC00470"
]
},
{
"pap_id": "60",
"title": "In vitro inhibition of mitochondrial respiratory rate by antidepressants.",
"authors": "Hroudová, Jana; Fišar, Zdeněk",
"chapter": "",
"pages": "345-352",
"journal": "Toxicology Letters",
"pub_date": "2012-09-18",
"pub_year": 2012,
"volume": "213",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.toxlet.2012.07.017",
"doi": "10.1016/j.toxlet.2012.07.017",
"pmid": "22842584.0",
"pmcid": "",
"abstract": "Mitochondria represent a possible drug target with unexplored therapeutic and toxicological potential. The possibility was suggested that antidepressants, mood stabilizers and other drugs may show some therapeutic and/or toxic effects through their action on mitochondrial functions. There are no sufficient data about the effect of these drugs on mitochondrial respiration in the brain. We investigated the in vitro effects of amitriptyline, fluoxetine, tianeptine, ketamine, lithium, valproate, olanzapine, chlorpromazine and propranolol on mitochondrial respiration in crude mitochondrial fractions of pig brains. Respiration was energized using substrates of complex I or complex II and dose dependent drug-induced changes in mitochondrial respiratory rate were measured by high-resolution respirometry. Antidepressants, but not mood stabilizers, ketamine and propranolol were found to inhibit mitochondrial respiratory rate. The effective dose of antidepressants reaching half the maximal respiratory rate was in the range of 0.07-0.46 mmol/L. Partial inhibition was found for all inhibitors. Differences between individual drugs with similar physicochemical properties indicate selectivity of drug-induced changes in mitochondrial respiratory rate. Our findings suggest that mood stabilizers do not interfere with brain mitochondrial respiration, whereas direct mitochondrial targeting is involved in mechanisms of action of pharmacologically different antidepressants. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.",
"references": [
"RC01056",
"RC01048"
]
},
{
"pap_id": "61",
"title": "Bupivacaine myotoxicity is mediated by mitochondria.",
"authors": "Irwin, William; Fontaine, Eric; Agnolucci, Laura; Penzo, Daniele; Betto, Romeo; Bortolotto, Susan; Reggiani, Carlo; Salviati, Giovanni; Bernardi, Paolo",
"chapter": "",
"pages": "12221-12227",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2002-04-05",
"pub_year": 2002,
"volume": "277",
"issue": "14",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.M108938200",
"doi": "10.1074/jbc.M108938200",
"pmid": "11790774.0",
"pmcid": "",
"abstract": "We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mm or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca(2+), release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca(2+) dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.",
"references": [
"RC01051",
"RC01050",
"RC01049"
]
},
{
"pap_id": "62",
"title": "Activities of respiratory chain complexes and citrate synthase influenced by pharmacologically different antidepressants and mood stabilizers.",
"authors": "Hroudova, Jana; Fisar, Zdenek",
"chapter": "",
"pages": "336-342",
"journal": "Neuro Endocrinology Letters",
"pub_date": "1905-07-02",
"pub_year": 1905,
"volume": "31",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/20588251",
"doi": "",
"pmid": "20588251.0",
"pmcid": "",
"abstract": "OBJECTIVE: Mitochondrial dysfunctions, impaired bioenergetics and dysfunction of neurotrophins are included in many neurodegenerative and psychiatric diseases. We investigated in vitro effects of pharmacologically different antidepressants and mood stabilizers on mitochondrial enzymes to discover, which mitochondrial functions could be involved in pathophysiology of mood disorders. METHODS: In vitro effects of eight pharmacologically different antidepressants (desipramine, amitriptyline, imipramine, citalopram, venlafaxine, mirtazapine, tianeptine, and moclobemide) and three mood stabilizers (lithium, valproate, and olanzapine) on the activities of mitochondrial enzymes (citrate synthase and enzymes in electron transport chain, i.e. complexes I, II, IV) were measured in crude mitochondrial fraction isolated from pig brain. RESULTS: Most of the antidepressants and mood stabilizers inhibited the activities of respiratory electron transport chain complexes, complexes I and IV were the most affected. Statistically significant decrease of the complex I activity was caused by desipramine, amitriptyline, imipramine, citalopram, mirtazapine, valproate and olanzapine. Complex II was significantly inhibited only by amitriptyline, imipramine, citalopram and venlafaxine. Complex IV was significantly inhibited by all tested drugs except for citalopram and moclobemide. Unchanged or slightly increased citrate synthase activity was observed; significant activation of the enzyme was observed after citalopram, tianeptine and olanzapine. CONCLUSIONS: Our results indicate that antidepressants may act generally as inhibitors of complex I and complex IV of the electron transport chain. These mitochondrial enzymes are suggested as proper candidates in searching of new biological markers of mood disorders, targets of new antidepressants or predictors of response to pharmacotherapy.",
"references": [
"RC01054",
"RC01053",
"RC01052"
]
},
{
"pap_id": "63",
"title": "",
"authors": "",
"chapter": "",
"pages": "",
"journal": "",
"pub_date": "",
"pub_year": 1900,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "",
"doi": "",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": []
},
{
"pap_id": "64",
"title": "Role of mitochondrial permeability transition in human renal tubular epithelial cell death induced by aristolochic acid.",
"authors": "Qi, Xinming; Cai, Yan; Gong, Likun; Liu, Linlin; Chen, Fangping; Xiao, Ying; Wu, Xiongfei; Li, Yan; Xue, Xiang; Ren, Jin",
"chapter": "",
"pages": "105-110",
"journal": "Toxicology and Applied Pharmacology",
"pub_date": "2007-07-01",
"pub_year": 2007,
"volume": "222",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.taap.2007.03.029",
"doi": "10.1016/j.taap.2007.03.029",
"pmid": "17521691.0",
"pmcid": "",
"abstract": "Aristolochic acid (AA), a natural nephrotoxin and carcinogen, can induce a progressive tubulointerstitial nephropathy. However, the mechanism by which AA causes renal injury remains largely unknown. Here we reported that the mitochondrial permeability transition (MPT) plays an important role in the renal injury induced by aristolochic acid I (AAI). We found that in the presence of Ca(2+), AAI caused mitochondrial swelling, leakage of Ca(2+), membrane depolarization, and release of cytochrome c in isolated kidney mitochondria. These alterations were suppressed by cyclosporin A (CsA), an agent known to inhibit MPT. Culture of HK-2 cell, a human renal tubular epithelial cell line for 24 h with AAI caused a decrease in cellular ATP, mitochondrial membrane depolarization, cytochrome c release, and increase of caspase 3 activity. These toxic effects of AAI were attenuated by CsA and bongkrekic acid (BA), another specific MPT inhibitor. Furthermore, AAI greatly inhibited the activity of mitochondrial adenine nucleotide translocator (ANT) in isolated mitochondria. We suggested that ANT may mediate, at least in part, the AAI-induced MPT. Taken together, these results suggested that MPT plays a critical role in the pathogenesis of HK-2 cell injury induced by AAI and implied that MPT might contribute to human nephrotoxicity of aristolochic acid.",
"references": [
"RC01057"
]
},
{
"pap_id": "65",
"title": "Effects of indomethacin on energy metabolism in rat and human jejunal tissue in vitro.",
"authors": "Jacob, M; Bjarnason, I; Simpson, R J",
"chapter": "",
"pages": "493-498",
"journal": "Clinical Science",
"pub_date": "2001-11-01",
"pub_year": 2001,
"volume": "101",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/cs1010493",
"doi": "10.1042/cs1010493",
"pmid": "11672454.0",
"pmcid": "",
"abstract": "Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause enteropathy, but the mechanism by which this toxicity occurs is less well established. This paper sets out to test the hypothesis that these drugs affect oxidative phosphorylation in jejunal tissue, thereby interfering with energy metabolism and rendering the tissue vulnerable to damage. Jejunal tissue obtained from rats and humans was used for in vitro determinations of oxygen uptake, lactate production and energy charge levels in the presence of indomethacin, a commonly used NSAID. In the rat jejunal tissue, drug concentrations of 0.5 mM and 2.5 mM produced significant decreases in oxygen uptake (P< 0.01) and energy charge levels in the tissue (P< 0.05). There was a corresponding increase in lactate production by the tissue at these indomethacin concentrations (P< 0.05). Rat jejunum examined by electron microscopy after incubation with various concentrations of indomethacin showed ultrastructural effects of the drug on mitochondrial morphology. In human tissue, an inhibitory effect of indomethacin on oxygen uptake was seen, but the effects on lactate production and energy charge were less conclusive. These findings suggest that indomethacin affects mitochondria and thereby impairs energy metabolism in jejunal tissue.",
"references": [
"RC01059",
"RC01058"
]
},
{
"pap_id": "66",
"title": "Effect of ochratoxin A on rat liver mitochondrial respiration and oxidative phosphorylation",
"authors": "Wei, Y; Lu, C; Lin, T; Wei, R",
"chapter": "",
"pages": "119-130",
"journal": "Toxicology",
"pub_date": "1985-08-01",
"pub_year": 1985,
"volume": "36",
"issue": "2-3",
"Issn": "0300483X",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0300483X85900460",
"doi": "10.1016/0300-483X(85)90046-0",
"pmid": "",
"pmcid": "",
"abstract": "The in vitro effects of ochratoxin A on the membrane structure and bioenergetic functions of rat liver mitochondria were studied. It was found that when the toxin was added to the assay medium the respiratory control of the isolated mitochondria was decreased as the concentration of the toxin increased. The mitochondrial respiration was gradually uncoupled by the toxin when its concentration was raised above 1.2 × 10−6 M, and became fully uncoupled at 6.2 × 10−4 M. The oxidative phosphorylation was not damaged until the toxin concentration was higher than 9.3 × 10−5 M. On the other hand, ochratoxin A inhibited the electron transfer functions of the mitochondria. At the concentration above 1.0 × 10−4 M, ochratoxin A inhibited the succinate dehydrogenase, succinate-cytochrome c reductase, and succinate oxidase activities of the respiratory chain. Fifty percent of succinate-cytochrome c reductase and succinate oxidase activity was lost in the presence of 8.0 × 10−4 and 6.2 × 10−4 M ochratoxin A, respectively. The inhibition kinetic studies revealed that ochratoxin A is an uncompetitive inhibitor of both succinate-cytochrome c reductase and succinate dehydrogenase, and the inhibition constants for the 2 enzyme activities were estimated to be 4.4 × 10−4 and 2.2 × 10−4 M, respectively. However, the toxin did not inhibit either cytochrome oxidase or NADH dehydrogenase activity of the mitochondrial respiratory chain. It is thus concluded that ochratoxin A exerts its effect on the mitochondrial respiration and oxidative phosphorylation through the impairment of the mitochondrial membrane and inhibition of the succinate-supported electron transfer activities of the respiratory chain.",
"references": [
"RC01061",
"RC01060"
]
},
{
"pap_id": "67",
"title": "On the effects of paraquat on isolated mitochondria. Evidence that paraquat causes opening of the cyclosporin A-sensitive permeability transition pore synergistically with nitric oxide.",
"authors": "Costantini, P; Petronilli, V; Colonna, R; Bernardi, P",
"chapter": "",
"pages": "77-88",
"journal": "Toxicology",
"pub_date": "1995-05-05",
"pub_year": 1995,
"volume": "99",
"issue": "1-2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0300-483X(94)02997-9",
"doi": "10.1016/0300-483X(94)02997-9",
"pmid": "7539163.0",
"pmcid": "",
"abstract": "This paper reports an investigation on the effects of the bipyridylium herbicide, paraquat, on rat liver mitochondria in vitro. We show that paraquat induces a Ca(2+)-dependent permeability increase of the inner mitochondrial membrane leading to membrane depolarization, uncoupling and matrix swelling. The permeability increase is not observed in the absence of Ca2+ accumulation, and is not due to a direct effect of paraquat on the membrane energy level, as assessed by measurements of membrane potential, respiration and mitochondrial permeability to solutes at high concentrations of paraquat in the presence of excess ethylene-bis(oxoethylenenitrilo)tetraacetic acid (EGTA), a Ca2+ chelator. The Ca(2+)-dependent permeability increase is due to inappropriate opening of the endogenous permeability transition pore (MTP), a regulated, voltage-dependent channel of the inner mitochondrial membrane. The pore is primarily affected by paraquat through a shift of the gating potential to more negative values, allowing pore opening at physiological membrane potential. This effect apparently involves oxidation of a critical dithiol in the pore voltage sensor, while other regulatory aspects of the MTP (matrix pH and Ca2+) are unaffected by paraquat, which is not transported inside the mitochondrial matrix. The effects of paraquat on MTP opening depend on inhibition of electron transfer at Site I by rotenone, or by respiratory chain inhibition by nitric oxide, one of the proposed endogenous mediators of paraquat toxicity to the lung (Berisha, H.I., Hedayatollah, P., Absood, A., and Said, S.I. (1994) Proc. Natl. Acad. Sci. USA 91, 7445-7449). Taken together, these data provide an additional biochemical mechanism by which paraquat may affect cell function, and support the idea that mitochondrial damage is an important determinant in paraquat toxicity (Hirai, K.-I., Ikeda, K., and Wang, G.-Y. (1992) Toxicology 72, 1-16).",
"references": [
"RC01064",
"RC01063",
"RC01062"
]
},
{
"pap_id": "68",
"title": "Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.",
"authors": "Simon, Nicolas; Morin, Christophe; Urien, Saïk; Tillement, Jean-Paul; Bruguerolle, Bernard",
"chapter": "",
"pages": "369-376",
"journal": "British Journal of Pharmacology",
"pub_date": "2003-01-01",
"pub_year": 2003,
"volume": "138",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/sj.bjp.0705038",
"doi": "10.1038/sj.bjp.0705038",
"pmid": "12540528.0",
"pmcid": "PMC1573667",
"abstract": "1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.",
"references": [
"RC01065"
]
}
]
}
