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"count": 334,
"next": "https://mitotox.org/api/papers/list?format=api&page=3",
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"results": [
{
"pap_id": "19",
"title": "Inhibitory effects of some cyclohexylaralkylamines related to perhexiline on sodium influx, binding of [3H]batrachotoxinin A 20-alpha-benzoate and [3H]nitrendipine and on guinea pig left atria contractions.",
"authors": "Grima, M; Velly, J; Decker, N; Marciniak, G; Schwartz, J",
"chapter": "",
"pages": "173-185",
"journal": "European Journal of Pharmacology",
"pub_date": "1988-03-01",
"pub_year": 1988,
"volume": "147",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0014-2999(88)90776-5",
"doi": "10.1016/0014-2999(88)90776-5",
"pmid": "3366174.0",
"pmcid": "",
"abstract": "The antagonist activities of some cyclohexylaralkylamines derived from perhexiline on the fast Na+ channel and slow Ca2+ channel in rat brain and rat heart were examined and compared to the antagonist activities of nifedipine, verapamil, prenylamine and perhexiline. Prenylamine, perhexiline and the cyclohexylaralkylamine derivatives inhibited the [3H]batrachotoxinin A 20-alpha-benzoate binding more than the [3H]nitrendipine binding in rat brain. The nature of the interaction of the cyclohexylaralkylamines with the binding of [3H]batrachotoxinin and [3H]nitrendipine was non-competitive. The synaptosomal 22Na uptake induced by protoveratrine B, a Na+ channel agonist, was also inhibited. Prenylamine, perhexiline and perhexiline derivatives were more potent on the fast Na+ channel than on the Ca2+ channel in contrast to nifedipine and verapamil. The inhibition of Na+ and Ca2+ channels was also shown in guinea pig left atria. Perhexiline, prenylamine and the perhexiline derivatives inhibited the protoveratrine B-induced contraction more than they inhibited that induced by CaCl2, in contrast with nifedipine and verapamil. Our results showed that prenylamine, perhexiline and its related cyclohexylaralkylamines inhibited the fast Na+ channel far more than the slow Ca2+ channel in rat brain, rat heart and guinea pig atria.",
"references": []
},
{
"pap_id": "190",
"title": "State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate.",
"authors": "Jabo\u0001rek, M; Yarov-Yarovoy, V; Paucek, P; Garlid, K D",
"chapter": "",
"pages": "13578-13582",
"journal": "The Journal of Biological Chemistry",
"pub_date": "1998-05-29",
"pub_year": 1998,
"volume": "273",
"issue": "22",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/9593694",
"doi": "",
"pmid": "9593694.0",
"pmcid": "",
"abstract": "The mitochondrial KATP channel (mitoKATP) is hypothesized to be the receptor for the cardioprotective effects of K+ channel openers (KCO) and for the blocking of cardioprotection by glyburide and 5-hydroxydecanoate (5-HD). Studies on glyburide have indicated that this drug is inactive in isolated mitochondria. No studies of the effects of 5-HD on isolated mitochondria have been reported. This paper examines the effects of glyburide and 5-HD on K+ flux in isolated, respiring mitochondria. We show that mitoKATP is completely insensitive to glyburide and 5-HD under the experimental conditions in which the open state of the channel is induced by the absence of ATP and Mg2+. On the other hand, mitoKATP became highly sensitive to glyburide and 5-HD when the open state was induced by Mg2+, ATP, and a physiological opener, such as GTP, or a pharmacological opener, such as diazoxide. In these open states, glyburide (K1/2 values 1-6 microM) and 5-HD (K1/2 values 45-75 microM) inhibited specific, mitoKATP-mediated K+ flux in both heart and liver mitochondria from rat. These results are consistent with a role for mitoKATP in cardioprotection and show that different open states of mitoKATP, although catalyzing identical K+ fluxes, exhibit very different susceptibilities to channel inhibitors.",
"references": [
"RC03477",
"RC03476"
]
},
{
"pap_id": "191",
"title": "Inhibition of mitochondrial ATPase by dicarbopolyborate, a new enzyme inhibitor.",
"authors": "Drahota, Z; Mares, V; Rauchov?, H; Saf, P; Kalous, M",
"chapter": "",
"pages": "583-586",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "1994-10-01",
"pub_year": 1994,
"volume": "26",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/BF00762743",
"doi": "10.1007/BF00762743",
"pmid": "7896773.0",
"pmcid": "",
"abstract": "Polyborate anions were found to inhibit mitochondrial ATPase. Mercapto and chloro derivatives of dicarbononaborates showed full inhibition of the enzyme activity at 0.5-0.8 mM. The inhibitory effect of dodecaborates was lower. The inhibition was of competitive type with respect to ATP. The inhibition of soluble F1-ATPase indicates a direct interaction of the polyborate anion with the catalytic part of the enzyme molecule.",
"references": []
},
{
"pap_id": "192",
"title": "Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase).",
"authors": "Miyadera, Hiroko; Shiomi, Kazuro; Ui, Hideaki; Yamaguchi, Yuichi; Masuma, Rokuro; Tomoda, Hiroshi; Miyoshi, Hideto; Osanai, Arihiro; Kita, Kiyoshi; Omura, Satoshi",
"chapter": "",
"pages": "473-477",
"journal": "Proceedings of the National Academy of Sciences of the United States of America",
"pub_date": "2003-01-21",
"pub_year": 2003,
"volume": "100",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1073/pnas.0237315100",
"doi": "10.1073/pnas.0237315100",
"pmid": "12515859.0",
"pmcid": "PMC141019",
"abstract": "Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues.",
"references": [
"RC03576",
"RC03575",
"RC03574",
"RC03573"
]
},
{
"pap_id": "193",
"title": "Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.",
"authors": "Deschamps, D; DeBeco, V; Fisch, C; Fromenty, B; Guillouzo, A; Pessayre, D",
"chapter": "",
"pages": "948-961",
"journal": "Hepatology",
"pub_date": "1994-04-01",
"pub_year": 1994,
"volume": "19",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/8138270",
"doi": "",
"pmid": "8138270.0",
"pmcid": "",
"abstract": "In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.",
"references": [
"RC00811",
"RC00812",
"RC00813",
"RC00814",
"RC00815",
"RC00816",
"RC00817",
"RC00818",
"RC00819",
"RC00820",
"RC00821",
"RC00824",
"RC00825",
"RC00826",
"RC00827",
"RC00828",
"RC00829",
"RC00830",
"RC00831",
"RC00832",
"RC00833",
"RC00834",
"RC00835",
"RC00836",
"RC00838",
"RC00840",
"RC00841",
"RC00842",
"RC00843",
"RC00844",
"RC00845",
"RC00846",
"RC00847",
"RC00848",
"RC00849",
"RC00850",
"RC00851",
"RC00852",
"RC00853",
"RC00854",
"RC00855",
"RC00856",
"RC00857",
"RC00858",
"RC00859",
"RC00860",
"RC00861",
"RC00862",
"RC00863",
"RC00864"
]
},
{
"pap_id": "194",
"title": "Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance.",
"authors": "Young, Matthew J",
"chapter": "",
"pages": "74",
"journal": "Frontiers in molecular biosciences",
"pub_date": "1905-07-09",
"pub_year": 1905,
"volume": "4",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.3389/fmolb.2017.00074",
"doi": "10.3389/fmolb.2017.00074",
"pmid": "29214156.0",
"pmcid": "PMC5702650",
"abstract": "Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat human immunodeficiency virus (HIV) the cause of acquired immunodeficiency syndrome. Development of severe mitochondrial toxicity has been well documented in patients infected with HIV and administered NRTIs. In vitro biochemical experiments have demonstrated that the replicative mitochondrial DNA (mtDNA) polymerase gamma, Polg, is a sensitive target for inhibition by metabolically active forms of NRTIs, nucleotide reverse transcriptase inhibitors (NtRTIs). Once incorporated into newly synthesized daughter strands NtRTIs block further DNA polymerization reactions. Human cell culture and animal studies have demonstrated that cell lines and mice exposed to NRTIs display mtDNA depletion. Further complicating NRTI off-target effects on mtDNA maintenance, two additional DNA polymerases, Pol beta and PrimPol, were recently reported to localize to mitochondria as well as the nucleus. Similar to Polg, in vitro work has demonstrated both Pol beta and PrimPol incorporate NtRTIs into nascent DNA. Cell culture and biochemical experiments have also demonstrated that antiviral ribonucleoside drugs developed to treat hepatitis C infection act as off-target substrates for POLRMT, the mitochondrial RNA polymerase and primase. Accompanying the above-mentioned topics, this review examines: (1) mtDNA maintenance in human health and disease, (2) reports of DNA polymerases theta and zeta (Rev3) localizing to mitochondria, and (3) additional drugs with off-target effects on mitochondrial function. Lastly, mtDNA damage may induce cell death; therefore, the possibility of utilizing compounds that disrupt mtDNA maintenance to kill cancer cells is discussed.",
"references": [
"RC03683",
"RC03682",
"RC03681",
"RC03680",
"RC03679",
"RC03678",
"RC03677",
"RC03676",
"RC03675",
"RC03674"
]
},
{
"pap_id": "195",
"title": "Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells.",
"authors": "Benbrik, E; Chariot, P; Bonavaud, S; Ammi-Sa?d, M; Frisdal, E; Rey, C; Gherardi, R; Barlovatz-Meimon, G",
"chapter": "",
"pages": "19-25",
"journal": "Journal of the Neurological Sciences",
"pub_date": "1997-07-01",
"pub_year": 1997,
"volume": "149",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/s0022-510x(97)05376-8",
"doi": "10.1016/s0022-510x(97)05376-8",
"pmid": "9168161.0",
"pmcid": "",
"abstract": "Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polymerase and cause termination of synthesis of growing mtDNA strands and mtDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human muscle biopsies, were exposed to various concentrations of AZT (4-5000 micromol/l), ddI (5-1000 micromol/l) and ddC (1-1000 micromol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipid droplet accumulation, lactate production and respiratory chain enzyme activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent inhibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic lipid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (complex I) and citrate sinthase activities were unchanged. Zalcitabine (ddC) and, to a lesser extent, ddI, were the most potent inhibitors of mitochondrial function. In conclusion, AZT, ddI and ddC all exert cytotoxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy in HIV-infected patients. AZT myopathy might not simply result from a direct mitochondrial toxic effect of crude AZT.",
"references": []
},
{
"pap_id": "196",
"title": "Zidovudine induces downregulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs.",
"authors": "Sun, Ren; Eriksson, Staffan; Wang, Liya",
"chapter": "",
"pages": "6758-6766",
"journal": "Antimicrobial Agents and Chemotherapy",
"pub_date": "2014-11-01",
"pub_year": 2014,
"volume": "58",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1128/AAC.03613-14",
"doi": "10.1128/AAC.03613-14",
"pmid": "25182642.0",
"pmcid": "PMC4249380",
"abstract": "Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs. Copyright ? 2014, American Society for Microbiology. All Rights Reserved.",
"references": [
"RC03578",
"RC03577"
]
},
{
"pap_id": "197",
"title": "Drug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences.",
"authors": "Vuda, Madhusudanarao; Kamath, Ashwin",
"chapter": "",
"pages": "63-74",
"journal": "Mitochondrion",
"pub_date": "2016-11-01",
"pub_year": 2016,
"volume": "31",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.mito.2016.10.005",
"doi": "10.1016/j.mito.2016.10.005",
"pmid": "27771494.0",
"pmcid": "",
"abstract": "Several commonly used medications impair mitochondrial function resulting in adverse effects or toxicities. Drug induced mitochondrial dysfunction may be a consequence of increased production of reactive oxygen species, altered mitochondrial permeability transition, impaired mitochondrial respiration, mitochondrial DNA damage or inhibition of beta-oxidation of fatty acids. The clinical manifestation depends on the specific drug and its effect on mitochondria. Given the ubiquitous presence of mitochondria and its central role in cellular metabolism, drug-mitochondrial interactions may manifest clinically as hepatotoxicity, enteropathy, myelosuppression, lipodystrophy syndrome or neuropsychiatric adverse effects, to name a few. The current review focuses on specific drug groups which adversely affect mitochondria, the mechanisms involved and the clinical consequences based on the data available from experimental and clinical studies. Knowledge of these adverse drug-mitochondrial interactions may help the clinicians foresee potential issues in individual patients, prevent adverse drug reactions or alter drug regimens to enhance patient safety. Copyright ? 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.",
"references": [
"RC03605",
"RC03606",
"RC03607",
"RC03608",
"RC03609",
"RC03610",
"RC03611",
"RC03612",
"RC03604",
"RC03613",
"RC03614",
"RC03615",
"RC03616",
"RC03617",
"RC03618",
"RC03619",
"RC03620",
"RC03621",
"RC03622",
"RC03623",
"RC03624",
"RC03625",
"RC03626",
"RC03627",
"RC03628",
"RC03629",
"RC03630",
"RC03631",
"RC03632",
"RC03633",
"RC03634",
"RC03635",
"RC03636",
"RC03637",
"RC03638",
"RC03639",
"RC03640",
"RC03641",
"RC03642",
"RC03643",
"RC03644",
"RC03645"
]
},
{
"pap_id": "198",
"title": "Aminooxyacetic acid inhibits the malate-aspartate shuttle in isolated nerve terminals and prevents the mitochondria from utilizing glycolytic substrates.",
"authors": "Kauppinen, R A; Sihra, T S; Nicholls, D G",
"chapter": "",
"pages": "173-178",
"journal": "Biochimica et Biophysica Acta",
"pub_date": "1987-09-14",
"pub_year": 1987,
"volume": "930",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0167-4889(87)90029-2",
"doi": "10.1016/0167-4889(87)90029-2",
"pmid": "3620514.0",
"pmcid": "",
"abstract": "Aminooxyacetate, an inhibitor of pyridoxal-dependent enzymes, is routinely used to inhibit gamma-aminobutyrate metabolism. The bioenergetic effects of the inhibitor on guinea-pig cerebral cortical synaptosomes are investigated. It prevents the reoxidation of cytosolic NADH by the mitochondria by inhibiting the malate-aspartate shuttle, causing a 26 mV negative shift in the cytosolic NAD+/NADH redox potential, an increase in the lactate/pyruvate ratio and an inhibition of the ability of the mitochondria to utilize glycolytic pyruvate. The 3-hydroxybutyrate/acetoacetate ratio decreased significantly, indicating oxidation of the mitochondrial NAD+/NADH couple. The results are consistent with a predominant role of the malate-aspartate shuttle in the reoxidation of cytosolic NADH in isolated nerve terminals. Aminooxyacetate limits respiratory capacity and lowers mitochondrial membrane potential and synaptosomal ATP/ADP ratios to an extent similar to glucose deprivation. Thus, the inhibitor induces a functional 'hypoglycaemia' in nerve terminals and should be used with caution.",
"references": [
"RC03482"
]
},
{
"pap_id": "199",
"title": "Bafilomycin A1 is a potassium ionophore that impairs mitochondrial functions.",
"authors": "Teplova, Vera V; Tonshin, Anton A; Grigoriev, Pavel A; Saris, Nils-Erik L; Salkinoja-Salonen, Mirja S",
"chapter": "",
"pages": "321-329",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "2007-08-01",
"pub_year": 2007,
"volume": "39",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s10863-007-9095-9",
"doi": "10.1007/s10863-007-9095-9",
"pmid": "17917797.0",
"pmcid": "",
"abstract": "Novel activities of bafilomycin A1, a macrolide antibiotic known as an inhibitor of V-ATPases, were discovered. Bafilomycin A1 induced uptake of potassium ions by energized mitochondria and caused mitochondrial swelling, loss of membrane potential, uncoupling of oxidative phosphorylation, inhibition of the maximal respiration rates, and induced pyridine nucleotide oxidation. The mitochondrial effects provoked by nanomolar concentrations of bafilomycin A1 were connected to its activity as a potent, K(+)-specific ionophore. The K(+) ionophoric activity of bafilomycin A1 was observed also in black lipid membranes, indicating that it was an inherent property of the bafilomycin A1 molecule. It was found that bafilomycin A1 is a K(+) carrier but not a channel former. Bafilomycin A1 is the first and currently unique macrolide antibiotic with K(+) ionophoric properties. The novel properties of bafilomycin A1 may explain some of the biological effects of this plecomacrolide antibiotic, independent of V-ATPase inhibition.",
"references": [
"RC03483"
]
},
{
"pap_id": "2",
"title": "Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells.",
"authors": "Raza, Haider; John, Annie; Benedict, Sheela",
"chapter": "",
"pages": "15-24",
"journal": "European Journal of Pharmacology",
"pub_date": "2011-10-01",
"pub_year": 2011,
"volume": "668",
"issue": "1-2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.ejphar.2011.06.016",
"doi": "10.1016/j.ejphar.2011.06.016",
"pmid": "21722632.0",
"pmcid": "",
"abstract": "It is widely accepted that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduce the risk of cancer. The anti-cancer and anti-inflammatory effects of NSAIDs are associated with the inhibition of prostaglandin synthesis and cyclooxygenase-2 activity. Several other mechanisms which contribute to the anti-cancer effect of these drugs in different cancer models both in vivo and in vitro are also presumed to be involved. The precise molecular mechanism, however, is still not clear. We investigated, therefore, the effects of acetylsalicylic acid (ASA, aspirin) on multiple cellular and functional targets, including mitochondrial bioenergetics, using human hepatoma HepG2 cancer cells in culture. Our results demonstrate that ASA induced G0/G1 cell cycle arrest and apoptosis in HepG2 cells. ASA increased the production of reactive oxygen species, reduced the cellular glutathione (GSH) pool and inhibited the activities of the mitochondrial respiratory enzyme complexes, NADH-ubiquinone oxidoreductase (complex I), cytochrome c oxidase (complex IV) and the mitochondrial matrix enzyme, aconitase. Apoptosis was triggered by alteration in mitochondrial permeability transition, inhibition of ATP synthesis, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c and activation of pro-apoptotic caspase-3 and the DNA repairing enzyme, poly (-ADP-ribose) polymerase (PARP). These findings strongly suggest that ASA-induced toxicity in human hepatoma HepG2 cells is mediated by increased metabolic and oxidative stress, accompanied by mitochondrial dysfunction which result in apoptosis. Copyright © 2011 Elsevier B.V. All rights reserved.",
"references": [
"RC00068",
"RC00067",
"RC00066",
"RC00065"
]
},
{
"pap_id": "20",
"title": "Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation.",
"authors": "Kennedy, Jennifer A; Beck-Oldach, Konstanz; McFadden-Lewis, Kate; Murphy, Geraldine A; Wong, Yee W; Zhang, Yi; Horowitz, John D",
"chapter": "",
"pages": "13-19",
"journal": "European Journal of Pharmacology",
"pub_date": "2006-02-15",
"pub_year": 2006,
"volume": "531",
"issue": "1-3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.ejphar.2005.11.058",
"doi": "10.1016/j.ejphar.2005.11.058",
"pmid": "16413015.0",
"pmcid": "",
"abstract": "The prophylactic anti-anginal agent, perhexiline, may also be effective in acute coronary syndromes and advanced aortic valvular stenosis, conditions associated with enhanced inflammation. Its potential effects on superoxide formation via NADPH oxidase were measured by lucigenin-mediated chemiluminescence. Perhexiline inhibited superoxide formation in intact neutrophils stimulated with formyl Met Leu Phe (fMLP) 4 muM or with phorbol myristate acetate (PMA) 162 nM - IC50 2.3 microM (1.5-3.6), n=4. Sub-unit assembly of NADPH oxidase by PMA was unaffected by pretreatment with perhexiline 2 microM, a concentration which reduced superoxide formation by 44+/-5% (n=4) in intact neutrophils. Perhexiline inhibited preassembled neutrophil NADPH oxidase and that in membranes of pig valve interstitial cells, human umbilical vein endothelial cells (HUVECs) and cardiac fibroblasts, but not that in rat aorta (rings or membrane preparations). These data imply that perhexiline inhibits the phagocytic NADPH oxidase directly, and that pig aortic valvular interstitial cells possess a similar enzyme, a conclusion supported by immunohistochemical localisation of the gp91phox subunit in these cells. However further study is required to clarify the effect of perhexiline on different NADPH oxidase isoforms particularly in the vasculature.",
"references": [
"RC00880"
]
},
{
"pap_id": "200",
"title": "Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia.",
"authors": "Yuan, Na; Song, Lin; Zhang, Suping; Lin, Weiwei; Cao, Yan; Xu, Fei; Fang, Yixuan; Wang, Zhen; Zhang, Han; Li, Xin; Wang, Zhijian; Cai, Jinyang; Wang, Jian; Zhang, Yi; Mao, Xinliang; Zhao, Wenli; Hu, Shaoyan; Chen, Suning; Wang, Jianrong",
"chapter": "",
"pages": "345-356",
"journal": "Haematologica",
"pub_date": "2015-03-01",
"pub_year": 2015,
"volume": "100",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.3324/haematol.2014.113324",
"doi": "10.3324/haematol.2014.113324",
"pmid": "25512644.0",
"pmcid": "PMC4349273",
"abstract": "B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia. Copyright? Ferrata Storti Foundation.",
"references": [
"RC03486",
"RC03485",
"RC03484"
]
},
{
"pap_id": "201",
"title": "Bioenergetics",
"authors": "Nicholls, David",
"chapter": "",
"pages": "",
"journal": "",
"pub_date": "1905-07-05",
"pub_year": 1905,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://www.elsevier.com/books/bioenergetics/nicholls/978-0-12-388425-1",
"doi": "",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03494",
"RC03493",
"RC03492",
"RC03491",
"RC03490",
"RC03489",
"RC03488",
"RC03487"
]
},
{
"pap_id": "202",
"title": "Cation transport and specificity of ionomycin. Comparison with ionophore A23187 in rat liver mitochondria.",
"authors": "Kauffman, R F; Taylor, R W; Pfeiffer, D R",
"chapter": "",
"pages": "2735-2739",
"journal": "The Journal of Biological Chemistry",
"pub_date": "1980-04-10",
"pub_year": 1980,
"volume": "255",
"issue": "7",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/6766939",
"doi": "",
"pmid": "6766939.0",
"pmcid": "",
"abstract": "Based on the effects of ionomycin upon mitochondrial respiration, ionomycin was shown to be an effective ionophore for Ca2+ in rat liver mitochondria. The ionomycin-induced efflux of Ca2+ across the inner membrane was more sensitive to loading the mitochondria with Ca2+ than was efflux catalyzed by A23187. At saturating concentrations of Ca2+, the turnover number for ionomycin was 3- to 5-fold greater than that of A23187. Ionomycin catalyzed the efflux of mitochondrial Mg2+ at rates comparable to those observed with A23187. Ionomycin also mediated an efflux of K+ provided that the mitochondria were depleted of their endogenous divalent metal ions. The apparent turnover numbers for K+ efflux suggest that ionomycin is more specific for divalent metal ions than A23187.",
"references": [
"RC03496",
"RC03495"
]
},
{
"pap_id": "203",
"title": "Ionophore a23187: cation binding and transport properties",
"authors": "Pfeiffer, Douglas R.; Taylor, Richard W.; Lardy, Henry A.",
"chapter": "",
"pages": "402-423",
"journal": "Annals of the New York Academy of Sciences",
"pub_date": "1978-04-01",
"pub_year": 1978,
"volume": "307",
"issue": "1 Calcium Trans",
"Issn": "0077-8923",
"Isbn": "",
"url": "http://doi.wiley.com/10.1111/j.1749-6632.1978.tb41965.x",
"doi": "10.1111/j.1749-6632.1978.tb41965.x",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03497"
]
},
{
"pap_id": "204",
"title": "The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative phosphorylation.",
"authors": "Naven, Russell T; Swiss, Rachel; Klug-McLeod, Jacquelyn; Will, Yvonne; Greene, Nigel",
"chapter": "",
"pages": "271-278",
"journal": "Toxicological Sciences",
"pub_date": "2013-01-01",
"pub_year": 2013,
"volume": "131",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/toxsci/kfs279",
"doi": "10.1093/toxsci/kfs279",
"pmid": "22977170.0",
"pmcid": "",
"abstract": "Mitochondrial dysfunction has been implicated as an important factor in the development of idiosyncratic organ toxicity. An ability to predict mitochondrial dysfunction early in the drug development process enables the deselection of those drug candidates with potential safety liabilities, allowing resources to be focused on those compounds with the highest chance of success to the market. A database of greater than 2000 compounds was analyzed to identify structural and physicochemical features associated with the uncoupling of oxidative phosphorylation (herein defined as an increase in basal respiration). Many toxicophores associated with potent uncoupling activity were identified, and these could be divided into two main mechanistic classes, protonophores and redox cyclers. For the protonophores, potent uncoupling activity was often promoted by high lipophilicity and apparent stabilization of the anionic charge resulting from deprotonation of the protonophore. The potency of redox cyclers did not appear to be prone to variations in lipophilicity. Only 11 toxicophores were of sufficient predictive performance that they could be incorporated into a structural-alert model. Each alert was associated with one of three confidence levels (high, medium, and low) depending upon the lipophilicity-activity profile of the structural class. The final model identified over 68% of those compounds with potent uncoupling activity and with a value for specificity above 99%. We discuss the advantages and limitations of this approach and conclude that although structural alert methodology is useful for identifying toxicophores associated with mitochondrial dysfunction, they are not a replacement for the mitochondrial dysfunction assays in early screening paradigms.",
"references": [
"RC03498",
"RC03500",
"RC03501",
"RC03502",
"RC03503",
"RC03504",
"RC03505",
"RC03506",
"RC03507",
"RC03508",
"RC03509",
"RC03510",
"RC03511",
"RC03512",
"RC03513",
"RC03514",
"RC03515",
"RC03516",
"RC03517",
"RC03522",
"RC03523"
]
},
{
"pap_id": "205",
"title": "Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI).",
"authors": "Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honor?",
"chapter": "",
"pages": "93-102",
"journal": "Toxicology in Vitro",
"pub_date": "2016-03-01",
"pub_year": 2016,
"volume": "31",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2015.11.020",
"doi": "10.1016/j.tiv.2015.11.020",
"pmid": "26627130.0",
"pmcid": "",
"abstract": "Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 ? 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 ? 2.48 ?M with Kinact/KI ratio of 0.343 min(-1) ?M(-1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis. Copyright ? 2015 Elsevier Ltd. All rights reserved.",
"references": []
},
{
"pap_id": "206",
"title": "Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria.",
"authors": "Syed, Muzeeb; Skonberg, Christian; Hansen, Steen Honor?",
"chapter": "",
"pages": "26-40",
"journal": "Toxicology in Vitro",
"pub_date": "2016-04-01",
"pub_year": 2016,
"volume": "32",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tiv.2015.12.003",
"doi": "10.1016/j.tiv.2015.12.003",
"pmid": "26689325.0",
"pmcid": "",
"abstract": "Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC50: 6.48 ? 2.74 ?M)>celecoxib (IC50: 14.92 ? 6.40 ?M)>valdecoxib (IC50: 161.4 ? 28.6 ?M)>rofecoxib (IC50: 238.4 ? 79.2 ?M)>etoricoxib (IC50: 405.1 ? 116.3 ?M). Mechanism based inhibition of ATP synthesis (Kinact 0.078 min(-1) and KI 21.46 ?M and Kinact/KI ratio 0.0036 min(-1)?M(-1)) was shown by lumiracoxib and data suggest that the opening of the MPT pore may not be the mechanism of toxicity. A positive correlation (with r(2)=0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs and these metabolites did not alter the inhibition profile of ATP synthesis of the parent compound. The results suggest that coxibs themselves could be involved in the hepatotoxic action through inhibition of ATP synthesis. Copyright ? 2015 Elsevier B.V. All rights reserved.",
"references": []
},
{
"pap_id": "207",
"title": "Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs",
"authors": "Moreno-S?nchez, Rafael; Bravo, Concepci?n; V?squez, C?sar; Ayala, Guadalupe; Silveira, Luis H; Mart1\u0001\u0001\u0003nez-Lav1\u0001\u0001\u0003n, Manuel",
"chapter": "",
"pages": "743-752",
"journal": "Biochemical Pharmacology",
"pub_date": "1999-04-01",
"pub_year": 1999,
"volume": "57",
"issue": "7",
"Issn": "62952",
"Isbn": "",
"url": "http://linkinghub.elsevier.com/retrieve/pii/S000629529800330X",
"doi": "10.1016/S0006-2952(98)00330-X",
"pmid": "",
"pmcid": "",
"abstract": "The effects of the anti-inflammatory drugs diclofenac, piroxicam, indomethacin, naproxen, nabumetone, nimesulide, and meloxicam on mitochondrial respiration, ATP synthesis, and membrane potential were determined. Except for nabumetone and naproxen, the other drugs stimulated basal and uncoupled respiration, inhibited ATP synthesis, and collapsed membrane potential in mitochondria incubated in the presence of either glutamate + malate or succinate. Plots of membrane potential versus ATP synthesis (or respiration) showed proportional variations in both parameters, induced by different concentrations of nimesulide, meloxicam, piroxicam, or indomethacin, but not by diclofenac. The activity of the adenine nucleotide translocase was blocked by diclofenac and nimesulide; diclofenac also slightly inhibited mitochondrial ATPase activity. Naproxen did not affect any of the mitochondrial parameters measured. Nabumetone inhibited respiration, ATP synthesis, and membrane potential in the presence of glutamate + malate, but not with succinate. NADH oxidation in submitochondrial particles also was inhibited by nabumetone. Nabumetone inhibited O2 uptake in intact cells and in whole heart, whereas the other five drugs stimulated respiration. These observations revealed that in situ mitochondria are an accessible target. Except for diclofenac, a negative inotropic effect on cardiac contractility was induced by the drugs. The data indicated that nimesulide, meloxicam, piroxicam, and indomethacin behaved as mitochondrial uncouplers, whereas nabumetone exerted a specific inhibition of site 1 of the respiratory chain. Diclofenac was an uncoupler too, but it also affected the adenine nucleotide translocase and the H+-ATPase.",
"references": []
},
{
"pap_id": "208",
"title": "Chloramphenicol-induced mitochondrial dysfunction is associated with decreased transferrin receptor expression and ferritin synthesis in K562 cells and is unrelated to IRE-IRP interactions.",
"authors": "Leiter, L M; Thatte, H S; Okafor, C; Marks, P W; Golan, D E; Bridges, K R",
"chapter": "",
"pages": "334-344",
"journal": "Journal of Cellular Physiology",
"pub_date": "1999-09-01",
"pub_year": 1999,
"volume": "180",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/(SICI)1097-4652(199909)180:3<334::AID-JCP4>3.0.CO;2-Q",
"doi": "10.1002/(SICI)1097-4652(199909)180:3<334::AID-JCP4>3.0.CO;2-Q",
"pmid": "10430173.0",
"pmcid": "",
"abstract": "Chloramphenicol is an antibiotic that consistently suppresses the bone marrow and induces sideroblastic anemia. It is also a rare cause of aplastic anemia. These toxicities are thought to be related to mitochondrial dysfunction, since chloramphenicol inhibits mitochondrial protein synthesis. We hypothesized that chloramphenicol-induced mitochondrial impairment alters the synthesis of ferritin and the transferrin receptor. After treating K562 erythroleukemia cells with a therapeutic dose of chloramphenicol (10 microg/ml) for 4 days, there was a marked decrease in cell surface transferrin receptor expression and de novo ferritin synthesis associated with significant decreases in cytochrome c oxidase activity, ATP levels, respiratory activity, and cell growth. Decreases in the transferrin receptor and ferritin were associated with reduced and unchanged message levels, respectively. The mechanism by which mitochondrial dysfunction alters these important proteins in iron homeostasis is not clear. A global decrease in synthetic processes seems unlikely, since the expression of the cellular adhesion proteins VLA4 and CD58 was not significantly decreased by chloramphenicol, nor were the message levels of beta-actin or ferritin. The alterations were not accompanied by changes in binding of the iron response protein (IRP) to the iron-responsive element (IRE), although cytosolic aconitase activity was reduced by 27% in chloramphenicol-treated cells. A disturbance in iron homeostasis due to alterations in the transferrin receptor and ferritin may explain the hypochromic-microcytic anemia and the accumulation of nonferritin iron in the mitochondria in some individuals after chloramphenicol therapy. Also, these studies provide evidence of a link between mitochondrial impairment and iron metabolism in K562 cells.",
"references": []
},
{
"pap_id": "209",
"title": "The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin.",
"authors": "Berson, Alain; Cazanave, Sophie; Descatoire, V?ronique; Tinel, Marina; Grodet, Alain; Wolf, Claude; Feldmann, G?rard; Pessayre, Dominique",
"chapter": "",
"pages": "444-454",
"journal": "The Journal of Pharmacology and Experimental Therapeutics",
"pub_date": "2006-07-01",
"pub_year": 2006,
"volume": "318",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1124/jpet.106.104125",
"doi": "10.1124/jpet.106.104125",
"pmid": "16617166.0",
"pmcid": "",
"abstract": "Like other nonsteroidal anti-inflammatory drugs, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide) triggers hepatitis in a few recipients. Although nimesulide has been shown to uncouple mitochondrial respiration and cause hepatocyte necrosis in the absence of albumin, mechanisms for cell death are incompletely understood, and comparisons with human concentrations are difficult because 99% of nimesulide is albumin-bound. We studied the effects of nimesulide, with or without a physiological concentration of albumin, in isolated rat liver mitochondria or microsomes and in human hepatoma cells. Nimesulide did not undergo monoelectronic nitro reduction in microsomes. In mitochondria incubated without albumin, nimesulide (50 microM) decreased the mitochondrial membrane potential (DeltaPsim), increased basal respiration, and potentiated the mitochondrial permeability transition (MPT) triggered by calcium preloading. In HUH-7 cells incubated for 24 h without albumin, nimesulide (1 mM) decreased the DeltaPsim and cell NADPH and increased the glutathione disulfide/reduced glutathione ratio and cell peroxides; nimesulide triggered MPT, ATP depletion, high cell calcium, and caused mostly necrosis, with rare apoptotic cells. Coincubation with either cyclosporin A (an MPT inhibitor) or the combination of fructose-1,6-diphosphate (a glycolysis substrate) and oligomycin (an ATPase inhibitor) prevented the decrease in DeltaPsim, ATP depletion, and cell death. A physiological concentration of albumin abolished the effects of nimesulide on isolated mitochondria or HUH-7 cells. In conclusion, the weak acid, nimesulide, uncouples mitochondria and triggers MPT and ATP depletion in isolated mitochondria or hepatoma cells incubated without albumin. However, in the presence of albumin, only a fraction of the drug enters cells or organelles, and uncoupling and toxicity are not observed.",
"references": []
},
{
"pap_id": "21",
"title": "Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain.",
"authors": "García-Ruiz, Inmaculada; Solís-Muñoz, Pablo; Fernández-Moreira, Daniel; Muñoz-Yagüe, Teresa; Solís-Herruzo, José A",
"chapter": "",
"pages": "1900-03-28",
"journal": "BMC Biology",
"pub_date": "2013-08-01",
"pub_year": 2013,
"volume": "11",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1186/1741-7007-11-88",
"doi": "10.1186/1741-7007-11-88",
"pmid": "23915000.0",
"pmcid": "PMC3751493",
"abstract": "BACKGROUND: Thiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class of antidiabetic agents, decreases the activity of the MRC. In isolated mitochondria from mouse liver, we measured the effects of PGZ treatment on MRC complex activities, fully-assembled complex I and its subunits, gene expression of complex I and III subunits, and [3H]PGZ binding to mitochondrial complexes. RESULTS: In vitro, PGZ decreased activity of complexes I and III of the MRC, but in vivo only complex I activity was decreased in mice treated for 12 weeks with 10 mg/kg/day of PGZ. In vitro treatment of isolated liver mitochondria with PGZ disassembled complex I, resulting in the formation of several subcomplexes. In mice treated with PGZ, fully assembled complex I was increased and two additional subcomplexes were found. Formation of supercomplexes CI+CIII2+CIVn and CI+CIII2 decreased in mouse liver mitochondria exposed to PGZ, while formation of these supercomplexes was increased in mice treated with PGZ. Two-dimensional analysis of complex I using blue native/sodium dodecyl sulfate polyacrylamide gel electrophoresis (BN/SDS-PAGE) showed that in vitro PGZ induced the formation of four subcomplexes of 600 (B), 400 (C), 350 (D), and 250 (E) kDa, respectively. Subcomplexes B and C had NADH:dehydrogenase activity, while subcomplexes C and D contained subunits of complex I membrane arm. Autoradiography and coimmunoprecipitation assays showed [3H]PGZ binding to subunits NDUFA9, NDUFB6, and NDUFA6. Treatment with PGZ increased mitochondrial gene transcription in mice liver and HepG2 cells. In these cells, PGZ decreased intracellular ATP content and enhanced gene expression of specific protein 1 and peroxisome-proliferator activated receptor (PPAR)γ coactivator 1α (PGC-1α). CONCLUSIONS: PGZ binds complex I subunits, which induces disassembly of this complex, reduces its activity, depletes cellular ATP, and, in mice and HepG2 cells, upregulates nuclear DNA-encoded gene expression of complex I and III subunits.",
"references": [
"RC00881"
]
},
{
"pap_id": "210",
"title": "Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat.",
"authors": "Somasundaram, S; Sigthorsson, G; Simpson, R J; Watts, J; Jacob, M; Tavares, I A; Rafi, S; Roseth, A; Foster, R; Price, A B; Wrigglesworth, J M; Bjarnason, I",
"chapter": "",
"pages": "639-650",
"journal": "Alimentary Pharmacology & Therapeutics",
"pub_date": "2000-05-01",
"pub_year": 2000,
"volume": "14",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1046/j.1365-2036.2000.00723.x",
"doi": "10.1046/j.1365-2036.2000.00723.x",
"pmid": "10792129.0",
"pmcid": "",
"abstract": "BACKGROUND: The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation. AIMS: To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat. METHODS: We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a 'topical' effect and (iii) the two together, using (iv) indomethacin as a positive control. RESULTS: Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin. CONCLUSIONS: These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.",
"references": []
},
{
"pap_id": "211",
"title": "Mitochondrial Toxicity Associated with Linezolid",
"authors": "Soriano, Alex; Mir?, Oscar; Mensa, Josep",
"chapter": "",
"pages": "2305-2306",
"journal": "The New England Journal of Medicine",
"pub_date": "2005-11-24",
"pub_year": 2005,
"volume": "353",
"issue": "21",
"Issn": "0028-4793",
"Isbn": "",
"url": "http://www.nejm.org/doi/abs/10.1056/NEJM200511243532123",
"doi": "10.1056/NEJM200511243532123",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": []
},
{
"pap_id": "212",
"title": "The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro effects of cephaloglycin and imipenem.",
"authors": "Tune, B M; Hsu, C Y",
"chapter": "",
"pages": "815-821",
"journal": "Journal of the American Society of Nephrology",
"pub_date": "1990-11-01",
"pub_year": 1990,
"volume": "1",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/2133431",
"doi": "",
"pmid": "2133431.0",
"pmcid": "",
"abstract": "The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.",
"references": []
},
{
"pap_id": "213",
"title": "Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics.",
"authors": "Elmorsy, Ekramy; Smith, Paul A",
"chapter": "",
"pages": "857-862",
"journal": "Biochemical and Biophysical Research Communications",
"pub_date": "2015-05-08",
"pub_year": 2015,
"volume": "460",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.bbrc.2015.03.122",
"doi": "10.1016/j.bbrc.2015.03.122",
"pmid": "25824037.0",
"pmcid": "",
"abstract": "Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III. Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically. Copyright ? 2015 Elsevier Inc. All rights reserved.",
"references": []
},
{
"pap_id": "214",
"title": "Role of uncoupling protein 1 in the anti-obesity effect of beta3-adrenergic agonist in the dog.",
"authors": "Omachi, A; Matsushita, Y; Kimura, K; Saito, M",
"chapter": "",
"pages": "214-219",
"journal": "Research in veterinary science",
"pub_date": "2008-10-01",
"pub_year": 2008,
"volume": "85",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.rvsc.2007.11.003",
"doi": "10.1016/j.rvsc.2007.11.003",
"pmid": "18406437.0",
"pmcid": "",
"abstract": "We have reported that chronic treatment with beta3-adrenoceptor agonists reduces body fat content and induces the expression of mitochondrial thermogenic uncoupling protein 1 (UCP1) in adipose tissue in the dog. To evaluate the role of UCP1 in the anti-obesity effect of the agonists, we isolated adipocytes from subcutaneous fat pad of beagles before and after a 2-week treatment with AJ-9677, a specific beta3-adrenoceptor agonist, and examined their thermogenic activity in vitro. Histological and protein analysis revealed that adipose tissues before the treatment were composed of unilocular cells filled with a single large droplet, while the tissues after the treatment contained many smaller and some multilocular adipocytes expressing UCP1 and abundant mitochondrial proteins. Before the treatment, oxygen consumption rate was very low and did not change even when the cells were stimulated by AJ-9677. Two-week AJ-9677 treatment increased basal oxygen consumption rate by 7-fold, and produced a clear responsiveness to AJ-9677 stimulation. Thus, chronic treatment with AJ-9677 induced UCP1 in adipocytes, where oxygen consumption increased in response to AJ-9677 stimulation. It was suggested that UCP1-dependent energy expenditure in adipose tissue contributes to the anti-obesity effect of beta3-adrenoceptor agonist in dogs.",
"references": [
"RC03499"
]
},
{
"pap_id": "215",
"title": "Serotonin stimulates mitochondrial transport in hippocampal neurons.",
"authors": "Chen, Sigeng; Owens, Geoffrey C; Crossin, Kathryn L; Edelman, David B",
"chapter": "",
"pages": "472-483",
"journal": "Molecular and Cellular Neurosciences",
"pub_date": "2007-12-01",
"pub_year": 2007,
"volume": "36",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.mcn.2007.08.004",
"doi": "10.1016/j.mcn.2007.08.004",
"pmid": "17904380.0",
"pmcid": "",
"abstract": "Axonal transport of mitochondria is critical for proper neuronal function. However, little is known about the extracellular signals that regulate this process. In the present study, we show that the neuromodulator serotonin (5-HT) greatly enhances mitochondrial movement in the axons of rat hippocampal neurons in vitro. Administration of a 5-HT1A receptor antagonist inhibited mitochondrial movement, whereas addition of fluoxetine, a selective serotonin reuptake inhibitor, promoted mitochondrial movement. 5-HT receptors are known to activate the Akt/Protein kinase B pathway. Consistent with this, directional mitochondrial movement was almost completely blocked by a specific Akt inhibitor. Moreover, an inhibitor of glycogen synthase kinase-3beta (GSK3beta), a kinase whose activity is blocked by Akt-mediated phosphorylation, promoted mitochondrial movement. These findings show that 5-HT1A receptor activation stimulates mitochondrial movement in hippocampal neurons by inhibiting GSK3beta activity via Akt. Our findings suggest that 5-HT may mediate the redistribution of energy sources within responsive neurons, a possibility that has significant implications for understanding the global biological effects of this important neuromodulator.",
"references": [
"RC03588",
"RC03587",
"RC03586",
"RC03585",
"RC03584",
"RC03582"
]
},
{
"pap_id": "216",
"title": "Dopamine inhibits mitochondrial motility in hippocampal neurons.",
"authors": "Chen, Sigeng; Owens, Geoffrey C; Edelman, David B",
"chapter": "",
"pages": "e2804",
"journal": "Plos One",
"pub_date": "2008-07-30",
"pub_year": 2008,
"volume": "3",
"issue": "7",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1371/journal.pone.0002804",
"doi": "10.1371/journal.pone.0002804",
"pmid": "18665222.0",
"pmcid": "PMC2467486",
"abstract": "BACKGROUND: The trafficking of mitochondria within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT), acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampal neurons by increasing Akt activity, and consequently decreasing glycogen synthase kinase (GSK3beta) activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3beta signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R) agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine 1 receptor (D1R) agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatment with either a D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity. CONCLUSIONS/SIGNIFICANCE: Our observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effects of these two neuromodulators may be important in determining the distribution of energy sources in neurons.",
"references": [
"RC03592",
"RC03591",
"RC03590",
"RC03589",
"RC03583"
]
},
{
"pap_id": "217",
"title": "Mitochondrial swelling impairs the transport of organelles in cerebellar granule neurons.",
"authors": "Kaasik, Allen; Safiulina, Dzhamilja; Choubey, Vinay; Kuum, Malle; Zharkovsky, Alexander; Veksler, Vladimir",
"chapter": "",
"pages": "32821-32826",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2007-11-09",
"pub_year": 2007,
"volume": "282",
"issue": "45",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.M702295200",
"doi": "10.1074/jbc.M702295200",
"pmid": "17785462.0",
"pmcid": "",
"abstract": "Organelle transport in neuronal processes is central to the organization, developmental fate, and functions of neurons. Organelles must be transported through the slender, highly branched neuronal processes, making the axonal transport vulnerable to any perturbation. However, some intracellular structures like mitochondria are able to considerably modify their volume. We therefore hypothesized that swollen mitochondria could impair the traffic of other organelles in neurite shafts. To test this hypothesis, we have investigated the effects of mitochondrial swellers on the organelle traffic. Our data demonstrate that treatment of neurons with potassium ionophore valinomycin led to the fast time-dependent inhibition of organelle movement in cerebellar granule neurons. Similar inhibition was observed in neurons treated with the inhibitors of the mitochondrial respiratory chain, sodium azide and antimycin, which also induced swelling. No decrease in the motility of organelles was observed in cultures treated with inhibitors of ATP production or transport, oligomycin or bongkrekic acid, suggesting that inhibition of the ATP-generating activity itself without swelling does not affect the motility of organelles. The effect of swellers on the traffic was more important in thin processes, thus indicating the role of steric hindrance of swollen mitochondria. We propose that the size and morphology of the transported cargo is also relevant for seamless axonal transport and speculate that mitochondrial swelling could be one of the reasons for impaired organelle transport in neuronal processes.",
"references": [
"RC03601",
"RC03600",
"RC03599"
]
},
{
"pap_id": "218",
"title": "ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak.",
"authors": "Debattisti, Valentina; Gerencser, Akos A; Saotome, Masao; Das, Sudipto; Hajn?czky, Gy?rgy",
"chapter": "",
"pages": "1667-1680",
"journal": "Cell reports",
"pub_date": "2017-11-07",
"pub_year": 2017,
"volume": "21",
"issue": "6",
"Issn": "22111247",
"Isbn": "",
"url": "http://linkinghub.elsevier.com/retrieve/pii/S2211124717315085",
"doi": "10.1016/j.celrep.2017.10.060",
"pmid": "29117569.0",
"pmcid": "PMC5710826",
"abstract": "Mitochondrial distribution and motility are recognized as central to many cellular functions, but their regulation by signaling mechanisms remains to be elucidated. Here, we report that reactive oxygen species (ROS), either derived from an extracellular source or intracellularly generated, control mitochondrial distribution and function by dose-dependently, specifically, and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential, or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated mitogen-activated protein kinase (MAPK), p38?, is required for the motility inhibition. Furthermore, anchoring mitochondria directly to kinesins without involvement of the physiological adaptors between the organelles and the motor protein prevents the H2O2-induced decrease in mitochondrial motility. Thus, ROS engage p38? and the motor adaptor complex to exert changes in mitochondrial motility, which likely has both physiological and pathophysiological relevance. Copyright ? 2017 The Authors. Published by Elsevier Inc. All rights reserved.",
"references": [
"RC03603",
"RC03602"
]
},
{
"pap_id": "219",
"title": "Axonal mitochondrial transport and potential are correlated.",
"authors": "Miller, Kyle E; Sheetz, Michael P",
"chapter": "",
"pages": "2791-2804",
"journal": "Journal of Cell Science",
"pub_date": "2004-06-01",
"pub_year": 2004,
"volume": "117",
"issue": "Pt 13",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1242/jcs.01130",
"doi": "10.1242/jcs.01130",
"pmid": "15150321.0",
"pmcid": "",
"abstract": "Disruption of axonal transport leads to a disorganized distribution of mitochondria and other organelles and is thought to be responsible for some types of neuronal disease. The reason for bidirectional transport of mitochondria is unknown. We have developed and applied a set of statistical methods and found that axonal mitochondria are uniformly distributed. Analysis of fast axonal transport showed that the uniform distribution arose from the clustering of the stopping events of fast axonal transport in the middle of the gaps between stationary mitochondria. To test whether transport was correlated with ATP production, we added metabolic inhibitors locally by micropipette. Whereas applying CCCP (a mitochondrial uncoupler) blocked mitochondrial transport, as has been previously reported, treatment with antimycin (an inhibitor of electron transport at complex III) caused increases in retrograde mitochondrial transport. Application of 2-deoxyglucose did not decrease transport compared with the mannitol control. To determine whether mitochondrial transport was correlated with mitochondrial potential, we stained the neurons with the mitochondrial potential-sensing dye JC-1. We found that approximately 90% of mitochondria with high potential were transported towards the growth cone and approximately 80% of mitochondria with low potential were transported towards the cell body. These experiments show for the first time that a uniform mitochondrial distribution is generated by local regulation of the stopping events of fast mitochondrial transport, and that the direction of mitochondrial transport is correlated with mitochondrial potential. These results have implications for axonal clogging, autophagy, apoptosis and Alzheimer's disease.",
"references": [
"RC03595",
"RC03594"
]
},
{
"pap_id": "22",
"title": "Effect of tricyclic drugs on mitochondrial membrane.",
"authors": "Eto, K; Fukuda, T; Araki, Y; Inoue, B; Ogata, M",
"chapter": "",
"pages": "289-295",
"journal": "Acta medica Okayama",
"pub_date": "1985-08-01",
"pub_year": 1985,
"volume": "39",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.18926/AMO/31500",
"doi": "10.18926/AMO/31500",
"pmid": "2931948.0",
"pmcid": "",
"abstract": "The effects of tricyclic drugs (clomipramine, imipramine, chlorpromazine and promethazine) on isolated liver mitochondria of rats were examined. All the drugs tested accelerated state 4 respiration. Their stimulative potency at concentrations below 100 microM was in the order of chlorpromazine greater than clomipramine greater than imipramine, promethazine. On state 3 respiration, the chlorine containing drugs had an inhibitive effect at high concentrations, while the other drugs seemed to have a slightly stimulative effect. These drugs stimulated latent ATPase activity of mitochondria. Clomipramine and chlorpromazine inhibited 2, 4-dinitrophenol-stimulated ATPase activity in a dose-dependent fashion. Imipramine also inhibited 2, 4-dinitrophenol-stimulated ATPase activity at high concentrations. Promethazine, however, had almost no effect. All the drugs induced potassium release from mitochondrial vesicles, and their potency was in the order of clomipramine greater than chlorpromazine greater than imipramine greater than promethazine. These results suggest that clomipramine, imipramine, chlorpromazine and promethazine cause impediments in both mitochondrial respiration and ion compartmentation, and that the chlorine containing drugs are more toxic than others on the functions of the mitochondrial membrane.",
"references": [
"RC00896",
"RC00895",
"RC00894",
"RC00893",
"RC00892",
"RC00891",
"RC00890",
"RC00889",
"RC00888",
"RC00887",
"RC00886",
"RC00885",
"RC00883",
"RC00882"
]
},
{
"pap_id": "220",
"title": "A new class of uncoupling agents--carbonyl cyanide phenylhydrazones.",
"authors": "Heytler, P G; Prichard, W W",
"chapter": "",
"pages": "272-275",
"journal": "Biochemical and Biophysical Research Communications",
"pub_date": "1962-05-04",
"pub_year": 1962,
"volume": "7",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0006-291X(62)90189-4",
"doi": "10.1016/0006-291X(62)90189-4",
"pmid": "13907155.0",
"pmcid": "",
"abstract": "",
"references": [
"RC03596"
]
},
{
"pap_id": "221",
"title": "Uncoupling of Oxidative Phosphorylation by Carbonyl Cyanide Phenylhydrazones. I. Some Characteristics of m-CI-CCP Action on Mitochondria and Chloroplasts",
"authors": "Heytler, P. G.",
"chapter": "",
"pages": "357-361",
"journal": "Biochemistry",
"pub_date": "1963-03-01",
"pub_year": 1963,
"volume": "2",
"issue": "2",
"Issn": "0006-2960",
"Isbn": "",
"url": "http://pubs.acs.org/doi/abs/10.1021/bi00902a031",
"doi": "10.1021/bi00902a031",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03597"
]
},
{
"pap_id": "222",
"title": "The mechanism of uncoupling of oxidative phosphorylation by 2,4-dinitrophenol.",
"authors": "Pinchot, G B",
"chapter": "",
"pages": "4577-4583",
"journal": "The Journal of Biological Chemistry",
"pub_date": "1967-10-01",
"pub_year": 1967,
"volume": "242",
"issue": "20",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/4964808",
"doi": "",
"pmid": "4964808.0",
"pmcid": "",
"abstract": "",
"references": [
"RC03598"
]
},
{
"pap_id": "223",
"title": "Development of an in silico profiler for mitochondrial toxicity",
"authors": "Nelms, Mark D; Mellor, Claire L; Cronin, Mark T D; Madden, Judith C; Enoch, Steven J",
"chapter": "",
"pages": "1891-1902",
"journal": "Chemical Research in Toxicology",
"pub_date": "2015-10-01",
"pub_year": 2015,
"volume": "28",
"issue": "10",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1021/acs.chemrestox.5b00275",
"doi": "10.1021/acs.chemrestox.5b00275",
"pmid": "26375963.0",
"pmcid": "",
"abstract": "This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. ((2009) Toxicol. In Vitro, 23, 134-140). These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the molecular initiating event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the adverse outcome pathway paradigm. Additionally, the profiler could be utilized in screening large data sets in order to identify chemicals with the potential to induce mitochondrial toxicity.",
"references": [
"RC03524",
"RC03521",
"RC03520",
"RC03519",
"RC03518"
]
},
{
"pap_id": "224",
"title": "Mitochondrial dysfunction caused by drugs and environmental toxicants",
"authors": "Enoch, Steve; Mellor, Claire; Nelms, Mark",
"chapter": "Structure-Activity Modeling of Mitochondrial Dysfunction",
"pages": "25-34",
"journal": "",
"pub_date": "2018-03-16",
"pub_year": 2018,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "9.78E+12",
"url": "http://doi.wiley.com/10.1002/9781119329725.ch3",
"doi": "10.1002/9781119329725.ch3",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03525"
]
},
{
"pap_id": "225",
"title": "Increased susceptibility to troglitazone-induced mitochondrial permeability transition in type 2 diabetes mellitus model rat.",
"authors": "Segawa, Masahiro; Sekine, Shuichi; Sato, Tomoyuki; Ito, Kousei",
"chapter": "",
"pages": "339-351",
"journal": "The Journal of toxicological sciences",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "43",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.2131/jts.43.339",
"doi": "10.2131/jts.43.339",
"pmid": "29743445.0",
"pmcid": "",
"abstract": "Troglitazone, a member of the thiazolidinedione class of antidiabetic drugs, was withdrawn from the market because it causes severe liver injury. One of the mechanisms for this adverse effect is thought to be mitochondrial toxicity. To investigate the characteristics of troglitazone-induced liver toxicity in more depth, the toxicological effects of troglitazone on hepatocytes and liver mitochondria were investigated using a rat model of type 2 diabetes mellitus (T2DM). Troglitazone was found to increase mitochondrial permeability transition (MPT) in the liver mitochondria of diabetic rats to a greater extent than in control rats, whereas mitochondrial membrane potential and oxidative phosphorylation were not affected. To identify the factors associated with this increase in susceptibility to MPT in diabetic rats, we assessed the oxidative status of the liver mitochondria and found a decrease in mitochondrial glutathione content and an increase in phospholipid peroxidation. Moreover, incorporation of oxidized cardiolipin, a mitochondrion-specific phospholipid, was involved in the troglitazone-induced alteration in susceptibility to MPT. In conclusion, liver mitochondria display disease-associated mitochondrial lipid peroxidation in T2DM, which facilitates the higher susceptibility to troglitazone-induced MPT. Thus, greater susceptibility of liver mitochondria may be a host factor leading to troglitazone-induced hepatotoxicity in T2DM.",
"references": [
"RC04992",
"RC04991",
"RC04990",
"RC04989",
"RC04988",
"RC04987",
"RC04986",
"RC04985",
"RC04984",
"RC04983",
"RC04982",
"RC04981",
"RC04980",
"RC04979",
"RC04978",
"RC04977",
"RC03526"
]
},
{
"pap_id": "226",
"title": "Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes.",
"authors": "Rachek, Lyudmila I; Yuzefovych, Larysa V; Ledoux, Susan P; Julie, Neil L; Wilson, Glenn L",
"chapter": "",
"pages": "348-354",
"journal": "Toxicology and Applied Pharmacology",
"pub_date": "2009-11-01",
"pub_year": 2009,
"volume": "240",
"issue": "3",
"Issn": "1096-0333",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.taap.2009.07.021",
"doi": "10.1016/j.taap.2009.07.021",
"pmid": "19632256.0",
"pmcid": "PMC2767118",
"abstract": "Thiazolidinediones (TZDs), such as troglitazone (TRO) and rosiglitazone (ROSI), improve insulin resistance by acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). TRO was withdrawn from the market because of reports of serious hepatotoxicity. A growing body of evidence suggests that TRO caused mitochondrial dysfunction and induction of apoptosis in human hepatocytes but its mechanisms of action remain unclear. We hypothesized that damage to mitochondrial DNA (mtDNA) is an initiating event involved in TRO-induced mitochondrial dysfunction and hepatotoxicity. Primary human hepatocytes were exposed to TRO and ROSI. The results obtained revealed that TRO, but not ROSI at equimolar concentrations, caused a substantial increase in mtDNA damage and decreased ATP production and cellular viability. The reactive oxygen species (ROS) scavenger, N-acetyl cystein (NAC), significantly diminished the TRO-induced cytotoxicity, suggesting involvement of ROS in TRO-induced hepatocyte cytotoxicity. The PPARgamma antagonist (GW9662) did not block the TRO-induced decrease in cell viability, indicating that the TRO-induced hepatotoxicity is PPARgamma-independent. Furthermore, TRO induced hepatocyte apoptosis, caspase-3 cleavage and cytochrome c release. Targeting of a DNA repair protein to mitochondria by protein transduction using a fusion protein containing the DNA repair enzyme Endonuclease III (EndoIII) from Escherichia coli, a mitochondrial translocation sequence (MTS) and the protein transduction domain (PTD) from HIV-1 TAT protein protected hepatocytes against TRO-induced toxicity. Overall, our results indicate that significant mtDNA damage caused by TRO is a prime initiator of the hepatoxicity caused by this drug.",
"references": [
"RC03530",
"RC03529",
"RC03528",
"RC03527"
]
},
{
"pap_id": "227",
"title": "Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis",
"authors": "Massart, Julie; Begriche, Karima; Buron, Nelly; Porceddu, Mathieu; Borgne-Sanchez, Annie; Fromenty, Bernard",
"chapter": "",
"pages": "147-157",
"journal": "Current pathobiology reports",
"pub_date": "2013-09-01",
"pub_year": 2013,
"volume": "1",
"issue": "3",
"Issn": "2167-485X",
"Isbn": "",
"url": "http://link.springer.com/10.1007/s40139-013-0022-y",
"doi": "10.1007/s40139-013-0022-y",
"pmid": "",
"pmcid": "",
"abstract": "Drug-induced inhibition of mitochondrial fatty acid ?-oxidation (mtFAO) is a key mechanism whereby drugs can induce steatosis. The type and severity of this liver lesion is dependent on the residual mtFAO flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure, which can be favored by genetic predispositions. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is by itself a benign lesion. In the long-term, however, macrovacuolar steatosis can progress with some drugs to steatohepatitis. Interestingly, drugs that are more likely to cause steatohepatitis are those impairing the mitochondrial respiratory chain (MRC) activity. Indeed, MRC impairment favors not only hepatic fat accretion but also oxidative stress and lipid peroxidation. Drugs inhibiting mtFAO could be more toxic in obese patients with preexisting nonalcoholic fatty liver disease (NAFLD) since higher mtFAO is a key metabolic adaptation to curb fat accretion during NAFLD.",
"references": [
"RC03558",
"RC03557",
"RC03556",
"RC03555",
"RC03554",
"RC03553",
"RC03552",
"RC03551",
"RC03550",
"RC03540",
"RC03539",
"RC03538",
"RC03536",
"RC03535",
"RC03534",
"RC03533",
"RC03532",
"RC03531"
]
},
{
"pap_id": "228",
"title": "Specific inhibition of phosphate transport in mitochondria by N-ethylmaleimide",
"authors": "Hatase, O.; Wakabayashi, T.; Allmann, D. W.; Southard, J. H.; Green, D. E.",
"chapter": "",
"pages": "1月15日",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "1973-01-01",
"pub_year": 1973,
"volume": "5",
"issue": "1",
"Issn": "0145-479X",
"Isbn": "",
"url": "http://link.springer.com/10.1007/BF01458353",
"doi": "10.1007/BF01458353",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC01241"
]
},
{
"pap_id": "229",
"title": "Mitochondrial thioredoxin in regulation of oxidant-induced cell death.",
"authors": "Chen, Yan; Cai, Jiyang; Jones, Dean P",
"chapter": "",
"pages": "6596-6602",
"journal": "FEBS Letters",
"pub_date": "2006-11-01",
"pub_year": 2006,
"volume": "580",
"issue": "28-29",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.febslet.2006.11.007",
"doi": "10.1016/j.febslet.2006.11.007",
"pmid": "17113580.0",
"pmcid": "PMC1761693",
"abstract": "Mitochondrial thioredoxin (mtTrx) can be oxidized in response to inducers of oxidative stress; yet the functional consequences of the oxidation have not been determined. This study evaluated the redox status of mtTrx and its association to oxidant-induced apoptosis. Results showed that mtTrx was oxidized after exposure to peroxides and diamide. Overexpression of mtTrx protected against diamide-induced oxidation and cytotoxicity. Oxidation of mtTrx was also achieved by knocking down its reductase; and lead to increased susceptibility to cell death. The data indicate that the redox status of mtTrx is a regulatory mechanism underlying the vulnerability of mitochondria to oxidative injury.",
"references": [
"RC01244"
]
},
{
"pap_id": "23",
"title": "Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro.",
"authors": "Modica-Napolitano, Josephine S; Lagace, Christopher J; Brennan, William A; Aprille, June R",
"chapter": "",
"pages": "951-959",
"journal": "Archives of Pharmacal Research",
"pub_date": "2003-11-01",
"pub_year": 2003,
"volume": "26",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/bf02980205",
"doi": "10.1007/bf02980205",
"pmid": "14661862.0",
"pmcid": "",
"abstract": "A series of typical (chlorpromazine, haloperidol and thioridazine) and atypical (risperidone, quetiapine, clozapine and olanzapine) antipsychotics were tested for effects on integrated bioenergetic functions of isolated rat liver mitochondria. Polarographic measurement of oxygen consumption in freshly isolated mitochondria showed that electron transfer activity at respiratory complex I is inhibited by chlorpromazine, haloperidol, risperidone, and quetiapine, but not by clozapine, olanzapine, or thioridazine. Chlorpromazine and thioridazine act as modest uncouplers of oxidative phosphorylation. The typical neuroleptics inhibited NADH-coenzyme Q reductase in freeze-thawed mitochondria, which is a direct measure of complex I enzyme activity. The inhibition of NADH-coenzyme Q reductase activity by the atypicals risperidone and quetiapine was 2-4 fold less than that for the typical neuroleptics. Clozapine and olanzapine had only slight effects on NADH-coenzyme Q reductase activity, even at 200 microM. The relative potencies of these neuroleptic drugs as inhibitors of mitochondrial bioenergetic function is similar to their relative potencies as risk factors in the reported incidence of extrapyramidal symptoms, including tardive dyskinesia (TD). This suggests that compromised bioenergetic function may be involved in the cellular pathology underlying TD.",
"references": [
"RC01055",
"RC00903",
"RC00902",
"RC00901",
"RC00900",
"RC00899",
"RC00898",
"RC00897"
]
},
{
"pap_id": "230",
"title": "Phosphate carrier of liver mitochondria: the reaction of its SH groups with mersalyl, 5,5'-dithio-bis-nitrobenzoate, and N-ethylmaleimide and the modulation of reactivity by the energy state of the mitochondria.",
"authors": "Fonyo, A; Vignais, P V",
"chapter": "",
"pages": "137-149",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "1980-08-01",
"pub_year": 1980,
"volume": "12",
"issue": "3月4日",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/BF00744679",
"doi": "10.1007/BF00744679",
"pmid": "7217038.0",
"pmcid": "",
"abstract": "The inhibitory effect of three SH reagents, mersalyl, 5,5'-dithio-bis-nitrobenzoate, and N-ethylmaleimide, on Pi transport in rat liver mitochondria was investigated under a variety of conditions. Mersalyl binds at room temperature with both high (Kd less than 10 microM) and low affinity to mitochondria. Inhibition of Pi transport by mersalyl goes in parallel with titration of the high-affinity sites, inhibition being complete when 3.5-4.5 nmol/mg protein is bound to the mitochondria. At concentrations of mersalyl equal to or higher than 10 microM, inhibition of Pi transport occurs in less than 10 sec. At concentrations of mersalyl lower than 10 microM, the rate of reaction with the Pi carrier is considerably decreased. At a concentration of 100 microM, 5,5'-dithio-bis-nitrobenzoate fully inhibits Pi transport in about 1 min at room temperature. Nearly total inhibition is attained when as little as 40-50 pmol/mg is bound to mitochondria. Upon incubation longer than 1 min, additional SH groups, not belonging to the Pi carrier, begin to react. The uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone decreases the rate of reaction of mersalyl, 5,5'-dithio-bis-nitrobenzoate, and N-ethylmaleimide with the Pi carrier. Preincubation with Pi has a similar effect. We propose that both carbonyl cyanide p-trifluoromethoxyphenylhydrazone and Pi act by increasing the acidity of the mitochondrial matrix. Protonation of the Pi carrier at the matrix side would change the accessibility of its SH groups at the outer surface of the inner membrane. This might correspond to a membrane-Bohr effect, possibly related to the opening of a gating pore in the Pi carrier.",
"references": [
"RC01243"
]
},
{
"pap_id": "231",
"title": "The molecular mechanism of transport by the mitochondrial ADP/ATP carrier.",
"authors": "Ruprecht, Jonathan J; King, Martin S; Z?gg, Thomas; Aleksandrova, Antoniya A; Pardon, Els; Crichton, Paul G; Steyaert, Jan; Kunji, Edmund R S",
"chapter": "",
"pages": "435-447.e15",
"journal": "Cell",
"pub_date": "2019-01-24",
"pub_year": 2019,
"volume": "176",
"issue": "3",
"Issn": "928674",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S0092867418315174",
"doi": "10.1016/j.cell.2018.11.025",
"pmid": "30611538.0",
"pmcid": "PMC6349463",
"abstract": "Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family. VIDEO ABSTRACT. Copyright ? 2018 The Author(s). Published by Elsevier Inc. All rights reserved.",
"references": [
"RC01246",
"RC01245"
]
},
{
"pap_id": "232",
"title": "Inhibitors of fatty acid oxidation.",
"authors": "Schulz, H",
"chapter": "",
"pages": "1443-1449",
"journal": "Life Sciences",
"pub_date": "1987-04-13",
"pub_year": 1987,
"volume": "40",
"issue": "15",
"Issn": "243205",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0024320587903754",
"doi": "10.1016/0024-3205(87)90375-4",
"pmid": "3550347.0",
"pmcid": "",
"abstract": "This review discusses inhibitors of fatty acid oxidation for which sites and mechanisms of inhibition are reasonably well understood. Included in this review are hypoglycin, an inhibitor of butyryl-CoA dehydrogenase (EC 1.3.99.2), 4-pentenoic acid, 2-bromooctanoic acid, and 4-bromocrotonic acid all of which inhibit mitochondrial thiolases (EC 2.3.1.9 and 2.3.1.16) as well as several inhibitors of carnitine palmitoyltransferase I (EC 2.3.1.21) as for example 2-tetradecylglycidic acid, 2-bromopalmitic acid and aminocarnitine. Most of these inhibitors of fatty acid oxidation have been shown to cause hypoglycemia in animals and some also cause hypoketonemia. The advantages and limitations of using these inhibitors in metabolic studies are discussed.",
"references": [
"RC01252",
"RC01251",
"RC01250",
"RC01249",
"RC01248",
"RC01247"
]
},
{
"pap_id": "233",
"title": "A novel regulatory mechanism of the mitochondrial Ca2+ uniporter revealed by the p38 mitogen-activated protein kinase inhibitor SB202190.",
"authors": "Montero, Mayte; Lobaton, Carmen D; Moreno, Alfredo; Alvarez, Javier",
"chapter": "",
"pages": "1955-1957",
"journal": "The FASEB Journal",
"pub_date": "2002-12-01",
"pub_year": 2002,
"volume": "16",
"issue": "14",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1096/fj.02-0553fje",
"doi": "10.1096/fj.02-0553fje",
"pmid": "12368236.0",
"pmcid": "",
"abstract": "It is widely acknowledged that mitochondrial Ca2+ uptake modulates the cytosolic [Ca2+] ([Ca2+]c) acting as a transient Ca2+ buffer. In addition, mitochondrial [Ca2+] ([Ca2+]M) regulates the rate of respiration and may trigger opening of the permeability transition pore and start apoptosis. However, no mechanism for the physiological regulation of mitochondrial Ca2+ uptake has been described. We show here that SB202190, an inhibitor of p38 mitogen-activated protein (MAP) kinase, strongly stimulates ruthenium red-sensitive mitochondrial Ca2+ uptake, both in intact and in permeabilized HeLa cells. The [Ca2+]M peak induced by agonists was increased about fourfold in the presence of the inhibitor, with a concomitant reduction in the [Ca2+]c peak. The stimulation occurred fast and was rapidly reversible. In addition, experiments in permeabilized cells perfused with controlled [Ca2+] showed that SB202190 stimulated mitochondrial Ca2+ uptake by more than 10-fold, but only in the physiological [Ca2+]c range (1-4 mM). Other structurally related p38 MAP kinase inhibitors (SB203580, PD169316, or SB220025) produced little or no effect. Our data suggest that in HeLa cells, a protein kinase sensitive to SB202190 tonically inhibits the mitochondrial Ca2+ uniporter. This novel regulatory mechanism may be of paramount importance to modulate mitochondrial Ca2+ uptake under different physiopathological conditions.",
"references": [
"RC03559"
]
},
{
"pap_id": "234",
"title": "Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids.",
"authors": "Montero, Mayte; Lobat?n, Carmen D; Hern?ndez-Sanmiguel, Esther; Santodomingo, Jaime; Vay, Laura; Moreno, Alfredo; Alvarez, Javier",
"chapter": "",
"pages": "19-24",
"journal": "The Biochemical Journal",
"pub_date": "1905-06-26",
"pub_year": 1905,
"volume": "384",
"issue": "Pt 1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/BJ20040990",
"doi": "10.1042/BJ20040990",
"pmid": "15324303.0",
"pmcid": "PMC1134084",
"abstract": "During cell activation, mitochondria play an important role in Ca2+ homoeostasis due to the presence of a fast and specific Ca2+ channel in its inner membrane, the mitochondrial Ca2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca2+] changes and controls the intramitochondrial Ca2+ levels, thus modulating a variety of phenomena from respiratory rate to apoptosis. We have described recently that SB202190, an inhibitor of p38 MAPK (mitogen-activated protein kinase), strongly activated the uniporter. We show in the present study that a series of natural plant flavonoids, widely distributed in foods, produced also a strong stimulation of the mitochondrial Ca2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca2+ peak induced by histamine was also largely increased by the flavonoids. Stimulation of the uniporter by either flavonoids or SB202190 did not require ATP, suggesting a direct effect on the uniporter or an associated protein which is not mediated by protein phosphorylation. The most active compound, kaempferol, increased the rate of mitochondrial Ca2+ uptake by 85+/-15% (mean+/-S.E.M., n=4) and the histamine-induced mitochondrial Ca2+ peak by 139+/-19% (mean+/-S.E.M., n=5) at a concentration of 1 microM. Given that flavonoids can reach this concentration range in plasma after ingestion of flavonoid-rich food, these compounds could be modulating the uniporter under physiological conditions.",
"references": [
"RC03563",
"RC03562",
"RC03561",
"RC03560"
]
},
{
"pap_id": "235",
"title": "Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation.",
"authors": "Berson, A; Fau, D; Fornacciari, R; Degove-Goddard, P; Sutton, A; Descatoire, V; Haouzi, D; Lett?ron, P; Moreau, A; Feldmann, G; Pessayre, D",
"chapter": "",
"pages": "261-269",
"journal": "Journal of Hepatology",
"pub_date": "2001-02-01",
"pub_year": 2001,
"volume": "34",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/s0168-8278(00)00050-7",
"doi": "10.1016/s0168-8278(00)00050-7",
"pmid": "11281555.0",
"pmcid": "",
"abstract": "BACKGROUND/AIMS: Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large overdoses or intravenous misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A. METHODS: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice. RESULTS: Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 microM) concentrated in mitochondria, collapsed the membrane potential, inhibited beta-oxidation, and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 microM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell adenosine triphosphate (ATP) and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body weight), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor. CONCLUSIONS: Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concentrations or doses of buprenorphine is mainly related to its mitochondrial effects.",
"references": [
"RC03541"
]
},
{
"pap_id": "236",
"title": "Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: possible role in microvesicular steatosis induced by this antibiotic.",
"authors": "Fr?neaux, E; Labbe, G; Letteron, P; The Le Dinh, ; Degott, C; Gen?ve, J; Larrey, D; Pessayre, D",
"chapter": "",
"pages": "1056-1062",
"journal": "Hepatology",
"pub_date": "1988-10-01",
"pub_year": 1988,
"volume": "8",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/hep.1840080513",
"doi": "10.1002/hep.1840080513",
"pmid": "3417225.0",
"pmcid": "",
"abstract": "Intravenous administration of high doses of tetracycline may produce severe microvesicular steatosis of the liver in man. A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation and in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of tetracycline on the mitochondrial oxidation of fatty acids in mice and in man. In vitro, addition of tetracycline 0.25, 0.5, 1 or 2 mM inhibited by 15, 38, 56 and 65%, respectively, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation. Inhibition was reversible. Inhibition appeared even greater with human liver mitochondria. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A by mouse liver mitochondria, was inhibited by 25, 32 and 43%, respectively, in the presence of 0.5, 1 or 2 mM of tetracycline. In vivo, administration of tetracycline, 0.25 or 1 mmole per kg, inhibited by 53 and 84%, respectively, the exhalation of [14C]CO2 during the first 3 hours following the administration of a tracer dose of [U-14C]palmitic acid. Administration of tetracycline, 0.0625, 0.25 or 1 mmole per kg, 6 hr before the measurement, increased hepatic triglycerides by 100, 170 and 250%, respectively. After 1 mmole per kg, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 9-fold the control value; liver histology showed microvesicular steatosis at 6 and 24 hr. We conclude that tetracycline inhibits the mitochondrial oxidation of fatty acids in mice and in man.(ABSTRACT TRUNCATED AT 250 WORDS)",
"references": [
"RC03545",
"RC03544"
]
},
{
"pap_id": "237",
"title": "Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice.",
"authors": "Fromenty, B; Freneaux, E; Labbe, G; Deschamps, D; Larrey, D; Letteron, P; Pessayre, D",
"chapter": "",
"pages": "3743-3751",
"journal": "Biochemical Pharmacology",
"pub_date": "1989-11-01",
"pub_year": 1989,
"volume": "38",
"issue": "21",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0006-2952(89)90580-7",
"doi": "10.1016/0006-2952(89)90580-7",
"pmid": "2597170.0",
"pmcid": "",
"abstract": "Tianeptine is a new tricyclic antidepressant which is metabolized mainly by beta-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of beta-oxidation products from [1-14C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1-14C]octanoic acid and by 51% that from [1-14C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both beta-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of [14C]CO2 from [1-14C]octanoic acid and [1-14C]butyric acid, but did not significantly decrease that from [1-14C]palmitic acid. After administration of high doses of tianeptine, however, formation of [14C]CO2 from [1-14C]palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (greater than 24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.",
"references": [
"RC03543",
"RC03542"
]
},
{
"pap_id": "238",
"title": "Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.",
"authors": "Deschamps, D; DeBeco, V; Fisch, C; Fromenty, B; Guillouzo, A; Pessayre, D",
"chapter": "",
"pages": "948-961",
"journal": "Hepatology",
"pub_date": "1994-04-01",
"pub_year": 1994,
"volume": "19",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/8138270",
"doi": "",
"pmid": "8138270.0",
"pmcid": "",
"abstract": "In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.",
"references": [
"RC03537"
]
},
{
"pap_id": "239",
"title": "Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids.",
"authors": "Freneaux, E; Fromenty, B; Berson, A; Labbe, G; Degott, C; Letteron, P; Larrey, D; Pessayre, D",
"chapter": "",
"pages": "529-535",
"journal": "The Journal of Pharmacology and Experimental Therapeutics",
"pub_date": "1990-11-01",
"pub_year": 1990,
"volume": "255",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/2123005",
"doi": "",
"pmid": "2123005.0",
"pmcid": "",
"abstract": "The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.",
"references": [
"RC03546"
]
},
{
"pap_id": "24",
"title": "2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death.",
"authors": "Grundlingh, Johann; Dargan, Paul I; El-Zanfaly, Marwa; Wood, David M",
"chapter": "",
"pages": "205-212",
"journal": "Journal of Medical Toxicology",
"pub_date": "2011-09-01",
"pub_year": 2011,
"volume": "7",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s13181-011-0162-6",
"doi": "10.1007/s13181-011-0162-6",
"pmid": "21739343.0",
"pmcid": "PMC3550200",
"abstract": "2,4-Dinitrophenol (DNP) is reported to cause rapid loss of weight, but unfortunately is associated with an unacceptably high rate of significant adverse effects. DNP is sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncoupling of oxidative phosphorylation; the classic symptom complex associated with toxicity of phenol-based products such as DNP is a combination of hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Fatalities related to exposure to DNP have been reported since the turn of the twentieth century. To date, there have been 62 published deaths in the medical literature attributed to DNP. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarise the previous fatalities associated with exposure to DNP.",
"references": [
"RC00907",
"RC00906",
"RC00905",
"RC00904"
]
},
{
"pap_id": "240",
"title": "Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone.",
"authors": "Kennedy, J A; Unger, S A; Horowitz, J D",
"chapter": "",
"pages": "273-280",
"journal": "Biochemical Pharmacology",
"pub_date": "1996-07-26",
"pub_year": 1996,
"volume": "52",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0006-2952(96)00204-3",
"doi": "10.1016/0006-2952(96)00204-3",
"pmid": "8694852.0",
"pmcid": "",
"abstract": "The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated \"apparent inhibitory constant (Ki)\" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti-ischaemic effects of both perhexiline and amiodarone.",
"references": [
"RC03549",
"RC03548",
"RC03547"
]
},
{
"pap_id": "241",
"title": "Pharmacological Modulation of Mitochondrial Ca2+ Content Regulates Sarcoplasmic Reticulum Ca2+ Release via Oxidation of the Ryanodine Receptor by Mitochondria-Derived Reactive Oxygen Species.",
"authors": "Hamilton, Shanna; Terentyeva, Radmila; Kim, Tae Yun; Bronk, Peter; Clements, Richard T; O-Uchi, Jin; Csord?s, Gy?rgy; Choi, Bum-Rak; Terentyev, Dmitry",
"chapter": "",
"pages": "1831",
"journal": "Frontiers in physiology",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "9",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.3389/fphys.2018.01831",
"doi": "10.3389/fphys.2018.01831",
"pmid": "30622478.0",
"pmcid": "PMC6308295",
"abstract": "In a physiological setting, mitochondria increase oxidative phosphorylation during periods of stress to meet increased metabolic demand. This in part is mediated via enhanced mitochondrial Ca2+ uptake, an important regulator of cellular ATP homeostasis. In a pathophysiological setting pharmacological modulation of mitochondrial Ca2+ uptake or retention has been suggested as a therapeutic strategy to improve metabolic homeostasis or attenuate Ca2+-dependent arrhythmias in cardiac disease states. To explore the consequences of mitochondrial Ca2+ accumulation, we tested the effects of kaempferol, an activator of mitochondrial Ca2+ uniporter (MCU), CGP-37157, an inhibitor of mitochondrial Na+/Ca2+ exchanger, and MCU inhibitor Ru360 in rat ventricular myocytes (VMs) from control rats and rats with hypertrophy induced by thoracic aortic banding (TAB). In periodically paced VMs under ?-adrenergic stimulation, treatment with kaempferol (10 ?mol/L) or CGP-37157 (1 ?mol/L) enhanced mitochondrial Ca2+ accumulation monitored by mitochondrial-targeted Ca2+ biosensor mtRCamp1h. Experiments with mitochondrial membrane potential-sensitive dye TMRM revealed this was accompanied by depolarization of the mitochondrial matrix. Using redox-sensitive OMM-HyPer and ERroGFP_iE biosensors, we found treatment with kaempferol or CGP-37157 increased the levels of reactive oxygen species (ROS) in mitochondria and the sarcoplasmic reticulum (SR), respectively. Confocal Ca2+ imaging showed that accelerated Ca2+ accumulation reduced Ca2+ transient amplitude and promoted generation of spontaneous Ca2+ waves in VMs paced under ISO, suggestive of abnormally high activity of the SR Ca2+ release channel ryanodine receptor (RyR). Western blot analyses showed increased RyR oxidation after treatment with kaempferol or CGP-37157 vs. controls. Furthermore, in freshly isolated TAB VMs, confocal Ca2+ imaging demonstrated that enhancement of mitochondrial Ca2+ accumulation further perturbed global Ca2+ handling, increasing the number of cells exhibiting spontaneous Ca2+ waves, shortening RyR refractoriness and decreasing SR Ca2+ content. In ex vivo optically mapped TAB hearts, kaempferol exacerbated proarrhythmic phenotype. On the contrary, incubation of cells with MCU inhibitor Ru360 (2 ?mol/L, 30 min) normalized RyR oxidation state, improved intracellular Ca2+ homeostasis and reduced triggered activity in ex vivo TAB hearts. These findings suggest facilitation of mitochondrial Ca2+ uptake in cardiac disease can exacerbate proarrhythmic disturbances in Ca2+ homeostasis via ROS and enhanced activity of oxidized RyRs, while strategies to reduce mitochondrial Ca2+ accumulation can be protective.",
"references": [
"RC03570",
"RC03569",
"RC03568",
"RC03567",
"RC03566",
"RC03565",
"RC03564"
]
},
{
"pap_id": "242",
"title": "Clinical effects of chemical exposures on mitochondrial function.",
"authors": "Zolkipli-Cunningham, Zarazuela; Falk, Marni J",
"chapter": "",
"pages": "90-99",
"journal": "Toxicology",
"pub_date": "2017-11-01",
"pub_year": 2017,
"volume": "391",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tox.2017.07.009",
"doi": "10.1016/j.tox.2017.07.009",
"pmid": "28757096.0",
"pmcid": "PMC6078194",
"abstract": "Mitochondria are critical for the provision of ATP for cellular energy requirements. Tissue and organ functions are dependent on adequate ATP production, especially when energy demand is high. Mitochondria also play a role in a vast array of important biochemical pathways including apoptosis, generation and detoxification of reactive oxygen species, intracellular calcium regulation, steroid hormone and heme synthesis, and lipid metabolism. The complexity of mitochondrial structure and function facilitates its diverse roles but also enhances its vulnerability. Primary disorders of mitochondrial bioenergetics, or Primary Mitochondrial Diseases (PMD) are due to inherited genetic defects in the nuclear or mitochondrial genomes that result in defective oxidative phosphorylation capacity and cellular energy production. Secondary mitochondrial dysfunction is observed in a wide range of diseases such as Alzheimer's and Parkinson's disease. Several lines of evidence suggest that environmental exposures cause substantial mitochondrial dysfunction. Whereby literature from experimental and human studies on exposures associated with Alzheimer's and Parkinson's diseases exist, the significance of exposures as potential triggers in Primary Mitochondrial Disease (PMD) is an emerging clinical question that has not been systematically studied. Copyright ? 2017 Elsevier B.V. All rights reserved.",
"references": [
"RC03662",
"RC03661",
"RC03660",
"RC03659",
"RC03658",
"RC03657",
"RC03656",
"RC03655",
"RC03654",
"RC03653",
"RC03652",
"RC03651",
"RC03650",
"RC03649",
"RC03648",
"RC03647",
"RC03646"
]
},
{
"pap_id": "243",
"title": "Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity.",
"authors": "Du, Kuo; Farhood, Anwar; Jaeschke, Hartmut",
"chapter": "",
"pages": "761-773",
"journal": "Archives of Toxicology",
"pub_date": "2017-02-01",
"pub_year": 2017,
"volume": "91",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s00204-016-1692-0",
"doi": "10.1007/s00204-016-1692-0",
"pmid": "27002509.0",
"pmcid": "PMC5033665",
"abstract": "Acetaminophen (APAP) hepatotoxicity is characterized by an extensive mitochondrial oxidant stress. However, its importance as a drug target has not been clarified. To investigate this, fasted C57BL/6J mice were treated with 300?mg/kg APAP and the mitochondria-targeted antioxidant Mito-Tempo (MT) was given 1.5?h later. APAP caused severe liver injury in mice, as indicated by the increase in plasma ALT activities and centrilobular necrosis. MT dose-dependently reduced the injury. Importantly, MT did not affect APAP-protein adducts formation, glutathione depletion or c-jun N-terminal kinase activation and its mitochondrial translocation. In contrast, hepatic glutathione disulfide and peroxynitrite formation were dose-dependently reduced by MT, indicating its effective mitochondrial oxidant stress scavenging capacity. Consequently, mitochondrial translocation of Bax and release of mitochondrial intermembrane proteins such as apoptosis-inducing factor were prevented, and nuclear DNA fragmentation was eliminated. To demonstrate the importance of mitochondria-specific antioxidant property of MT, we compared its efficacy with Tempo, which has the same pharmacological mode of action as MT but lacks the mitochondria targeting moiety. In contrast to the dramatic protection by MT, the same molar dose of Tempo did not significantly reduce APAP hepatotoxicity. In contrast, even a 3?h post-treatment with MT reduced 70?% of the injury, and the combination of MT with N-acetylcysteine (NAC) provided superior protection than NAC alone. We conclude that MT protects against APAP overdose in mice by attenuating the mitochondrial oxidant stress and preventing peroxynitrite formation and the subsequent mitochondrial dysfunction. MT is a promising therapeutic agent for APAP overdose patients.",
"references": [
"RC03571"
]
},
{
"pap_id": "244",
"title": "N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production.",
"authors": "EzeriF\u0001a, Daria; Takano, Yoko; Hanaoka, Kenjiro; Urano, Yasuteru; Dick, Tobias P",
"chapter": "",
"pages": "447-459.e4",
"journal": "Cell Chemical Biology",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "25",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.chembiol.2018.01.011",
"doi": "10.1016/j.chembiol.2018.01.011",
"pmid": "29429900.0",
"pmcid": "PMC6455997",
"abstract": "The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC-derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria. We provide evidence suggesting the possibility that sulfane sulfur species produced by 3-mercaptopyruvate sulfurtransferase and sulfide:quinone oxidoreductase are the actual mediators of the immediate antioxidative and cytoprotective effects provided by NAC. Copyright ? 2018 Elsevier Ltd. All rights reserved.",
"references": [
"RC03572"
]
},
{
"pap_id": "245",
"title": "Ferroptosis: an iron-dependent form of nonapoptotic cell death.",
"authors": "Dixon, Scott J; Lemberg, Kathryn M; Lamprecht, Michael R; Skouta, Rachid; Zaitsev, Eleina M; Gleason, Caroline E; Patel, Darpan N; Bauer, Andras J; Cantley, Alexandra M; Yang, Wan Seok; Morrison, Barclay; Stockwell, Brent R",
"chapter": "",
"pages": "1060-1072",
"journal": "Cell",
"pub_date": "1905-07-04",
"pub_year": 1905,
"volume": "149",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.cell.2012.03.042",
"doi": "10.1016/j.cell.2012.03.042",
"pmid": "22632970.0",
"pmcid": "PMC3367386",
"abstract": "Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright ? 2012 Elsevier Inc. All rights reserved.",
"references": [
"RC03668",
"RC03667",
"RC03666",
"RC03664",
"RC03663"
]
},
{
"pap_id": "246",
"title": "RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels.",
"authors": "Yagoda, Nicholas; von Rechenberg, Moritz; Zaganjor, Elma; Bauer, Andras J; Yang, Wan Seok; Fridman, Daniel J; Wolpaw, Adam J; Smukste, Inese; Peltier, John M; Boniface, J Jay; Smith, Richard; Lessnick, Stephen L; Sahasrabudhe, Sudhir; Stockwell, Brent R",
"chapter": "",
"pages": "864-868",
"journal": "Nature",
"pub_date": "1905-06-29",
"pub_year": 1905,
"volume": "447",
"issue": "7146",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/nature05859",
"doi": "10.1038/nature05859",
"pmid": "17568748.0",
"pmcid": "PMC3047570",
"abstract": "Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway.",
"references": [
"RC03665"
]
},
{
"pap_id": "247",
"title": "Mitochondrial fusion, fission, and mitochondrial toxicity.",
"authors": "Meyer, Joel N; Leuthner, Tess C; Luz, Anthony L",
"chapter": "",
"pages": "42-53",
"journal": "Toxicology",
"pub_date": "1905-07-09",
"pub_year": 1905,
"volume": "391",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.tox.2017.07.019",
"doi": "10.1016/j.tox.2017.07.019",
"pmid": "28789970.0",
"pmcid": "PMC5681418",
"abstract": "Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise. Copyright ? 2017 Elsevier B.V. All rights reserved.",
"references": [
"RC03714",
"RC03713",
"RC03712",
"RC03711",
"RC03710",
"RC03709",
"RC03708",
"RC03707",
"RC03706",
"RC03705",
"RC03704",
"RC03703",
"RC03702",
"RC03701",
"RC03700",
"RC03699",
"RC03698"
]
},
{
"pap_id": "248",
"title": "Mitochondria as a therapeutic target for common pathologies.",
"authors": "Murphy, Michael P; Hartley, Richard C",
"chapter": "",
"pages": "865-886",
"journal": "Nature Reviews. Drug Discovery",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "17",
"issue": "12",
"Issn": "1474-1776",
"Isbn": "",
"url": "http://www.nature.com/doifinder/10.1038/nrd.2018.174",
"doi": "10.1038/nrd.2018.174",
"pmid": "30393373.0",
"pmcid": "",
"abstract": "Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.",
"references": [
"RC03696",
"RC03695",
"RC03694",
"RC03693",
"RC03692",
"RC03691",
"RC03690"
]
},
{
"pap_id": "249",
"title": "Glycolysis inhibition for anticancer treatment.",
"authors": "Pelicano, H; Martin, D S; Xu, R-H; Huang, P",
"chapter": "",
"pages": "4633-4646",
"journal": "Oncogene",
"pub_date": "2006-08-01",
"pub_year": 2006,
"volume": "25",
"issue": "34",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/sj.onc.1209597",
"doi": "10.1038/sj.onc.1209597",
"pmid": "16892078.0",
"pmcid": "",
"abstract": "Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.",
"references": [
"RC03689",
"RC03688",
"RC03687",
"RC03686",
"RC03685",
"RC03684"
]
},
{
"pap_id": "25",
"title": "Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose on breast cancer cells.",
"authors": "Zhang, Fanjie; Aft, Rebecca L",
"chapter": "",
"pages": "S41-3",
"journal": "Journal of cancer research and therapeutics",
"pub_date": "2009-09-01",
"pub_year": 2009,
"volume": "5 Suppl 1",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.4103/0973-1482.55140",
"doi": "10.4103/0973-1482.55140",
"pmid": "20009293.0",
"pmcid": "",
"abstract": "BACKGROUND: Accelerated glucose uptake for anaerobic glycolysis is one of the major metabolic changes found in malignant cells. This property has been exploited for imaging malignancies and as a possible anticancer therapy. The nonmetabolizable glucose analog 2-deoxyglucose (2 DG) interferes with glucose metabolism leading to breast cancer cell death. AIMS: To determine whether 2DG can synergize with chemotherapeutic agents commonly used in breast cancer treatment and identify cellular characteristics associated with sensitivity to 2DG. MATERIALS AND METHODS: SkBr3 breast cancer cells were incubated with varying concentrations of 5-fluorouracil (5FU), doxorubicin, cisplatin, cyclophosphamide, or herceptin with or without 2DG. Cell viability was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS: Combining 2DG with doxorubicin, 5 FU, cyclophosphamide, and herceptin resulted in enhanced cell death compared with each agent alone, while in combination with cisplatin, the amount of cell death was additive. Mouse embryo fibroblasts (MEF) mutated for p53 (-/-) were 30% more sensitive to the cytotoxic effects of 2DG than the parental cell lines. Cells mutated for Bax/Bac, genes involved in protection from apoptosis, are slightly more sensitive than the parental cell lines. CONCLUSIONS: These results indicate that 2DG acts synergistically with specific chemotherapeutic agents in causing cell death and the class of chemicals most sensitive appear to be those which cause DNA damage.",
"references": [
"RC00908"
]
},
{
"pap_id": "250",
"title": "The significance of mitochondrial toxicity testing in drug development.",
"authors": "Dykens, James A; Will, Yvonne",
"chapter": "",
"pages": "777-785",
"journal": "Drug Discovery Today",
"pub_date": "2007-09-01",
"pub_year": 2007,
"volume": "12",
"issue": "17-18",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.drudis.2007.07.013",
"doi": "10.1016/j.drudis.2007.07.013",
"pmid": "17826691.0",
"pmcid": "",
"abstract": "Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for mitochondrial function, cell models that better report mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.",
"references": [
"RC03671"
]
},
{
"pap_id": "251",
"title": "The toxicity of fluoroacetate and the tricarboxylic acid cycle",
"authors": "Li?becq, Claude; Peters, Rudolph Albert",
"chapter": "",
"pages": "215-230",
"journal": "Biochimica et biophysica acta",
"pub_date": "1949-01-01",
"pub_year": 1949,
"volume": "3",
"issue": "",
"Issn": "63002",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0006300249900955",
"doi": "10.1016/0006-3002(49)90095-5",
"pmid": "",
"pmcid": "",
"abstract": "1.1. The hypothesis that fluoroacetate is a competitive inhibitor for acetate in tissue metabolism (Bartlett and Barron) has been examined and found incapable of explaining some of the enzymatic effects of the poison.2.2. Using a homogenate from guinea pig kidney, free from residual oxidizable substrates, and reinforced with Mg++ and adenine nucleotides, it was found that this readily oxidizes fumarate and citrate. In presence of fluoroacetate, citrate accumulates during the oxidation of fumarate, without an accompanying accumulation of acetate.3.3. With the same homogenate, fumarate and pyruvate together give 20\u0013 50% increased oxygen uptake as compared with fumarate alone, and there is even formation of citrate in absence of poison. Fluoroacetate produces inhibition without accumulation of acetate, but this is less than with fumarate alone.4.4. Fluoroacetate has no action upon the pyruvate dehydrogenase component of the brain pyruvate oxidase system. It also has no effect upon the activity of the enzymes aconitase, oxalosuccinate decarboxylase, fumarase and oxaloacetate decarboxylase, as tested by a pigeon liver preparation.5.5. The fact that no single enzymatic reaction has been found to be inhibited by fluoroacetate6.and yet that the reactions of the tricarboxylic cycle are stopped with accumulation of citrate requires a hypothesis in addition to that proposed by Barron and Bartlett.7.6. It is suggested that, in the kidney preparation, fluoroacetate is not the inhibitor but that it is transformed into another substance which is inhibitory.8.7. The accumulation of citrate can be observed with concentrations of 0.05 mM (15 ?g Nafluoroacetate per bottle) which approximates to the amounts causing toxic effects in vivo.9.8. It was confirmed that malonate inhibits the enzymatic decarboxylation of oxaloacetate.10.9. Some experiments upon kidney brei are described.",
"references": [
"RC03672"
]
},
{
"pap_id": "252",
"title": "New method to assess mitophagy flux by flow cytometry.",
"authors": "Mauro-Lizcano, Marta; Esteban-Mart?nez, Lorena; Seco, Esther; Serrano-Puebla, Ana; Garcia-Ledo, Lucia; Figueiredo-Pereira, Cl?udia; Vieira, Helena L A; Boya, Patricia",
"chapter": "",
"pages": "833-843",
"journal": "Autophagy",
"pub_date": "1905-07-07",
"pub_year": 1905,
"volume": "11",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1080/15548627.2015.1034403",
"doi": "10.1080/15548627.2015.1034403",
"pmid": "25945953.0",
"pmcid": "PMC4509449",
"abstract": "Mitochondrial autophagy, also known as mitophagy, is an autophagosome-based mitochondrial degradation process that eliminates unwanted or damaged mitochondria after cell stress. Most studies dealing with mitophagy rely on the analysis by fluorescence microscopy of mitochondrial-autophagosome colocalization. However, given the fundamental role of mitophagy in the physiology and pathology of organisms, there is an urgent need for novel quantitative methods with which to study this process. Here, we describe a flow cytometry-based approach to determine mitophagy by using MitoTracker Deep Red, a widely used mitochondria-selective probe. Used in combination with selective inhibitors it may allow for the determination of mitophagy flux. Here, we test the validity of the use of this method in cell lines and in primary cell and tissue cultures.",
"references": [
"RC03728",
"RC03727",
"RC03726",
"RC03725",
"RC03724",
"RC03723",
"RC03722",
"RC03721",
"RC03720",
"RC03719",
"RC03718"
]
},
{
"pap_id": "253",
"title": "[The mitochondrial biochemical lesion in pentachlorophenol intoxication].",
"authors": "Buffa, P; Azzone, G F; Carafoli, E; Muscatelo, U",
"chapter": "",
"pages": "1816-1820",
"journal": "Bollettino della Societa Italiana di Biologia Sperimentale",
"pub_date": "1905-05-12",
"pub_year": 1905,
"volume": "35",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/13805750",
"doi": "",
"pmid": "13805750.0",
"pmcid": "",
"abstract": "",
"references": [
"RC03717"
]
},
{
"pap_id": "254",
"title": "[Enzymatic research at the mitochondrial level in experimental carbon monoxide poisoning. Behavior of the cytochrome oxidases, aldolases and glutamic-oxalacetic and glutamic-pyruvic transaminases in the hepatic and renal mitochondria].",
"authors": "Villa, T; Andri, L; Brasca, F",
"chapter": "",
"pages": "486-495",
"journal": "Folia medica. Folia medica (Naples, Italy)",
"pub_date": "1961-06-01",
"pub_year": 1961,
"volume": "44",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://www.ncbi.nlm.nih.gov/pubmed/13781376",
"doi": "",
"pmid": "13781376.0",
"pmcid": "",
"abstract": "",
"references": [
"RC03716"
]
},
{
"pap_id": "255",
"title": "Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer.",
"authors": "Stacpoole, Peter W",
"chapter": "",
"pages": "",
"journal": "Journal of the National Cancer Institute",
"pub_date": "1905-07-09",
"pub_year": 1905,
"volume": "109",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/jnci/djx071",
"doi": "10.1093/jnci/djx071",
"pmid": "29059435.0",
"pmcid": "",
"abstract": "The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. Inhibition of PDC activity by pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation has been associated with the pathobiology of many disorders of metabolic integration, including cancer. Consequently, the PDC/PDK axis has long been a therapeutic target. The most common underlying mechanism accounting for PDC inhibition in these conditions is post-transcriptional upregulation of one or more PDK isoforms, leading to phosphorylation of the E1? subunit of PDC. Such perturbations of the PDC/PDK axis induce a \"glycolytic shift,\" whereby affected cells favor adenosine triphosphate production by glycolysis over mitochondrial oxidative phosphorylation and cellular proliferation over cellular quiescence. Dichloroacetate is the prototypic xenobiotic inhibitor of PDK, thereby maintaining PDC in its unphosphorylated, catalytically active form. However, recent interest in the therapeutic targeting of the PDC/PDK axis for the treatment of cancer has yielded a new generation of small molecule PDK inhibitors. Ongoing investigations of the central role of PDC in cellular energy metabolism and its regulation by pharmacological effectors of PDKs promise to open multiple exciting vistas into the biochemical understanding and treatment of cancer and other diseases. ? The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.",
"references": [
"RC03747",
"RC03746",
"RC03745",
"RC03744",
"RC03743",
"RC03742"
]
},
{
"pap_id": "256",
"title": "Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells.",
"authors": "Zhang, Wenjia; Su, Jing; Xu, Huadan; Yu, Shanshan; Liu, Yanan; Zhang, Yong; Sun, Liankun; Yue, Ying; Zhou, Xiaoli",
"chapter": "",
"pages": "e0179672",
"journal": "Plos One",
"pub_date": "1905-07-09",
"pub_year": 1905,
"volume": "12",
"issue": "6",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1371/journal.pone.0179672",
"doi": "10.1371/journal.pone.0179672",
"pmid": "28617852.0",
"pmcid": "PMC5472302",
"abstract": "Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.",
"references": [
"RC03752",
"RC03751",
"RC03750",
"RC03749",
"RC03748"
]
},
{
"pap_id": "257",
"title": "The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations.",
"authors": "O'Connor, Roddy S; Guo, Lili; Ghassemi, Saba; Snyder, Nathaniel W; Worth, Andrew J; Weng, Liwei; Kam, Yoonseok; Philipson, Benjamin; Trefely, Sophie; Nunez-Cruz, Selene; Blair, Ian A; June, Carl H; Milone, Michael C",
"chapter": "",
"pages": "6289",
"journal": "Scientific Reports",
"pub_date": "1905-07-10",
"pub_year": 1905,
"volume": "8",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/s41598-018-24676-6",
"doi": "10.1038/s41598-018-24676-6",
"pmid": "29674640.0",
"pmcid": "PMC5908836",
"abstract": "Etomoxir (ETO) is a widely used small-molecule inhibitor of fatty acid oxidation (FAO) through its irreversible inhibitory effects on the carnitine palmitoyl-transferase 1a (CPT1a). We used this compound to evaluate the role of fatty acid oxidation in rapidly proliferating T cells following costimulation through the CD28 receptor. We show that ETO has a moderate effect on T cell proliferation with no observable effect on memory differentiation, but a marked effect on oxidative metabolism. We show that this oxidative metabolism is primarily dependent upon glutamine rather than FAO. Using an shRNA approach to reduce CPT1a in T cells, we further demonstrate that the inhibition of oxidative metabolism in T cells by ETO is independent of its effects on FAO at concentrations exceeding 5 ?M. Concentrations of ETO above 5 ?M induce acute production of ROS with associated evidence of severe oxidative stress in proliferating T cells. In aggregate, these data indicate that ETO lacks specificity for CTP1a above 5 ?M, and caution should be used when employing this compound for studies in cells due to its non-specific effects on oxidative metabolism and cellular redox.",
"references": [
"RC03673"
]
},
{
"pap_id": "258",
"title": "Acetaminophen\u0010 induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition",
"authors": "Hinson, Jack A.; Reid, Angela B.; McCullough, Sandra S.; James, Laura P.",
"chapter": "",
"pages": "805-822",
"journal": "Drug Metabolism Reviews",
"pub_date": "2004-06-01",
"pub_year": 2004,
"volume": "36",
"issue": "3月4日",
"Issn": "0360-2532",
"Isbn": "",
"url": "http://www.tandfonline.com/doi/full/10.1081/DMR-200033494",
"doi": "10.1081/DMR-200033494",
"pmid": "15554248.0",
"pmcid": "",
"abstract": "Large doses of the analgesic acetaminophen cause centrilobular hepatic necrosis in man and in experimental animals. It has been previously shown that acetaminophen is metabolically activated by CYP enzymes to N-acetyl-p-benzoquinone imine. This species is normally detoxified by GSH, but following a toxic dose GSH is depleted and the metabolite covalently binds to a number of different proteins. Covalent binding occurs only to the cells developing necrosis. Recently we showed that these cells also contain nitrated tyrosine residues. Nitrotyrosine is mediated by peroxynitrite, a reactive nitrogen species formed by rapid reaction between nitric oxide and superoxide and is normally detoxified by GSH. Thus, acetaminophen toxicity occurs with increased oxygen/nitrogen stress. This manuscript will review current data on acetaminophen covalent binding, increased oxygen/nitrogen stress, and mitochondrial permeability transition, a toxic mechanism that is both mediated by and leads to increased oxygen/nitrogen stress.",
"references": [
"RC03670"
]
},
{
"pap_id": "259",
"title": "Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver.",
"authors": "Zhao, Ping; Kalhorn, Thomas F; Slattery, John T",
"chapter": "",
"pages": "326-335",
"journal": "Hepatology",
"pub_date": "2002-08-01",
"pub_year": 2002,
"volume": "36",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1053/jhep.2002.34943",
"doi": "10.1053/jhep.2002.34943",
"pmid": "12143040.0",
"pmcid": "",
"abstract": "Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N-acetyl-p-benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1). However, CYP2E1 induction appears to be insufficient to explain the claimed magnitude of the interaction. We assessed the role of selective depletion of liver mitochondrial glutathione (GSH) by chronic ethanol. Rats were fed the Lieber-DeCarli diet for 10 days or 6 weeks. APAP toxicity in liver slices (% glutathione-S-transferase alpha released to the medium, GST release) and NAPQI toxicity in isolated liver mitochondria (succinate dehydrogenase inactivation, SDH) from these rats were compared with pair-fed controls. Ethanol induced CYP2E1 in both the 10-day and 6-week groups by approximately 2-fold. APAP toxicity in liver slices was higher in the 6-week ethanol group than the 10-day ethanol group. Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only. Ethanol selectively depleted liver mitochondrial GSH only in the 6-week group (by 52%) without altering cytosolic GSH. Significantly greater GSH loss and APAP covalent binding were observed in liver slice mitochondria of the 6-week ethanol group. Isolated mitochondria of the 6-week ethanol group were approximately 50% more susceptible to NAPQI (25-165 micromol/L) induced SDH inactivation. This increased susceptibility was reproduced in pair-fed control mitochondria pretreated with diethylmaleate. In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH.",
"references": [
"RC03669"
]
},
{
"pap_id": "26",
"title": "Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy.",
"authors": "Ma, Xiuquan; Jin, Mingzhi; Cai, Yu; Xia, Hongguang; Long, Kai; Liu, Junli; Yu, Qiang; Yuan, Junying",
"chapter": "",
"pages": "1474-1481",
"journal": "Chemistry & Biology",
"pub_date": "2011-11-23",
"pub_year": 2011,
"volume": "18",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.chembiol.2011.08.009",
"doi": "10.1016/j.chembiol.2011.08.009",
"pmid": "22118681.0",
"pmcid": "PMC3225892",
"abstract": "Autophagy is a cellular lysosome-dependent catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. We show that antimycin A, a known inhibitor of mETC complex III, can inhibit autophagy. A structural and functional study shows that four close analogs of antimycin A that have no effect on mitochondria inhibition also do not inhibit autophagy, whereas myxothiazol, another mETC complex III inhibitor with unrelated structure to antimycin A, inhibits autophagy. Additionally, antimycin A and myxothiazol cannot inhibit autophagy in mtDNA-depleted H4 and mtDNA-depleted HeLa cells. These data suggest that antimycin A inhibits autophagy through its inhibitory activity on mETC complex III. Our data suggest that mETC complex III may have a role in mediating autophagy induction. Copyright © 2011 Elsevier Ltd. All rights reserved.",
"references": [
"RC00909"
]
},
{
"pap_id": "260",
"title": "Novel small-molecule PGC-1alpha transcriptional regulator with beneficial effects on diabetic db/db mice.",
"authors": "Zhang, Li-Na; Zhou, Hua-Yong; Fu, Yan-Yun; Li, Yuan-Yuan; Wu, Fang; Gu, Min; Wu, Ling-Yan; Xia, Chun-Mei; Dong, Tian-Cheng; Li, Jing-Ya; Shen, Jing-Kang; Li, Jia",
"chapter": "",
"pages": "1297-1307",
"journal": "Diabetes",
"pub_date": "2013-04-01",
"pub_year": 2013,
"volume": "62",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.2337/db12-0703",
"doi": "10.2337/db12-0703",
"pmid": "23250358.0",
"pmcid": "PMC3609556",
"abstract": "Peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1? expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1? promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1? expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1? mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1? expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1? and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1? and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1? in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.",
"references": [
"RC03753"
]
},
{
"pap_id": "261",
"title": "Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney disease.",
"authors": "Miyamoto, Satoshi; Zhang, Guanshi; Hall, David; Oates, Peter J; Maity, Soumya; Madesh, Muniswamy; Han, Xianlin; Sharma, Kumar",
"chapter": "",
"pages": "7249-7260",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2020-05-01",
"pub_year": 2020,
"volume": "295",
"issue": "21",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.RA119.011110",
"doi": "10.1074/jbc.RA119.011110",
"pmid": "32277051.0",
"pmcid": "PMC7247302",
"abstract": "Exposure to chronic hyperglycemia because of diabetes mellitus can lead to development and progression of diabetic kidney disease (DKD). We recently reported that reduced superoxide production is associated with mitochondrial dysfunction in the kidneys of mouse models of type 1 DKD. We also demonstrated that humans with DKD have significantly reduced levels of mitochondrion-derived metabolites in their urine. Here we examined renal superoxide production in a type 2 diabetes animal model, the db/db mouse, and the role of a mitochondrial protectant, MTP-131 (also called elamipretide, SS-31, or Bendavia) in restoring renal superoxide production and ameliorating DKD. We found that 18-week-old db/db mice have reduced renal and cardiac superoxide levels, as measured by dihydroethidium oxidation, and increased levels of albuminuria, mesangial matrix accumulation, and urinary H2O2 Administration of MTP-131 significantly inhibited increases in albuminuria, urinary H2O2, and mesangial matrix accumulation in db/db mice and fully preserved levels of renal superoxide production in these mice. MTP-131 also reduced total renal lysocardiolipin and major lysocardiolipin subspecies and preserved lysocardiolipin acyltransferase 1 expression in db/db mice. These results indicate that, in type 2 diabetes, DKD is associated with reduced renal and cardiac superoxide levels and that MTP-131 protects against DKD and preserves physiological superoxide levels, possibly by regulating cardiolipin remodeling.",
"references": []
},
{
"pap_id": "262",
"title": "Oxaliplatin, a potent inhibitor of survivin, enhances paclitaxel-induced apoptosis and mitotic catastrophe in colon cancer cells.",
"authors": "Fujie, Yujiro; Yamamoto, Hirofumi; Ngan, Chew Yee; Takagi, Akimitsu; Hayashi, Taro; Suzuki, Rei; Ezumi, Koji; Takemasa, Ichiro; Ikeda, Masataka; Sekimoto, Mitsugu; Matsuura, Nariaki; Monden, Morito",
"chapter": "",
"pages": "453-463",
"journal": "Japanese journal of clinical oncology",
"pub_date": "2005-08-01",
"pub_year": 2005,
"volume": "35",
"issue": "8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/jjco/hyi130",
"doi": "10.1093/jjco/hyi130",
"pmid": "16024531.0",
"pmcid": "",
"abstract": "BACKGROUND: Clinical studies have demonstrated that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent, especially when combined with other reagents. The aim of the present study was to explore the mechanism of such action. METHODS: Using colon cancer cell lines, we examined changes in cell cycle, apoptosis and mitotic catastrophe induced by oxaliplatin and/or paclitaxel. RESULTS: Oxaliplatin at its IC(50) induced apoptosis and cell cycle arrest at G(2)-M phase. Western blot analyses indicated that oxaliplatin decreased mitosis-commencing protein cdc2 and anti-apoptotic proteins, phospho-Bcl(2) and Bcl-xl in the three colon cancer cells tested. Since cdc2 stabilizes survivin, a putative IAP (inhibitor of apoptosis) family member, through phosphorylation of Thr34, we examined the level of survivin and found a marked decrease due to oxaliplatin. This finding is of particular interest because survivin is a promising molecular target against various human cancers and a key molecule involved in both apoptosis and mitotic catastrophe. When used in combination with paclitaxel (taxol), a putative apoptosis-inducing reagent, the isobologram indicated that the taxol-oxaliplatin sequence or taxol plus oxaliplatin had synergic or additive effects, while the oxaliplatin-taxol sequence resulted in a prominent antagonism. The taxol-oxaliplatin sequence caused marked growth inhibition of DLD1 and SW480 cells, possibly due to upregulation of apoptotic and non-apoptotic pathways, respectively. Morphological surveys indicated that the non-apoptotic process could be mitotic catastrophe. CONCLUSION: Our results suggest that oxaliplatin that potently inhibited survivin may exert outstanding cytotoxic effects when combined with certain chemoreagents through enhancement of apoptosis and mitotic catastrophe.",
"references": [
"RC03729"
]
},
{
"pap_id": "263",
"title": "Quercetin induces mitochondrial biogenesis through activation of HO-1 in HepG2 cells.",
"authors": "Rayamajhi, Nabin; Kim, Seul-Ki; Go, Hiroe; Joe, Yeonsoo; Callaway, Zak; Kang, Jae-Gu; Ryter, Stefan W; Chung, Hun Taeg",
"chapter": "",
"pages": "154279",
"journal": "Oxidative medicine and cellular longevity",
"pub_date": "1905-07-05",
"pub_year": 1905,
"volume": "2013",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1155/2013/154279",
"doi": "10.1155/2013/154279",
"pmid": "24288584.0",
"pmcid": "PMC3833383",
"abstract": "The regeneration of mitochondria by regulated biogenesis plays an important homeostatic role in cells and tissues and furthermore may provide an adaptive mechanism in certain diseases such as sepsis. The heme oxygenase (HO-1)/carbon monoxide (CO) system is an inducible cytoprotective mechanism in mammalian cells. Natural antioxidants can provide therapeutic benefit, in part, by inducing the HO-1/CO system. This study focused on the mechanism by which the natural antioxidant quercetin can induce mitochondrial biogenesis in HepG2 cells. We found that quercetin treatment induced expression of mitochondrial biogenesis activators (PGC-1 ? , NRF-1, TFAM), mitochondrial DNA (mtDNA), and proteins (COX IV) in HepG2 cells. The HO inhibitor SnPP and the CO scavenger hemoglobin reversed the effects of quercetin on mitochondrial biogenesis in HepG2 cells. The stimulatory effects of quercetin on mitochondrial biogenesis could be recapitulated in vivo in liver tissue and antagonized by SnPP. Finally, quercetin conferred an anti-inflammatory effect in the liver of mice treated with LPS and prevented impairment of mitochondrial biogenesis by LPS in vivo. These salutary effects of quercetin in vivo were also antagonized by SnPP. Thus, our results suggest that quercetin enhances mitochondrial biogenesis mainly via the HO-1/CO system in vitro and in vivo. The beneficial effects of quercetin may provide a therapeutic basis in inflammatory diseases and sepsis.",
"references": [
"RC03756"
]
},
{
"pap_id": "264",
"title": "Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors",
"authors": "Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C.; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Liu, Qin; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon B.; Altieri, Dario C.; Flaherty, Keith T.; Herlyn, Meenhard",
"chapter": "",
"pages": "",
"journal": "The Journal of Clinical Investigation",
"pub_date": "2016-05-01",
"pub_year": 2016,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://www.jci.org/articles/view/82661",
"doi": "",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03754"
]
},
{
"pap_id": "265",
"title": "Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1? Signaling Pathways.",
"authors": "Gureev, Artem P; Shaforostova, Ekaterina A; Popov, Vasily N",
"chapter": "",
"pages": "435",
"journal": "Frontiers in genetics",
"pub_date": "1905-07-11",
"pub_year": 1905,
"volume": "10",
"issue": "",
"Issn": "1664-8021",
"Isbn": "",
"url": "https://www.frontiersin.org/article/10.3389/fgene.2019.00435/full",
"doi": "10.3389/fgene.2019.00435",
"pmid": "31139208.0",
"pmcid": "PMC6527603",
"abstract": "Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play a key role in energy homeostasis and metabolism of reactive oxygen species (ROS), require lifetime control and constant renewal. This explains recently peaked interest in the processes of mitochondrial biogenesis and mitophagy. The principal event of mitochondrial metabolism is regulation of mitochondrial DNA (mtDNA) transcription and translation, which is a complex coordinated process that involves at least two systems of transcription factors. It is commonly believed that its major regulatory proteins are PGC-1? and PGC-1?, which act as key factors connecting several regulator cascades involved in the control of mitochondrial metabolism. In recent years, the number of publications on the essential role of Nrf2/ARE signaling in the regulation of mitochondrial biogenesis has grown exponentially. Nrf2 is induced by various xenobiotics and oxidants that oxidize some Nrf2 negative regulators. Thus, ROS, in particular H2O2, were found to be strong Nrf2 activators. At present, there are two major concepts of mitochondrial biogenesis. Some authors suggest direct involvement of Nrf2 in the regulation of this process. Others believe that Nrf2 regulates expression of the antioxidant genes, while the major and only regulator of mitochondrial biogenesis is PGC-1?. Several studies have demonstrated the existence of the regulatory loop involving both PGC-1? and Nrf2. In this review, we summarized recent data on the Nrf2 role in mitochondrial biogenesis and its interaction with PGC-1? in the context of extending longevity.",
"references": [
"RC03757"
]
},
{
"pap_id": "266",
"title": "Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics",
"authors": "N? Bhaoighill, Muireann; Dunlop, Elaine A.",
"chapter": "",
"pages": "",
"journal": "Cancer Drug Resistance",
"pub_date": "1905-07-11",
"pub_year": 1905,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://cdrjournal.com/article/view/3277",
"doi": "10.20517/cdr.2019.87",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03755"
]
},
{
"pap_id": "267",
"title": "Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.",
"authors": "Lagouge, Marie; Argmann, Carmen; Gerhart-Hines, Zachary; Meziane, Hamid; Lerin, Carles; Daussin, Frederic; Messadeq, Nadia; Milne, Jill; Lambert, Philip; Elliott, Peter; Geny, Bernard; Laakso, Markku; Puigserver, Pere; Auwerx, Johan",
"chapter": "",
"pages": "1109-1122",
"journal": "Cell",
"pub_date": "1905-06-28",
"pub_year": 1905,
"volume": "127",
"issue": "6",
"Issn": "0092-8674",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.cell.2006.11.013",
"doi": "10.1016/j.cell.2006.11.013",
"pmid": "17112576.0",
"pmcid": "",
"abstract": "Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.",
"references": [
"RC03758"
]
},
{
"pap_id": "268",
"title": "Drug repurposing for mitochondrial diseases using a pharmacological model of complex I deficiency in the yeast Yarrowia lipolytica",
"authors": "Perlstein, Ethan Oren",
"chapter": "",
"pages": "",
"journal": "BioRxiv",
"pub_date": "2020-01-01",
"pub_year": 2020,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://biorxiv.org/lookup/doi/10.1101/2020.01.08.899666",
"doi": "10.1101/2020.01.08.899666",
"pmid": "",
"pmcid": "",
"abstract": "Mitochondrial diseases affect 1 in 5,000 live births around the world. They are caused by inherited or de novo mutations in over 350 nuclear-encoded and mtDNA-encoded genes. There is no approved treatment to stop the progression of any mitochondrial disease despite the enormous global unmet need. Affected families often self-compound cocktails of over-the-counter vitamins and generally recognized as safe nutritional supplements that have not received regulatory approval for efficacy. Finding a new use for an approved drug is called repurposing, an attractive path for mitochondrial diseases because of the reduced safety risks, low costs and fast timelines to a clinic-ready therapy or combination of therapies. Here I describe the first-ever drug repurposing screen for mitochondrial diseases involving complex I deficiency, e.g., Leigh syndrome, using the yeast Yarrowia lipolytica as a model system. Unlike the more commonly used yeast Saccharomyces cerevisiae but like humans, Yarrowia lipolytica has a functional and metabolically integrated respiratory complex I and is an obligate aerobe. In 384-well-plate liquid culture format without shaking, Yarrowia lipolytica cells grown in either glucose-containing media or acetate-containing media were treated with a half-maximal inhibitory concentration (3?M and 6?M, respectively) of the natural product and complex I inhibitor piericidin A. Out of 2,560 compounds in the Microsource Spectrum collection, 24 suppressors of piercidin A reached statistical significance in one or both media conditions. The suppressors include calcium channel blockers nisoldipine, amiodarone and tetrandrine as well as the farnesol-like sesquiterpenoids parthenolide, nerolidol and bisabolol, which may all be modulating mitochondrial calcium homeostasis. Estradiols and synthetic estrogen receptor agonists are the largest class of suppressors that rescue growth of piericidin-A-treated Yarrowia lipolytica cells in both glucose-containing and acetate-containing media. Analysis of structure-activity relationships suggests that estrogens may enhance bioenergetics by evolutionarily conserved interactions with mitochondrial membranes that promote mitochondrial filamentation and mitochondrial DNA replication.",
"references": []
},
{
"pap_id": "269",
"title": "High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons.",
"authors": "Varkuti, Boglarka H; Liu, Ze; Kepiro, Miklos; Pacifico, Rodrigo; Gai, Yunchao; Kamenecka, Ted; Davis, Ronald L",
"chapter": "",
"pages": "100931",
"journal": "iScience",
"pub_date": "1905-07-12",
"pub_year": 1905,
"volume": "23",
"issue": "3",
"Issn": "25890042",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S2589004220301152",
"doi": "10.1016/j.isci.2020.100931",
"pmid": "32146326.0",
"pmcid": "PMC7063260",
"abstract": "We developed a high-throughput assay for modulators of mitochondrial function in neurons measuring inner mitochondrial membrane potential (??m) and ATP production. The assay was used to screen a library of small molecules, which led to the identification of structural/functional classes of mitochondrial modulators such as local anesthetics, isoflavones, COXII inhibitors, adrenergic receptor blockers, and neurotransmitter system effectors. Our results show that some of the isolated compounds promote mitochondrial health, enhance oxygen consumption rate, and protect neurons against toxic insults found in the cellular environment of Alzheimer disease. These studies offer a set of compounds that may provide efficacy in protecting the mitochondrial system in neurodegenerative disorders. Copyright ? 2020 The Author(s). Published by Elsevier Inc. All rights reserved.",
"references": [
"RC03741",
"RC03740",
"RC03739",
"RC03738",
"RC03737",
"RC03736",
"RC03735",
"RC03734",
"RC03733",
"RC03732",
"RC03731"
]
},
{
"pap_id": "27",
"title": "The kinetic mechanism by which CCCP (carbonyl cyanide m-chlorophenylhydrazone) transports protons across membranes.",
"authors": "Kasianowicz, J; Benz, R; McLaughlin, S",
"chapter": "",
"pages": "179-190",
"journal": "The Journal of Membrane Biology",
"pub_date": "1905-06-06",
"pub_year": 1905,
"volume": "82",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/bf01868942",
"doi": "10.1007/bf01868942",
"pmid": "6096547.0",
"pmcid": "",
"abstract": "We demonstrate that a simple kinetic model describes the transport of protons across lipid bilayer membranes by the weak acid CCCP (carbonyl cyanide m-chlorophenylhydrazone). Four parameters characterize this model: the adsorption coefficients of the anionic and neutral forms of the weak acid onto the interface (beta A and beta HA) and the rate constants for the movement of A- and HA across the membrane (kappa A and kappa HA). These parameters were determined by equilibrium dialysis, electrophoretic mobility, membrane potential, membrane conductance, and spectrophotometric measurements. From these equilibrium and steady state measurements on diphytanoyl phosphatidylcholine/chlorodecane membranes we found that beta A = beta HA = 1.4 10(-3) cm, kappa A = 175 s-1 and kappa HA = 12,000 sec-1. These parameters and our model describe our kinetic experiments if we assume that the protonation reactions, which occur at the interfaces, remain at equilibrium. The model predicts a single exponential decay of the current in a voltage-clamp experiment. The model also predicts that the decay in the voltage across the membrane following an intense current pulse of short duration (approximately 50 nsec) can be described by the sum of two exponentials. The magnitudes and time constants of the relaxations that we observed in both voltage-clamp and charge-pulse experiments agree well with the predictions of the model for all values of pH, voltage and [CCCP].",
"references": [
"RC00910"
]
},
{
"pap_id": "270",
"title": "A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation.",
"authors": "Hallak, Maher; Vazana, Liat; Shpilberg, Ofer; Levy, Itai; Mazar, Julia; Nathan, Ilana",
"chapter": "",
"pages": "147-155",
"journal": "Apoptosis: An International Journal on Programmed Cell Death",
"pub_date": "2008-01-01",
"pub_year": 2008,
"volume": "13",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s10495-007-0156-7",
"doi": "10.1007/s10495-007-0156-7",
"pmid": "18058236.0",
"pmcid": "",
"abstract": "Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine's apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.",
"references": [
"RC03730"
]
},
{
"pap_id": "271",
"title": "Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone.",
"authors": "Felser, Andrea; Blum, Kim; Lindinger, Peter W; Bouitbir, Jamal; Kr?henb?hl, Stephan",
"chapter": "",
"pages": "480-490",
"journal": "Toxicological Sciences",
"pub_date": "2012-11-01",
"pub_year": 2012,
"volume": "131",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/toxsci/kfs298",
"doi": "10.1093/toxsci/kfs298",
"pmid": "23135547.0",
"pmcid": "",
"abstract": "Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50 ?M, respectively. The cellular ATP content started to decrease at 20 ?M for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 ?M and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial ?-oxidation at 10 ?M and amiodarone at 20 ?M. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of ?-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.",
"references": [
"RC03760",
"RC03759"
]
},
{
"pap_id": "272",
"title": "Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation.",
"authors": "Lett?ron, P; Brahimi-Bourouina, N; Robin, M A; Moreau, A; Feldmann, G; Pessayre, D",
"chapter": "",
"pages": "G1141-50",
"journal": "The American Journal of Physiology",
"pub_date": "1997-05-01",
"pub_year": 1997,
"volume": "272",
"issue": "5 Pt 1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1152/ajpgi.1997.272.5.G1141",
"doi": "10.1152/ajpgi.1997.272.5.G1141",
"pmid": "9176224.0",
"pmcid": "",
"abstract": "Glucocorticoid administration may produce fatty liver in humans. We investigated the effects of dexamethasone on hepatic mitochondria and lipid metabolism in mice. Dexamethasone 21-phosphate (20 microM) did not inhibit the mitochondrial inner membrane-bound very-long-chain acyl-CoA dehydrogenase but inhibited the matrixlocated long-, medium-, and short-chain dehydrogenases. Dexamethasone 21-phosphate (20 microM) inhibited the first beta-oxidation cycle of [1-(14C)]butyric acid and [1-(14C)]octanoic acid but not that of [1-(14C)]palmitic acid. Administration of dexamethasone 21-phosphate (100 mg/kg) decreased the in vivo oxidation of [1-(14C)]butyric acid and [1-(14C)]octanoic acid into [14C]CO2 but not that of [1-(14C)]palmitic acid and decreased the hepatic secretion of triglycerides. After 5 days of treatment (100 mg/kg daily), hepatic triglycerides were increased and both microvesicular steatosis and ultrastructural mitochondrial lesions were present. In conclusion, glucocorticoids inhibit medium- and short-chain acyl-CoA dehydrogenation and hepatic lipid secretion in mice. These effects may account for their steatogenic effects in humans.",
"references": []
},
{
"pap_id": "273",
"title": "Functional analysis of molecular and pharmacological modulators of mitochondrial fatty acid oxidation.",
"authors": "Ma, Yibao; Wang, Wei; Devarakonda, Teja; Zhou, Huiping; Wang, Xiang-Yang; Salloum, Fadi N; Spiegel, Sarah; Fang, Xianjun",
"chapter": "",
"pages": "1450",
"journal": "Scientific Reports",
"pub_date": "2020-01-01",
"pub_year": 2020,
"volume": "10",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/s41598-020-58334-7",
"doi": "10.1038/s41598-020-58334-7",
"pmid": "31996743.0",
"pmcid": "PMC6989517",
"abstract": "Fatty acid oxidation (FAO) is a key bioenergetic pathway often dysregulated in diseases. The current knowledge on FAO regulators in mammalian cells is limited and sometimes controversial. Previous FAO analyses involve nonphysiological culture conditions or lack adequate quantification. We herein described a convenient and quantitative assay to monitor dynamic FAO activities of mammalian cells in physiologically relevant settings. The method enabled us to assess various molecular and pharmacological modulators of the FAO pathway in established cell lines, primary cells and mice. Surprisingly, many previously proposed FAO inhibitors such as ranolazine and trimetazidine lacked FAO-interfering activity. In comparison, etomoxir at low micromolar concentrations was sufficient to saturate its target proteins and to block cellular FAO function. Oxfenicine, on the other hand, acted as a partial inhibitor of FAO. As another class of FAO inhibitors that transcriptionally repress FAO genes, antagonists of peroxisome proliferator-activated receptors (PPARs), particularly that of PPAR?, significantly decreased cellular FAO activity. Our assay also had sufficient sensitivity to monitor upregulation of FAO in response to environmental glucose depletion and other energy-demanding cues. Altogether this study provided a reliable FAO assay and a clear picture of biological properties of potential FAO modulators in the mammalian system.",
"references": [
"RC03782",
"RC03781",
"RC03780",
"RC03776",
"RC03775",
"RC03774",
"RC03773",
"RC03772"
]
},
{
"pap_id": "274",
"title": "Effects of trimetazidine on the calcium transport and oxidative phosphorylation of isolated rat heart mitochondria.",
"authors": "Guarnieri, C; Finelli, C; Zini, M; Muscari, C",
"chapter": "",
"pages": "90-95",
"journal": "Basic Research in Cardiology",
"pub_date": "1997-04-01",
"pub_year": 1997,
"volume": "92",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/BF00805569",
"doi": "10.1007/BF00805569",
"pmid": "9166988.0",
"pmcid": "",
"abstract": "Trimetazidine (TMZ) added in vitro to isolated cardiac mitochondria at concentrations 10-100 microM in the presence of 25-100 nM extramitochondrial Ca2+ increased Ca2+ uptake and matrix Ca2+ concentration. This effect was less evident in the presence of physiologically Na+ and Mg2+ extramitochondrial concentrations since only 100 microM TMZ was able to increase mitochondrial Ca2+ entry in the presence of 100 nM Ca2+. The drug stimulated a Ca(2+)-cooperative effect on mitochondrial Ca2+ transport, but did not modify the rate of Ca2+ egress stimulated by 10 mM NaCl. An increase in mitochondrial Ca2+ level produced by TMZ enhanced oxoglutarate dehydrogenase activity and then ATP synthesis, particularly when 50 nM extramitochondrial Ca2+ was used. These data suggest that a possible cardiac mechanism of action of TMZ at mitochondrial level could support ATP synthesis by elevating the mitochondrial Ca2+ level.",
"references": [
"RC03761"
]
},
{
"pap_id": "275",
"title": "Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism.",
"authors": "Clarke, B; Wyatt, K M; McCormack, J G",
"chapter": "",
"pages": "341-350",
"journal": "Journal of Molecular and Cellular Cardiology",
"pub_date": "1996-02-01",
"pub_year": 1996,
"volume": "28",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1006/jmcc.1996.0032",
"doi": "10.1006/jmcc.1996.0032",
"pmid": "8729066.0",
"pmcid": "",
"abstract": "Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.",
"references": [
"RC03762"
]
},
{
"pap_id": "276",
"title": "Mitofusins deficiency elicits mitochondrial metabolic reprogramming to pluripotency.",
"authors": "Son, M J; Kwon, Y; Son, M-Y; Seol, B; Choi, H-S; Ryu, S-W; Choi, C; Cho, Y S",
"chapter": "",
"pages": "1957-1969",
"journal": "Cell Death and Differentiation",
"pub_date": "2015-04-01",
"pub_year": 2015,
"volume": "22",
"issue": "12",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/cdd.2015.43",
"doi": "10.1038/cdd.2015.43",
"pmid": "25882047.0",
"pmcid": "PMC4816104",
"abstract": "Cell reprogramming technology has allowed the in vitro control of cell fate transition, thus allowing for the generation of highly desired cell types to recapitulate in vivo developmental processes and architectures. However, the precise molecular mechanisms underlying the reprogramming process remain to be defined. Here, we show that depleting p53 and p21, which are barriers to reprogramming, yields a high reprogramming efficiency. Deletion of these factors results in a distinct mitochondrial background with low expression of oxidative phosphorylation subunits and mitochondrial fusion proteins, including mitofusin 1 and 2 (Mfn1/2). Importantly, Mfn1/2 depletion reciprocally inhibits the p53-p21 pathway and promotes both the conversion of somatic cells to a pluripotent state and the maintenance of pluripotency. Mfn1/2 depletion facilitates the glycolytic metabolic transition through the activation of the Ras-Raf and hypoxia-inducible factor 1? (HIF1?) signaling at an early stage of reprogramming. HIF1? is required for increased glycolysis and reprogramming by Mfn1/2 depletion. Taken together, these results demonstrate that Mfn1/2 constitutes a new barrier to reprogramming, and that Mfn1/2 ablation facilitates the induction of pluripotency through the restructuring of mitochondrial dynamics and bioenergetics.",
"references": [
"RC03787",
"RC03786",
"RC03785",
"RC03784",
"RC03783"
]
},
{
"pap_id": "277",
"title": "Cell-Based Screening of Focused Bioactive Compound Libraries: Assessing Small Molecule Modulators of the Canonical Wnt Signaling and Autophagy-Lysosome Pathways",
"authors": "Lebedeva, Irina; Coleman, Jack; Taillon, Bruce; Liang, Fred; Liu, Dakai; Hulboy, Diana; Patton., Wayne",
"chapter": "",
"pages": "",
"journal": "",
"pub_date": "1905-07-04",
"pub_year": 1905,
"volume": "",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "https://www2.enzolifesciences.com/",
"doi": "",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC03795",
"RC03794",
"RC03793",
"RC03792",
"RC03791",
"RC03790",
"RC03789",
"RC03788"
]
},
{
"pap_id": "278",
"title": "Multiple Targets for Drug-Induced Mitochondrial Toxicity.",
"authors": "Wallace, Kendall B",
"chapter": "",
"pages": "2488-2492",
"journal": "Current Medicinal Chemistry",
"pub_date": "1905-07-07",
"pub_year": 1905,
"volume": "22",
"issue": "20",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.2174/0929867322666150514095424",
"doi": "10.2174/0929867322666150514095424",
"pmid": "25973981.0",
"pmcid": "",
"abstract": "Mitochondrial toxicity is rapidly gaining the interest of researchers and practitioners as a prominent liability in drug discovery and development, accounting for a growing proportion of preclinical drug attrition and post-market withdrawals or black box warnings by the U.S. FDA. To date, the focus of registries of drugs that elicit mitochondrial toxicity has been largely restricted to those that either inhibit the mitochondrial electron transport chain (ETC) or uncouple mitochondrial oxidative phosphorylation. Less appreciated are the toxicities that are secondary to the drug affecting either the molecular regulation, assembly or incorporation of the ETC into the inner mitochondrial membrane or those that limit substrate availability. The current article describes the complexities of molecular events and biochemical pathways required to sustain mitochondrial fidelity and substrate homeostasis with examples of drugs that interfere which the various pathways. The principal objective of this review is to shed light on the broader scope of drug-induced mitochondrial toxicities and how these secondary targets may account for a large portion of drug failures.",
"references": [
"RC03796",
"RC03797",
"RC03798",
"RC03799",
"RC03800",
"RC03801",
"RC03802",
"RC03803",
"RC03804",
"RC03805",
"RC03806",
"RC03807",
"RC03808",
"RC03809",
"RC03810",
"RC03811",
"RC03812",
"RC03813",
"RC03814",
"RC03815",
"RC03816",
"RC03817",
"RC03818",
"RC03819",
"RC03820",
"RC03821",
"RC03822",
"RC03823",
"RC03824",
"RC03825",
"RC03826"
]
},
{
"pap_id": "279",
"title": "Pyruvate uptake is inhibited by valproic acid and metabolites in mitochondrial membranes.",
"authors": "Aires, C?tia C P; Soveral, Gra?a; Lu?s, Paula B M; ten Brink, Herman J; de Almeida, Isabel Tavares; Duran, Marinus; Wanders, Ronald J A; Silva, Margarida F B",
"chapter": "",
"pages": "3359-3366",
"journal": "FEBS Letters",
"pub_date": "1905-06-30",
"pub_year": 1905,
"volume": "582",
"issue": "23-24",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.febslet.2008.08.028",
"doi": "10.1016/j.febslet.2008.08.028",
"pmid": "18775709.0",
"pmcid": "",
"abstract": "The pyruvate uptake rate in inverted submitochondrial vesicles prepared from rat liver was optimized and further characterized; the potential inhibitory effects of the anticonvulsive drug valproic acid or 2-n-propyl-pentanoic acid (VPA), Delta4-valproic acid or 2-n-propyl-4-pentenoic acid and the respective coenzyme A (CoA) conjugates were studied in the presence of a proton gradient. All tested VPA metabolites inhibited the pyruvate uptake, but the CoA esters were stronger inhibitors (40% and 60% inhibition, respectively, for valproyl-CoA and Delta4-valproyl-CoA, at 1mM). At the same concentration, the specific inhibitor 2-cyano-4-hydroxycinnamate decreased the pyruvate uptake rate by 70%. The reported inhibition of the mitochondrial pyruvate uptake may explain the significant impairment of the pyruvate-driven oxidative phosphorylation induced by VPA.",
"references": [
"RC03764",
"RC03763"
]
}
]
}
