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"count": 334,
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"previous": "https://mitotox.org/api/papers/list?format=api&page=3",
"results": [
{
"pap_id": "69",
"title": "Generation of reactive oxygen species by the mitochondrial electron transport chain.",
"authors": "Liu, Yuanbin; Fiskum, Gary; Schubert, David",
"chapter": "",
"pages": "780-787",
"journal": "Journal of Neurochemistry",
"pub_date": "2002-03-01",
"pub_year": 2002,
"volume": "80",
"issue": "5",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1046/j.0022-3042.2002.00744.x",
"doi": "10.1046/j.0022-3042.2002.00744.x",
"pmid": "11948241.0",
"pmcid": "",
"abstract": "Generation of reactive oxygen species (ROS) by the mitochondrial electron transport chain (ETC), which is composed of four multiprotein complexes named complex I-IV, is believed to be important in the aging process and in the pathogenesis of neurodegenerative diseases such as Parkinson's disease. Previous studies have identified the ubiquinone of complex III and an unknown component of complex I as the major sites of ROS generation. Here we show that the physiologically relevant ROS generation supported by the complex II substrate succinate occurs at the flavin mononucleotide group (FMN) of complex I through reversed electron transfer, not at the ubiquinone of complex III as commonly believed. Indirect evidence indicates that the unknown ROS-generating site within complex I is also likely to be the FMN group. It is therefore suggested that the major physiologically and pathologically relevant ROS-generating site in mitochondria is limited to the FMN group of complex I. These new insights clarify an elusive target for intervening mitochondrial ROS-related processes or diseases.",
"references": [
"RC01119"
]
},
{
"pap_id": "7",
"title": "Assessment of drug-induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96-well platform.",
"authors": "Nadanaciva, Sashi; Rana, Payal; Beeson, Gyda C; Chen, Denise; Ferrick, David A; Beeson, Craig C; Will, Yvonne",
"chapter": "",
"pages": "421-437",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "2012-08-01",
"pub_year": 2012,
"volume": "44",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s10863-012-9446-z",
"doi": "10.1007/s10863-012-9446-z",
"pmid": "22689143.0",
"pmcid": "",
"abstract": "High-throughput applicable screens for identifying drug-induced mitochondrial impairment are necessary in the pharmaceutical industry. Hence, we evaluated the XF96 Extracellular Flux Analyzer, a 96-well platform that measures changes in the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells. The sensitivity of the platform was bench-marked with known modulators of oxidative phosphorylation and glycolysis. Sixteen therapeutic agents were screened in HepG2 cells for mitochondrial effects. Four of these compounds, thiazolidinediones, were also tested in primary feline cardiomyocytes for cell-type specific effects. We show that the XF96 platform is a robust, sensitive system for analyzing drug-induced mitochondrial impairment in whole cells. We identified changes in cellular respiration and acidification upon addition of therapeutic agents reported to have a mitochondrial effect. Furthermore, we show that respiration and acidification changes upon addition of the thiazoldinediones were cell-type specific, with the rank order of mitochondrial impairment in whole cells being in accord with the known adverse effects of these drugs.",
"references": [
"RC00514",
"RC00515",
"RC00516",
"RC00517",
"RC00518",
"RC00519",
"RC00520",
"RC00521",
"RC00522",
"RC00523",
"RC00524",
"RC00525",
"RC00526",
"RC00527",
"RC00528",
"RC00529",
"RC00530",
"RC00531",
"RC00532",
"RC00533",
"RC00534",
"RC00535",
"RC00536",
"RC00537",
"RC00538",
"RC00539",
"RC00540",
"RC00541",
"RC00542",
"RC00543",
"RC00544",
"RC00545",
"RC00546",
"RC00547",
"RC00548",
"RC00549",
"RC00550",
"RC00551",
"RC00552",
"RC00553",
"RC00554",
"RC00555",
"RC00556",
"RC00557",
"RC00558",
"RC00559",
"RC00560",
"RC00561",
"RC00562",
"RC00563",
"RC00978",
"RC00992",
"RC00993",
"RC00994",
"RC01001",
"RC01002",
"RC01045"
]
},
{
"pap_id": "70",
"title": "A possible site of superoxide generation in the complex I segment of rat heart mitochondria.",
"authors": "Ohnishi, S Tsuyoshi; Ohnishi, Tomoko; Muranaka, Shikibu; Fujita, Hirofumi; Kimura, Hiroko; Uemura, Koichi; Yoshida, Ken-ichi; Utsumi, Kozo",
"chapter": "",
"pages": "1-15",
"journal": "Journal of Bioenergetics and Biomembranes",
"pub_date": "2005-02-01",
"pub_year": 2005,
"volume": "37",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1007/s10863-005-4117-y",
"doi": "10.1007/s10863-005-4117-y",
"pmid": "15906144.0",
"pmcid": "",
"abstract": "We searched for possible sites of superoxide generation in the complex I segment of the respiratory chain by studying both forward and reverse electron transfer reactions in isolated rat heart mitochondria. Superoxide production was monitored by measuring the release of hydrogen peroxide from mitochondria with a fluorescence spectrophotometer using the Amplex red/horseradish peroxidase system. In the forward electron transfer, a slow superoxide production in the presence of glutamate and malate was enhanced by both rotenone and piericidin A (specific inhibitors at the end of the complex I respiratory chain). Both diphenileneiodonium and ethoxyformic anhydride (inhibitors for respiratory components located upstream of the respiratory chain) inhibited the enhancement by rotenone and piericidin A. In contrast, in reverse electron transfer driven by ATP, both diphenileneiodonium and ethoxyformic anhydride enhanced the superoxide production. Piericidin A also increased superoxide production. Rotenone increased it only in the presence of piericidin A. Our results suggest that the major site of superoxide generation is not flavin, but protein-associated ubisemiquinones which are spin-coupled with iron-sulfur cluster N2.",
"references": [
"RC01122",
"RC01121",
"RC01120"
]
},
{
"pap_id": "71",
"title": "Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi",
"authors": "Avenot, Hervé F.; Michailides, Themis J.",
"chapter": "",
"pages": "643-651",
"journal": "Crop Protection",
"pub_date": "2010-07-01",
"pub_year": 2010,
"volume": "29",
"issue": "7",
"Issn": "2612194",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S0261219410000554",
"doi": "10.1016/j.cropro.2010.02.019",
"pmid": "",
"pmcid": "",
"abstract": "Succinate dehydrogenase (Complex II or succinate-ubiquinone oxidoreductase) is the smallest complex in the respiratory chain and transfers the electrons derived from succinate directly to the ubiquinone pool. Succinate dehydrogenase inhibitor (SDHI) fungicides specifically inhibit fungal respiration by blocking the ubiquinone-binding sites in the mitochondrial complex II and play an important role in the integrated management programmes of many plant diseases. In contrast to first generation of SDHI fungicides (e.g. carboxin) exceptionally active against basidiomycetes, newer active ingredients in this class (e.g. boscalid, penthiopyrad, fluopyram) show a broad-spectrum activity against various fungal species. However, the consistent use of site-specific fungicides such as SDHIs can result in the selection of resistant fungal genotypes which may ultimately lead to a rapid decline of fungicide performance. This paper reviews previous and recent advances in understanding the molecular mechanisms and other factors controlling the evolution of resistance to SDHI fungicides. Furthermore, we provide recommendations on the future use of new developed molecules of this group as well as future research prospects.",
"references": [
"RC01129",
"RC01128",
"RC01127",
"RC01126",
"RC01125",
"RC01124",
"RC01123"
]
},
{
"pap_id": "72",
"title": "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction.",
"authors": "Horsefield, Rob; Yankovskaya, Victoria; Sexton, Graham; Whittingham, William; Shiomi, Kazuro; Omura, Satoshi; Byrne, Bernadette; Cecchini, Gary; Iwata, So",
"chapter": "",
"pages": "7309-7316",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2006-03-17",
"pub_year": 2006,
"volume": "281",
"issue": "11",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.M508173200",
"doi": "10.1074/jbc.M508173200",
"pmid": "16407191.0",
"pmcid": "",
"abstract": "The transfer of electrons and protons between membrane-bound respiratory complexes is facilitated by lipid-soluble redox-active quinone molecules (Q). This work presents a structural analysis of the quinone-binding site (Q-site) identified in succinate:ubiquinone oxidoreductase (SQR) from Escherichia coli. SQR, often referred to as Complex II or succinate dehydrogenase, is a functional member of the Krebs cycle and the aerobic respiratory chain and couples the oxidation of succinate to fumarate with the reduction of quinone to quinol (QH(2)). The interaction between ubiquinone and the Q-site of the protein appears to be mediated solely by hydrogen bonding between the O1 carbonyl group of the quinone and the side chain of a conserved tyrosine residue. In this work, SQR was co-crystallized with the ubiquinone binding-site inhibitor Atpenin A5 (AA5) to confirm the binding position of the inhibitor and reveal additional structural details of the Q-site. The electron density for AA5 was located within the same hydrophobic pocket as ubiquinone at, however, a different position within the pocket. AA5 was bound deeper into the site prompting further assessment using protein-ligand docking experiments in silico. The initial interpretation of the Q-site was re-evaluated in the light of the new SQR-AA5 structure and protein-ligand docking data. Two binding positions, the Q(1)-site and Q(2)-site, are proposed for the E. coli SQR quinone-binding site to explain these data. At the Q(2)-site, the side chains of a serine and histidine residue are suitably positioned to provide hydrogen bonding partners to the O4 carbonyl and methoxy groups of ubiquinone, respectively. This allows us to propose a mechanism for the reduction of ubiquinone during the catalytic turnover of the enzyme.",
"references": [
"RC01130"
]
},
{
"pap_id": "73",
"title": "Thiophene carboxamide fungicides: Structure-activity relationships with the succinate dehydrogenase complex from wild-type and carboxin-resistant mutant strains of Ustilago maydis",
"authors": "White, G.A.; Thorn, G.D.",
"chapter": "",
"pages": "26-40",
"journal": "Pesticide biochemistry and physiology",
"pub_date": "1980-08-01",
"pub_year": 1980,
"volume": "14",
"issue": "1",
"Issn": "483575",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/0048357580900206",
"doi": "10.1016/0048-3575(80)90020-6",
"pmid": "",
"pmcid": "",
"abstract": "A variety of thiophene carboxamide compounds have been synthesized and tested on the succinate dehydrogenase complex (SDC) in mitochondria from a wild-type strain and carboxin-resistant strains of Ustilago maydis (corn smut). The site of action of thiophene carboxamides is identical to that of carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and thenoyltrifluoroacetone, that is, the succinate-ubiquinone reductase (complex II) span in the mitochondrial electron transfer chain. This investigation reveals new molecular structures which are strong inhibitors of wild-type and carboxin-resistant SDCs. The 5-amino analog of the parent anilide, 3-methylthiophene-2-carboxanilide (I), proved to be an especially potent inhibitor of the wild-type SDC (I50, 0.019 μM). Analogs of (I) such as 4′-carboethoxy, 4′-nbutyl, 4′-phenyl, and 4′-benzoyl were negatively correlated in activity to the carboxanilide (I) with respect to resistance level. A number of structures showed considerable selectivity for mutated SDCs from both highly and (particularly) moderately carboxin-resistant SDCs of U. maydis, markedly lowering the resistance level, i.e., the degree of resistance. Thus, in addition to the oxathiins, specific structural groups of thiophene carboxamides can also alleviate or reverse the effect of carboxin-selected mutation with reference to inhibition of the SDC. Of important significance was the finding that molecular selectivity for mutated, carboxin-resistant SDCs can be influenced by replacement of an oxathiin by a thiophene heterocyclic ring as well as by the substitutive group on the amide nitrogen, permitting different categories of mutant types and even mutants within a single category to be distinguished from one another. With all the structural combinations available, it appears quite possible, in terms of inhibition, to overcome any type of mutation in a fungal SDC which arises through selection by carboxin or other carboxamide compounds. A reasonable correlation generally exists between inhibition by thiophene carboxamides of the SDC and sporidial growth of wild-type and carboxin-resistant strains of U. maydis. A permeability barrier to 4′-substituted analogs of (I) was encountered in the wild-type strain but not mutant strains. Excellent protectant activity against bean rust (Uromyces phaseoli) was obtained with the 3′-nhexyl, 3′-nhexyloxy, and 4′-phenoxy analogs of (I).",
"references": [
"RC01131"
]
},
{
"pap_id": "74",
"title": "Crystallographic studies of the Escherichia coli quinol-fumarate reductase with inhibitors bound to the quinol-binding site.",
"authors": "Iverson, Tina M; Luna-Chavez, César; Croal, Laura R; Cecchini, Gary; Rees, Douglas C",
"chapter": "",
"pages": "16124-16130",
"journal": "The Journal of Biological Chemistry",
"pub_date": "2002-05-03",
"pub_year": 2002,
"volume": "277",
"issue": "18",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1074/jbc.M200815200",
"doi": "10.1074/jbc.M200815200",
"pmid": "11850430.0",
"pmcid": "",
"abstract": "The quinol-fumarate reductase (QFR) respiratory complex of Escherichia coli is a four-subunit integral-membrane complex that catalyzes the final step of anaerobic respiration when fumarate is the terminal electron acceptor. The membrane-soluble redox-active molecule menaquinol (MQH(2)) transfers electrons to QFR by binding directly to the membrane-spanning region. The crystal structure of QFR contains two quinone species, presumably MQH(2), bound to the transmembrane-spanning region. The binding sites for the two quinone molecules are termed Q(P) and Q(D), indicating their positions proximal (Q(P)) or distal (Q(D)) to the site of fumarate reduction in the hydrophilic flavoprotein and iron-sulfur protein subunits. It has not been established whether both of these sites are mechanistically significant. Co-crystallization studies of the E. coli QFR with the known quinol-binding site inhibitors 2-heptyl-4-hydroxyquinoline-N-oxide and 2-[1-(p-chlorophenyl)ethyl] 4,6-dinitrophenol establish that both inhibitors block the binding of MQH(2) at the Q(P) site. In the structures with the inhibitor bound at Q(P), no density is observed at Q(D), which suggests that the occupancy of this site can vary and argues against a structurally obligatory role for quinol binding to Q(D). A comparison of the Q(P) site of the E. coli enzyme with quinone-binding sites in other respiratory enzymes shows that an acidic residue is structurally conserved. This acidic residue, Glu-C29, in the E. coli enzyme may act as a proton shuttle from the quinol during enzyme turnover.",
"references": [
"RC01132"
]
},
{
"pap_id": "75",
"title": "Purification and characterization of Plasmodium falciparum succinate dehydrogenase.",
"authors": "Suraveratum, N; Krungkrai, S R; Leangaramgul, P; Prapunwattana, P; Krungkrai, J",
"chapter": "",
"pages": "215-222",
"journal": "Molecular and Biochemical Parasitology",
"pub_date": "2000-02-05",
"pub_year": 2000,
"volume": "105",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/s0166-6851(99)00180-2",
"doi": "10.1016/s0166-6851(99)00180-2",
"pmid": "10693744.0",
"pmcid": "",
"abstract": "Succinate dehydrogenase (SDH), a Krebs cycle enzyme and complex II of the mitochondrial electron transport system was purified to near homogeneity from the human malarial parasite Plasmodium falciparum cultivated in vitro by FPLC on Mono Q, Mono S and Superose 6 gel filtration columns. The malarial SDH activity was found to be extremely labile. Based on Superose 6 FPLC, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and nondenaturing-PAGE analyses, it was demonstrated that the malarial enzyme had an apparent native molecular mass of 90 +/- 8 kDa and contained two major subunits with molecular masses of 55 +/- 6 and 35 +/- 4 kDa (n = 8). The enzymatic reaction required both succinate and coenzyme Q (CoQ) for its maximal catalysis with Km values of 3 and 0.2 microM, and k(cat) values of 0.11 and 0.06 min(-1), respectively. Catalytic efficiency of the malarial SDH for both substrates were found to be relatively low (approximately 600-5000 M(-1) s(-1)). Fumarate, malonate and oxaloacetate were found to inhibit the malarial enzyme with Ki values of 81, 13 and 12 microM, respectively. The malarial enzyme activity was also inhibited by substrate analog of CoQ, 5-hydroxy-2-methyl-1,4-naphthoquinone, with a 50% inhibitory concentration of 5 microM. The quinone had antimalarial activity against the in vitro growth of P. falciparum with a 50% inhibitory concentration of 0.27 microM and was found to completely inhibit oxygen uptake of the parasite at a concentration of 0.88 microM. A known inhibitor of mammalian mitochondrial SDH, 2-thenoyltrifluoroacetone. had no inhibitory effect on both the malarial SDH activity and the oxygen uptake of the parasite at a concentration of 50 microM. Many properties observed in the malarial SDH were found to be different from the host mammalian enzyme.",
"references": []
},
{
"pap_id": "76",
"title": "Polymyxin B identified as an inhibitor of alternative NADH dehydrogenase and malate: quinone oxidoreductase from the Gram-positive bacterium Mycobacterium smegmatis.",
"authors": "Mogi, Tatsushi; Murase, Yoshiro; Mori, Mihoko; Shiomi, Kazuro; Omura, Satoshi; Paranagama, Madhavi P; Kita, Kiyoshi",
"chapter": "",
"pages": "491-499",
"journal": "Journal of Biochemistry",
"pub_date": "2009-10-01",
"pub_year": 2009,
"volume": "146",
"issue": "4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1093/jb/mvp096",
"doi": "10.1093/jb/mvp096",
"pmid": "19564154.0",
"pmcid": "",
"abstract": "Tuberculosis is the leading cause of death due to a single infectious agent in the world and the emergence of multidrug-resistant strains prompted us to develop new drugs with novel targets and mechanism. Here, we screened a natural antibiotics library with Mycobacterium smegmatis membrane-bound dehydrogenases and identified polymyxin B (cationic decapeptide) and nanaomycin A (naphtoquinone derivative) as inhibitors of alternative NADH dehydrogenase [50% inhibitory concentration (IC(50)) values of 1.6 and 31 microg/ml, respectively] and malate: quinone oxidoreductase (IC(50) values of 4.2 and 49 microg/ml, respectively). Kinetic analysis on inhibition by polymyxin B showed that the primary site of action was the quinone-binding site. Because of the similarity in K(m) value for ubiquinone-1 and inhibitor sensitivity, we examined amino acid sequences of actinobacterial enzymes and found possible binding sites for L-malate and quinones. Proposed mechanisms of polymyxin B and nanaomycin A for the bacteriocidal activity were the destruction of bacterial membranes and production of reactive oxygen species, respectively, while this study revealed their inhibitory activity on bacterial membrane-bound dehydrogenases. Screening of the library with bacterial respiratory enzymes resulted in unprecedented findings, so we are hoping that continuing efforts could identify lead compounds for new drugs targeting to mycobacterial respiratory enzymes.",
"references": [
"RC01138",
"RC01137",
"RC01136",
"RC01135",
"RC01134"
]
},
{
"pap_id": "77",
"title": "Mode of action of novel acaricide pyflubumide: Effects on the mitochondrial respiratory chain",
"authors": "Nakano, Motofumi; Yasokawa, Noriaki; Suwa, Akiyuki; Fujioka, Shinsuke; Furuya, Takashi; Sakata, Kazuyuki",
"chapter": "",
"pages": "19-24",
"journal": "Journal of pesticide science",
"pub_date": "1905-07-07",
"pub_year": 1905,
"volume": "40",
"issue": "1",
"Issn": "1348-589X",
"Isbn": "",
"url": "https://www.jstage.jst.go.jp/article/jpestics/40/1/40_D14-086/_article",
"doi": "10.1584/jpestics.D14-086",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC01140",
"RC01139"
]
},
{
"pap_id": "78",
"title": "Discovery and synthesis of crop protection products",
"authors": "Xiong, Li; Shen, Yan-Qing; Jiang, Li-Na; Zhu, Xiao-Lei; Yang, Wen-Chao; Huang, Wei; Yang, Guang-Fu",
"chapter": "Succinate dehydrogenase: an ideal target for fungicide discovery",
"pages": "175-194",
"journal": "",
"pub_date": "2015-01-01",
"pub_year": 2015,
"volume": "1204",
"issue": "",
"Issn": "0097-6156",
"Isbn": "0-8412-3101-X",
"url": "https://pubs.acs.org/doi/abs/10.1021/bk-2015-1204.ch013",
"doi": "10.1021/bk-2015-1204.ch013",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC01141"
]
},
{
"pap_id": "79",
"title": "Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate.",
"authors": "Greene, J G; Greenamyre, J T",
"chapter": "",
"pages": "430-436",
"journal": "Journal of Neurochemistry",
"pub_date": "1995-01-01",
"pub_year": 1995,
"volume": "64",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1046/j.1471-4159.1995.64010430.x",
"doi": "10.1046/j.1471-4159.1995.64010430.x",
"pmid": "7528265.0",
"pmcid": "",
"abstract": "Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are involved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor-mediated excitotoxic neuronal death. If this mechanism of \"secondary\" or \"weak\" excitotoxicity plays a role in neurodegenerative disease, NMDA antagonists and other \"antiexcitotoxic\" strategies may have therapeutic potential for these diseases.",
"references": [
"RC01146",
"RC01145",
"RC01144",
"RC01143",
"RC01142"
]
},
{
"pap_id": "8",
"title": "N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes.",
"authors": "Rodriguez, R J; Acosta, D",
"chapter": "",
"pages": "123-131",
"journal": "Toxicology",
"pub_date": "1997-02-28",
"pub_year": 1997,
"volume": "117",
"issue": "2-3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/s0300-483x(96)03560-3",
"doi": "10.1016/s0300-483x(96)03560-3",
"pmid": "9057891.0",
"pmcid": "",
"abstract": "Ketoconazole (KT) is an azole antifungal agent that has been associated with hepatotoxicity. The mechanism of its hepatotoxicity has not yet been resolved. It has been suggested that a reactive metabolite may be the cause of toxicity because the hepatic injury does not appear to be mediated through an immunoallergic mechanism. Several metabolites of KT have been reported in the literature of which the deacetylated metabolite, N-deacetyl ketoconazole (DAK), is the major metabolite which undergoes further metabolism by the flavin-containing monooxygenases (FMO) to form a potentially toxic dialdehyde. The objective of this study was to evaluate DAK's cytotoxicity and the role of FMO in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of the cytosolic enzyme, lactate dehydrogenase (LDH), into the medium and by assessing mitochondrial reduction of 3-(4,5-dimethythiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT). The cultures were exposed to various concentrations of DAK (20-160 microM) for 0.5-4 h. There was a significant increase (P < 0.05) in LDH leakage and an immediate decrease in MTT reduction (P < 0.05) as early as 0.5 h. The MTT reduction assay appeared to be more sensitive than the LDH assay in that lower concentrations were needed to observe a 50% reduction of MTT (107, 90, 75, 58 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively). The concentrations to observe 50% LDH leakage from the hepatocytes were 155, 133, 100, 70 microM DAK at 0.5, 1.0, 2.0 and 4.0 h, respectively. Moreover, co-treatment with methimazole, a competitive substrate for FMO, produced a significant decrease (P < 0.05) in % LDH leakage as early as 0.5 h, when compared to cells treated solely with DAK. Also, the toxicity was significantly (P < 0.05) enhanced as early as 0.5 h by n-octylamine, a known positive effector for FMO. These results demonstrate that DAK is a more potent cytotoxicant than its parent compound, KT, as reported previously by our laboratory (Rodriguez and Acosta, Toxicology, 96: 83-92, 1995) and its toxicity was expressed in a dose- and time-dependent manner. Furthermore, DAK's cytotoxicity was enhanced with n-octylamine and suppressed with methimazole, suggesting a role for FMO in the toxicity of the metabolite.",
"references": [
"RC00564",
"RC00565",
"RC00566",
"RC00567",
"RC00568",
"RC00569",
"RC00570",
"RC00571",
"RC00572",
"RC00573",
"RC00574",
"RC00575",
"RC00576",
"RC00577",
"RC00578",
"RC00579",
"RC00580",
"RC00581",
"RC00582",
"RC00583",
"RC00584",
"RC00585",
"RC00586",
"RC00587",
"RC00588",
"RC00589",
"RC00590",
"RC00591",
"RC00592",
"RC00593"
]
},
{
"pap_id": "80",
"title": "Identification of the BAL-labile factor.",
"authors": "Slater, E C; de Vries, S",
"chapter": "",
"pages": "717-718",
"journal": "Nature",
"pub_date": "1980-12-25",
"pub_year": 1980,
"volume": "288",
"issue": "5792",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1038/288717a0",
"doi": "10.1038/288717a0",
"pmid": "6256640.0",
"pmcid": "",
"abstract": "One of us has previously reported that treatment of the Keilin and Hartree heart-muscle preparation with 2,3-dimercaptopropanol (BAL), in the presence of air, leads to the complete inactivation of the succinate oxidase system with little if any effect on the activities of succinate dehydrogenase (until more than half the BAL was oxidized) or cytochrome c oxidase. The inactivation of the complete succinate oxidase system requires the oxidation of BAL by air in the presence of the enzyme. It is not caused by H2O2 or BAL disulphides produced during the oxidation of BAL. Spectroscopic studies identified the block as lying between cytochromes b and c. It was suggested that a BAL-labile factor is present which transfers electrons from cytochrome b to cytochrome c and which is destroyed by coupled oxidation with BAL. The factor is also required for NADH oxidation. Subsequent work showed it is not identical with cytochrome c1 (ref. 4), myoglobin present in the preparation or the antimycin-binding site. We report here that this factor is identical to the iron-sulphur protein in the central portion of the respiratory chain first identified by Rieske.",
"references": [
"RC01147"
]
},
{
"pap_id": "81",
"title": "Complete inhibition of electron transfer from ubiquinol to cytochrome b by the combined action of antimycin and myxothiazol.",
"authors": "von Jagow, G; Engel, W D",
"chapter": "",
"pages": "19-24",
"journal": "FEBS Letters",
"pub_date": "1981-12-21",
"pub_year": 1981,
"volume": "136",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0014-5793(81)81206-9",
"doi": "10.1016/0014-5793(81)81206-9",
"pmid": "7319059.0",
"pmcid": "",
"abstract": "",
"references": [
"RC01148"
]
},
{
"pap_id": "82",
"title": "Mechanistic differences in inhibition of ubiquinol cytochrome c reductase by the proximal Qo-site inhibitors famoxadone and methoxyacrylate stilbene.",
"authors": "Pember, Stephen O; Fleck, Lois C; Moberg, William K; Walker, Michael P",
"chapter": "",
"pages": "280-290",
"journal": "Archives of Biochemistry and Biophysics",
"pub_date": "2005-03-15",
"pub_year": 2005,
"volume": "435",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.abb.2004.12.013",
"doi": "10.1016/j.abb.2004.12.013",
"pmid": "15708371.0",
"pmcid": "",
"abstract": "Famoxadone (FAM) is a newly commercialized antibiotic for use against plant pathogenic fungi. It inhibits mitochondria ubiquinol:cytochrome c oxidoreductase (EC 1.10.2.2, bc(1) complex) function by binding to the proximal niche of the quinol oxidation site on the enzyme. FAM has effects on the enzyme characteristic of both type Ia (E-beta-methoxyacrylates) and type Ic (stigmatellin) inhibitors. Steady-state and tight-binding inhibition kinetics; as well as direct binding measurements with famoxadone (FAM) and methoxyacrylate stilbene (MOAS), indicated that FAM is a non-competitive inhibitor of the enzyme while methoxyacrylate stilbene (MOAS) is better described as a mixed-competitive inhibitor with respect to substrate. Mixed-competitive and non-competitive inhibition kinetics predicts a ternary enzyme-substrate-inhibitor (ESI) intermediate in the reaction sequence. Current views of the Qo domain architecture propose substrate binding niches in both distal and proximal regions of the domain. Since both inhibitors bind within the proximal niche, the formation of an ESI complex implicates substrate binding within the distal niche near the iron-sulfur protein (ISP) and cytochrome c(1) (C1). In the presence of saturating FAM, addition of substrate led to a slow, nearly stoichiometric reduction of C1 that was enzyme dependent, and independent of O(2)(-) production. Similar experiments with saturating MOAS led to a slow, sub-stoichiometric reduction of C1 by substrate. A comparison of the stoichiometries of reduction, and the apparent second order rate constants (K(cat)/K(m)) indicated that saturating MOAS elicits two distinct enzyme-inhibitor (EI) intermediates. One form does not bind substrate, but the other does. In contrast, saturating FAM leads to a predominant EI form capable of binding substrate. We suggest that these differences can be correlated to the respective effects of each inhibitor on the position of the ISP, and the integrity of a distal substrate binding site. The results also indicate that binding of these inhibitory substrate analogues to the proximal niche of the Qo domain significantly increases the DeltaG(double dagger) for reduction of C1.",
"references": [
"RC01149"
]
},
{
"pap_id": "83",
"title": "Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc(1) complex.",
"authors": "Esser, Lothar; Quinn, Byron; Li, Yong-Fu; Zhang, Minquan; Elberry, Maria; Yu, Linda; Yu, Chang-An; Xia, Di",
"chapter": "",
"pages": "281-302",
"journal": "Journal of Molecular Biology",
"pub_date": "2004-07-30",
"pub_year": 2004,
"volume": "341",
"issue": "1",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.jmb.2004.05.065",
"doi": "10.1016/j.jmb.2004.05.065",
"pmid": "15312779.0",
"pmcid": "",
"abstract": "Cytochrome bc(1) is an integral membrane protein complex essential for cellular respiration and photosynthesis; it couples electron transfer from quinol to cytochrome c to proton translocation across the membrane. Specific bc(1) inhibitors have not only played crucial roles in elucidating the mechanism of bc(1) function but have also provided leads for the development of novel antibiotics. Crystal structures of bovine bc(1) in complex with the specific Q(o) site inhibitors azoxystrobin, MOAS, myxothiazol, stigmatellin and 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole were determined. Interactions, conformational changes and possible mechanisms of resistance, specific to each inhibitor, were defined. Residues and secondary structure elements that are capable of discriminating different classes of Q(o) site inhibitors were identified for the cytochrome b subunit. Directions in the displacement of the cd1 helix of cytochrome b subunit in response to various Q(o) site inhibitors were correlated to the binary conformational switch of the extrinsic domain of the iron-sulfur protein subunit. The new structural information, together with structures previously determined, provide a basis that, combined with biophysical and mutational data, suggest a modification to the existing classification of bc(1) inhibitors. bc(1) inhibitors are grouped into three classes: class P inhibitors bind to the Q(o) site, class N inhibitors bind to the Q(i) site and the class PN inhibitors target both sites. Class P contains two subgroups, Pm and Pf, that are distinct by their ability to induce mobile or fixed conformation of iron-sulfur protein.",
"references": [
"RC01161",
"RC01159",
"RC01158",
"RC01157",
"RC01156",
"RC01155",
"RC01154",
"RC01150"
]
},
{
"pap_id": "84",
"title": "Oudemansin, strobilurin A, strobilurin B and myxothiazol: new inhibitors of the bc 1 segment of the respiratory chain with an E-β-methoxyacrylate system as common structural element",
"authors": "Becker, W.F.; Von Jagow, G.; Anke, T.; Steglich, W.",
"chapter": "",
"pages": "329-333",
"journal": "FEBS Letters",
"pub_date": "1981-09-28",
"pub_year": 1981,
"volume": "132",
"issue": "2",
"Issn": "145793",
"Isbn": "",
"url": "http://doi.wiley.com/10.1016/0014-5793%2881%2981190-8",
"doi": "10.1016/0014-5793(81)81190-8",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC01153",
"RC01152",
"RC01151"
]
},
{
"pap_id": "85",
"title": "A bioenergetics assay for studying the effects of environmental stressors on mitochondrial function in vivo in zebrafish larvae.",
"authors": "Raftery, Tara D; Jayasundara, Nishad; Di Giulio, Richard T",
"chapter": "",
"pages": "23-32",
"journal": "Comparative Biochemistry and Physiology. Toxicology & Pharmacology",
"pub_date": "2017-02-01",
"pub_year": 2017,
"volume": "192",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.cbpc.2016.12.001",
"doi": "10.1016/j.cbpc.2016.12.001",
"pmid": "27939721.0",
"pmcid": "PMC5218841",
"abstract": "Mitochondria, an integral component of cellular energy metabolism and other key functions, are extremely vulnerable to damage by environmental stressors. Although methods to measure mitochondrial function in vitro exist, sensitive, medium- to high-throughput assays that assess respiration within physiologically-relevant whole organisms are needed to identify drugs and/or chemicals that disrupt mitochondrial function, particularly at sensitive early developmental stages. Consequently, we have developed and optimized an assay to measure mitochondrial bioenergetics in zebrafish larvae using the XFe24 Extracellular Flux Analyzer. To prevent larval movement from confounding oxygen consumption measurements, we relied on MS-222-based anesthetization. We obtained stable measurement values in the absence of effects on average oxygen consumption rate and subsequently optimized the use of pharmacological agents for metabolic partitioning. To confirm assay reproducibility we demonstrated that triclosan, a positive control, significantly decreased spare respiratory capacity. We then exposed zebrafish from 5 hours post-fertilization (hpf) to 6days post-fertilization (dpf) to three polycyclic aromatic hydrocarbons (PAHs) - benzo(a)pyrene (BaP), phenanthrene (Phe), and fluoranthene (FL) - and measured various fundamental parameters of mitochondrial respiratory chain function, including maximal respiration, spare respiratory capacity, mitochondrial and non-mitochondrial respiration. Exposure to all three PAHs decreased spare respiratory capacity and maximal respiration. Additionally, Phe exposure increased non-mitochondrial respiration and FL exposure decreased mitochondrial respiration and increased non-mitochondrial respiration. Overall, this whole organism-based assay provides a platform for examining mitochondrial dysfunction in vivo at critical developmental stages. It has important implications in biomedical sciences, toxicology and ecophysiology, particularly to examine the effects of environmental chemicals and/or drugs on mitochondrial bioenergetics. Copyright © 2016 Elsevier Inc. All rights reserved.",
"references": [
"RC01254",
"RC01255",
"RC01256",
"RC01257",
"RC01258",
"RC01259",
"RC01260",
"RC01261",
"RC01262",
"RC01263",
"RC01264",
"RC01265",
"RC01266",
"RC01267",
"RC01268",
"RC01269",
"RC01270",
"RC01271",
"RC01272",
"RC01273",
"RC01274"
]
},
{
"pap_id": "86",
"title": "Comparative developmental toxicity of environmentally relevant oxygenated PAHs.",
"authors": "Knecht, Andrea L; Goodale, Britton C; Truong, Lisa; Simonich, Michael T; Swanson, Annika J; Matzke, Melissa M; Anderson, Kim A; Waters, Katrina M; Tanguay, Robert L",
"chapter": "",
"pages": "266-275",
"journal": "Toxicology and Applied Pharmacology",
"pub_date": "2013-09-01",
"pub_year": 2013,
"volume": "271",
"issue": "2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.taap.2013.05.006",
"doi": "10.1016/j.taap.2013.05.006",
"pmid": "23684558.0",
"pmcid": "PMC3976560",
"abstract": "Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are byproducts of combustion and photo-oxidation of parent PAHs. OPAHs are widely present in the environment and pose an unknown hazard to human health. The developing zebrafish was used to evaluate a structurally diverse set of 38 OPAHs for malformation induction, gene expression changes and mitochondrial function. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to a dilution series of 38 different OPAHs and evaluated for 22 developmental endpoints. AHR activation was determined via CYP1A immunohistochemistry. Phenanthrenequinone (9,10-PHEQ), 1,9-benz-10-anthrone (BEZO), xanthone (XAN), benz(a)anthracene-7,12-dione (7,12-B[a]AQ), and 9,10-anthraquinone (9,10-ANTQ) were evaluated for transcriptional responses at 48hpf, prior to the onset of malformations. qRT-PCR was conducted for a number of oxidative stress genes, including the glutathione transferase(gst), glutathione peroxidase(gpx), and superoxide dismutase(sod) families. Bioenergetics was assayed to measure in vivo oxidative stress and mitochondrial function in 26hpf embryos exposed to OPAHs. Hierarchical clustering of the structure-activity outcomes indicated that the most toxic of the OPAHs contained adjacent diones on 6-carbon moieties or terminal, para-diones on multi-ring structures. 5-carbon moieties with adjacent diones were among the least toxic OPAHs while the toxicity of multi-ring structures with more centralized para-diones varied considerably. 9,10-PHEQ, BEZO, 7,12-B[a]AQ, and XAN exposures increased expression of several oxidative stress related genes and decreased oxygen consumption rate (OCR), a measurement of mitochondrial respiration. Comprehensive in vivo characterization of 38 structurally diverse OPAHs indicated differential AHR dependency and a prominent role for oxidative stress in the toxicity mechanisms. Published by Elsevier Inc.",
"references": [
"RC01285",
"RC01284",
"RC01283",
"RC01282",
"RC01281",
"RC01280",
"RC01279",
"RC01278",
"RC01277",
"RC01276",
"RC01275"
]
},
{
"pap_id": "87",
"title": "Teratogenic, bioenergetic, and behavioral effects of exposure to total particulate matter on early development of zebrafish (Danio rerio) are not mimicked by nicotine.",
"authors": "Massarsky, Andrey; Jayasundara, Nishad; Bailey, Jordan M; Oliveri, Anthony N; Levin, Edward D; Prasad, G L; Di Giulio, Richard T",
"chapter": "",
"pages": "77-88",
"journal": "Neurotoxicology and Teratology",
"pub_date": "2015-10-01",
"pub_year": 2015,
"volume": "51",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.ntt.2015.09.006",
"doi": "10.1016/j.ntt.2015.09.006",
"pmid": "26391568.0",
"pmcid": "PMC4821439",
"abstract": "Cigarette smoke has been associated with a number of pathologies; however, the mechanisms leading to developmental effects are yet to be fully understood. The zebrafish embryo is regarded as a 'bridge model'; however, not many studies examined its applicability to cigarette smoke toxicity. This study examined the effects of total particulate matter (TPM) from 3R4F reference cigarettes on the early development of zebrafish (Danio rerio). Zebrafish embryos were exposed to two concentrations of TPM (0.4 and 1.4 μg/mL equi-nicotine units) or nicotine at equivalent doses. The exposures began at 2h post-fertilization (hpf) and lasted until 96 hpf. Several physiological parameters were assessed during or after the exposure. We show that TPM increased mortality, delayed hatching, and increased the incidence of deformities in zebrafish. TPM exposure also increased the incidence of hemorrhage and disrupted the angiogenesis of the major vessels in the brain. Moreover, TPM exposure reduced the larval body length, decreased the heart rate, and reduced the metabolic rate. Biomarkers of xenobiotic metabolism and oxidative stress were also affected. TPM-exposed zebrafish also differed behaviorally: at 24 hpf the embryos had a higher frequency of spontaneous contractions and at 144 hpf the larvae displayed swimming hyperactivity. This study demonstrates that TPM disrupts several aspects of early development in zebrafish. The effects reported for TPM were not attributable to nicotine, since embryos treated with nicotine alone did not differ significantly from the control group. Collectively, our work illustrates the utility of zebrafish as an alternative model to evaluate the toxic effects of cigarette smoke constituents. Copyright © 2015 Elsevier Inc. All rights reserved.",
"references": [
"RC01289",
"RC01288",
"RC01287",
"RC01286"
]
},
{
"pap_id": "88",
"title": "Lipid abundance in zebrafish embryos is regulated by complementary actions of the endocannabinoid system and retinoic acid pathway.",
"authors": "Fraher, Daniel; Ellis, Megan K; Morrison, Shona; McGee, Sean L; Ward, Alister C; Walder, Ken; Gibert, Yann",
"chapter": "",
"pages": "3596-3609",
"journal": "Endocrinology",
"pub_date": "2015-10-01",
"pub_year": 2015,
"volume": "156",
"issue": "10",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1210/EN.2015-1315",
"doi": "10.1210/EN.2015-1315",
"pmid": "26181105.0",
"pmcid": "",
"abstract": "The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization (WISH). Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA-modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. In addition, RA treatment increased expression of CCAAT/enhancer-binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPARγ) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPARγ to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development.",
"references": [
"RC01290",
"RC01291",
"RC01292",
"RC01293",
"RC01294",
"RC01295",
"RC01296",
"RC01297",
"RC01298",
"RC01299",
"RC01300",
"RC01301",
"RC01302",
"RC01303",
"RC01304",
"RC01305",
"RC01306",
"RC01307",
"RC01308",
"RC01309",
"RC01310",
"RC01311",
"RC01312",
"RC01313",
"RC01314",
"RC01315",
"RC01316",
"RC01317"
]
},
{
"pap_id": "89",
"title": "Triclosan is a mitochondrial uncoupler in live zebrafish.",
"authors": "Shim, Juyoung; Weatherly, Lisa M; Luc, Richard H; Dorman, Maxwell T; Neilson, Andy; Ng, Ryan; Kim, Carol H; Millard, Paul J; Gosse, Julie A",
"chapter": "",
"pages": "1662-1667",
"journal": "Journal of Applied Toxicology",
"pub_date": "2016-03-28",
"pub_year": 2016,
"volume": "36",
"issue": "12",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1002/jat.3311",
"doi": "10.1002/jat.3311",
"pmid": "27111768.0",
"pmcid": "PMC5040606",
"abstract": "Triclosan (TCS) is a synthetic antimicrobial agent used in many consumer goods at millimolar concentrations. As a result of exposure, TCS has been detected widely in humans. We have recently discovered that TCS is a proton ionophore mitochondrial uncoupler in multiple types of living cells. Here, we present novel data indicating that TCS is also a mitochondrial uncoupler in a living organism: 24-hour post-fertilization (hpf) zebrafish embryos. These experiments were conducted using a Seahorse Bioscience XFe 96 Extracellular Flux Analyzer modified for bidirectional temperature control, using the XF96 spheroid plate to position and measure one zebrafish embryo per well. Using this method, after acute exposure to TCS, the basal oxygen consumption rate (OCR) increases, without a decrease in survival or heartbeat rate. TCS also decreases ATP-linked respiration and spare respiratory capacity and increases proton leak: all indicators of mitochondrial uncoupling. Our data indicate, that TCS is a mitochondrial uncoupler in vivo, which should be taken into consideration when assessing the toxicity and/or pharmaceutical uses of TCS. This is the first example of usage of a Seahorse Extracellular Flux Analyzer to measure bioenergetic flux of a single zebrafish embryo per well in a 96-well assay format. The method developed in this study provides a high-throughput tool to identify previously unknown mitochondrial uncouplers in a living organism. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.",
"references": [
"RC01320",
"RC01319",
"RC01318"
]
},
{
"pap_id": "9",
"title": "Inhibitory effects of vitamin K3 on DNA polymerase and angiogenesis",
"authors": "Matsubara, ",
"chapter": "",
"pages": "",
"journal": "International Journal of Molecular Medicine",
"pub_date": "1905-06-20",
"pub_year": 1905,
"volume": "",
"issue": "",
"Issn": "11073756",
"Isbn": "",
"url": "http://www.spandidos-publications.com/ijmm/article.jsp?article_id=ijmm_22_3_381",
"doi": "10.3892/ijmm_00000034",
"pmid": "",
"pmcid": "",
"abstract": "",
"references": [
"RC00599",
"RC00598",
"RC00597"
]
},
{
"pap_id": "90",
"title": "The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos.",
"authors": "Bestman, Jennifer E; Stackley, Krista D; Rahn, Jennifer J; Williamson, Tucker J; Chan, Sherine S L",
"chapter": "",
"pages": "51-69",
"journal": "Differentiation; Research in Biological Diversity",
"pub_date": "2015-04-01",
"pub_year": 2015,
"volume": "89",
"issue": "3-4",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.diff.2015.01.001",
"doi": "10.1016/j.diff.2015.01.001",
"pmid": "25771346.0",
"pmcid": "PMC4466198",
"abstract": "The etiology of mitochondrial disease is poorly understood. Furthermore, treatment options are limited, and diagnostic methods often lack the sensitivity to detect disease in its early stages. Disrupted oxidative phosphorylation (OXPHOS) that inhibits ATP production is a common phenotype of mitochondrial disorders that can be induced in zebrafish by exposure to 2,4-dinitrophenol (DNP), a FDA-banned weight-loss agent and EPA-regulated environmental toxicant, traditionally used in research labs as an uncoupler of OXPHOS. Despite the DNP-induced OXPHOS inhibition we observed using in vivo respirometry, the development of the DNP-treated and control zebrafish were largely similar during the first half of embryogenesis. During this period, DNP-treated embryos induced gene expression of mitochondrial and nuclear genes that stimulated the production of new mitochondria and increased glycolysis to yield normal levels of ATP. DNP-treated embryos were incapable of sustaining this mitochondrial biogenic response past mid-embryogenesis, as shown by significantly lowered ATP production and ATP levels, decreased gene expression, and the onset of developmental defects. Examining neural tissues commonly affected by mitochondrial disease, we found that DNP exposure also inhibited motor neuron axon arbor outgrowth and the proper formation of the retina. We observed and quantified the molecular and physiological progression of mitochondrial dysfunction during development with this new model of OXPHOS dysfunction, which has great potential for use in diagnostics and therapies for mitochondrial disease. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.",
"references": [
"RC01328",
"RC01327",
"RC01326",
"RC01325",
"RC01324",
"RC01323",
"RC01322",
"RC01321"
]
},
{
"pap_id": "91",
"title": "Quercetin, a natural product supplement, impairs mitochondrial bioenergetics and locomotor behavior in larval zebrafish (Danio rerio).",
"authors": "Zhang, Ji-Liang; Laurence Souders, Christopher; Denslow, Nancy D; Martyniuk, Christopher J",
"chapter": "",
"pages": "30-38",
"journal": "Toxicology and Applied Pharmacology",
"pub_date": "2017-07-15",
"pub_year": 2017,
"volume": "327",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.taap.2017.04.024",
"doi": "10.1016/j.taap.2017.04.024",
"pmid": "28450151.0",
"pmcid": "",
"abstract": "Quercetin is a natural product that is sold as a supplement in health food stores. While there are reported benefits for this flavonoid as a dietary supplement due to antioxidant properties, the full scope of its biological interactions has not been fully addressed. To learn more about the mechanisms of action related to quercetin, we exposed zebrafish (Danio rerio) embryos to 1 and 10μg/L quercetin for 96h starting at 3h post fertilization. Quercetin up to 10μg/L did not induce significant mortality in developing fish, but did increase prevalence of an upward-curved dorsal plane in hatched larvae. To determine whether this developmental defect was potentially related to mitochondrial bioenergetics during development, we measured oxygen consumption rate in whole embryos following a 24-hour exposure to quercetin. Basal mitochondrial and ATP-linked respiration were decreased at 1 and 10μg/L quercetin, and maximal respiration was decreased at 10μg/L quercetin, suggesting that quercetin impairs mitochondrial bioenergetics. This is proposed to be related to the deformities observed during development. Due to the fact that ATP production was affected by quercetin, larval behaviors related to locomotion were investigated, as well as transcriptional responses of six myogenesis transcripts. Quercetin at 10μg/L significantly reduced the swimming velocity of zebrafish larvae. The expression levels of both myostatin A (mstna) and myogenic differentiation (myoD) were also altered by quercetin. Mstna, an inhibitory factor for myogenesis, was significantly increased at 1μg/L quercetin exposure, while myoD, a stimulatory factor for myogenesis, was significantly increased at 10μg/L quercetin exposure. There were no changes in transcripts related to apoptosis (bcl2, bax, casp3, casp7), but we did observe a decrease in mRNA levels for catalase (cat) in fish exposed to each dose, supporting an oxidative stress response. Our data support the hypothesis that quercetin may affect locomotion and induce deformities in zebrafish larvae by diminishing ATP production and by altering the expression of transcripts related to muscle formation and activity. Copyright © 2017 Elsevier Inc. All rights reserved.",
"references": [
"RC01333",
"RC01332",
"RC01331",
"RC01330",
"RC01329"
]
},
{
"pap_id": "92",
"title": "Mitochondrial bioenergetics and locomotor activity are altered in zebrafish (Danio rerio) after exposure to the bipyridylium herbicide diquat.",
"authors": "Wang, Xiao H; Souders, Christopher L; Zhao, Yuan H; Martyniuk, Christopher J",
"chapter": "",
"pages": "13-20",
"journal": "Toxicology Letters",
"pub_date": "2018-02-01",
"pub_year": 2018,
"volume": "283",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.toxlet.2017.10.022",
"doi": "10.1016/j.toxlet.2017.10.022",
"pmid": "29100808.0",
"pmcid": "",
"abstract": "Diquat is a non-selective bipyridylium herbicide which has replaced its sister compound paraquat, as paraquat is associated to an increased risk for Parkinson's disease. However, the propensity of diquat to propagate reactive oxygen species ensures that diquat remains an exposure risk in non-target organisms. In this study, zebrafish (Danio rerio) embryos were exposed to diquat (1, 10, 100μM) beginning at ∼6h post fertilization for up to 7days to learn more about the mechanisms underlying diquat toxicity during vertebrate development. Zebrafish embryos exposed to diquat for 96h did not show any significant mortality nor deformity compared to controls. Moreover, there was no difference in the timing of hatch, an indicator of stress, for fish exposed to diquat. To determine whether changes in mitochondrial bioenergetics occurred in early development as a response to diquat exposure, oxygen consumption rate was measured in whole embryos. Basal respiration and ATP production were decreased following a 24h diquat exposure at 100μM, suggesting that diquat negatively affects oxidative phosphorylation. We also assessed locomotor behavior as a sensitive endpoint for impaired activity and neurotoxicity. Seven day old (7 dpf) zebrafish treated with diquat at the highest doses tested (10-100μM) showed an increase (hyper-activity) in total distance travelled, velocity, movement cumulative duration, and overall activity compared to unexposed fish. Lastly, in 7d fish, we measured transcripts related to redox balance and apoptosis as diquat has been reported to induce oxidative stress and can affect mitochondrial bioenergetics. Larvae exposed to 10μM diquat showed higher transcript levels of catalase compared to control fish, implying that reactive oxygen species are produced following diquat exposure. Transcript levels of sod1, sod2, bcl2, bax and caspase 3 however did not vary in abundance among treatments with diquat. This study improves mechanistic understanding of diquat in fish at early stages of development and presents evidence that diquat disrupts mitochondrial bioenergetics and behavior. Copyright © 2017 Elsevier B.V. All rights reserved.",
"references": [
"RC01339",
"RC01338",
"RC01337",
"RC01336",
"RC01335",
"RC01334"
]
},
{
"pap_id": "93",
"title": "Tributyltin induces premature hatching and reduces locomotor activity in zebrafish (Danio rerio) embryos/larvae at environmentally relevant levels.",
"authors": "Liang, Xuefang; Souders, Christopher L; Zhang, Jiliang; Martyniuk, Christopher J",
"chapter": "",
"pages": "498-506",
"journal": "Chemosphere",
"pub_date": "2017-12-01",
"pub_year": 2017,
"volume": "189",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/j.chemosphere.2017.09.093",
"doi": "10.1016/j.chemosphere.2017.09.093",
"pmid": "28961535.0",
"pmcid": "",
"abstract": "Tributyltin (TBT) is an organotin compound that is the active ingredient of many biocides and antifouling agents. In addition to its well established role as an endocrine disruptor, TBT is also associated with adverse effects on the nervous system and behavior. In this study, zebrafish (Danio rerio) embryos were exposed to environmentally relevant concentrations of TBT (0.01, 0.1, 1 nM) to determine how low levels affected development and behavior. Fish exposed to 1 nM TBT hatched earlier when compared to controls. Following a 96-h exposure, total swimming distance, velocity, and activity of zebrafish larvae were reduced compared to controls. To identify putative mechanisms for these altered endpoints, we assessed embryo bioenergetics and gene expression. We reasoned that the accelerated hatch time could be related to ATP production and energy, thus embryos were exposed to TBT for 24 and 48-h exposure prior to hatch. There were no differences among groups for endpoints related to bioenergetics (i.e. basal, ATP-dependent, and maximal respiration). To address mechanisms related to changes in behavioral activity, we measured transcripts associated with muscle function (myf6, myoD, and myoG) and dopamine signaling (th, dat, dopamine receptors) as dopamine regulates behavior. No transcript was altered in expression by TBT in larvae, suggesting that other mechanisms exist that may explain changes in higher level endpoints. These results suggest that endpoints related to the whole animal (i.e. timing of hatch and locomotor behavior) are more sensitive to environmentally-relevant concentrations of TBT compared to the molecular and metabolic endpoints examined here. Copyright © 2017 Elsevier Ltd. All rights reserved.",
"references": [
"RC01343",
"RC01342",
"RC01341",
"RC01340"
]
},
{
"pap_id": "94",
"title": "Two binding sites of inhibitors in NADH: ubiquinone oxidoreductase (complex I). Relationship of one site with the ubiquinone-binding site of bacterial glucose:ubiquinone oxidoreductase.",
"authors": "Friedrich, T; van Heek, P; Leif, H; Ohnishi, T; Forche, E; Kunze, B; Jansen, R; Trowitzsch-Kienast, W; Höfle, G; Reichenbach, H",
"chapter": "",
"pages": "691-698",
"journal": "European Journal of Biochemistry / FEBS",
"pub_date": "1994-01-15",
"pub_year": 1994,
"volume": "219",
"issue": "1-2",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1111/j.1432-1033.1994.tb19985.x",
"doi": "10.1111/j.1432-1033.1994.tb19985.x",
"pmid": "8307034.0",
"pmcid": "",
"abstract": "The effect of ten naturally occurring and two synthetic inhibitors of NADH:ubiquinone oxidoreductase (complex I) of bovine heart, Neurospora crassa and Escherichia coli and glucose:ubiquinone oxidoreductase (glucose dehydrogenase) of Gluconobacter oxidans was investigated. These inhibitors could be divided into two classes with regard to their specificity and mode of action. Class I inhibitors, including the naturally occurring piericidin A, annonin VI, phenalamid A2, aurachins A and B, thiangazole and the synthetic fenpyroximate, inhibit complex I from all three species in a partially competitive manner and glucose dehydrogenase in a competitive manner, both with regard to ubiquinone. Class II inhibitors including the naturally occurring rotenone, phenoxan, aureothin and the synthetic benzimidazole inhibit complex I from all species in an non-competitive manner, but have no effect on the glucose dehydrogenase. Myxalamid PI could not be classified as above because it inhibits only the mitochondrial complex I and in a competitive manner. All inhibitors affect the electron-transfer step from the high-potential iron-sulphur cluster to ubiquinone. Class I inhibitors appear to act directly at the ubiquinone-catalytic site which is related in complex I and glucose dehydrogenase.",
"references": [
"RC01381",
"RC01363",
"RC01359",
"RC01358",
"RC01357",
"RC01356",
"RC01355",
"RC01349",
"RC01348",
"RC01345",
"RC01344"
]
},
{
"pap_id": "95",
"title": "The inhibition of mitochondrial reduced nicotinamide-adenine dinucleotide oxidation by rotenoids",
"authors": "Burgos, J.; Redfearn, E.R.",
"chapter": "",
"pages": "475-483",
"journal": "Biochimica et Biophysica Acta (BBA) - Enzymology and Biological Oxidation",
"pub_date": "1965-01-01",
"pub_year": 1965,
"volume": "110",
"issue": "3",
"Issn": "9266593",
"Isbn": "",
"url": "https://linkinghub.elsevier.com/retrieve/pii/S0926659365800601",
"doi": "10.1016/S0926-6593(65)80060-1",
"pmid": "",
"pmcid": "",
"abstract": "1.Rotenone and other rotenoids have been shown to inhibit mitochondrial electron transport at a site on the oxygen-side of the NADH2 dehydrogenase (NADH2: (acceptor) oxidoreductase, EC 1.6.99.3) flavoprotein.2.The inhibition is characterized by a lag period of several minutes before the full effect of the inhibitor becomes apparent.3.It was confirmed that like antimycin A, the rotenoids become tightly bound to the mitochondrial particles. However, the relationship between the concentration of inhibitor and the degree of inhibition appears to have a hyperbolic form rather than the characteristic S-shape obtained with antimycin A.4.Sulphydryl reagents, such as N-ethylmaleimide and p-hydroxymercuri-benzoate, have a considerable potentiating effect on rotenoid inhibition.5.A study was made of the relationship between the chemical structure and inhibitory potency of a number of rotenoids and certain structural features essential for inhibition were established.6.The possibility that rotenoids and a number of other inhibitors and treatments are acting at a common site on the oxygen-side of the NADH2 dehydrogenase flavoprotein is discussed.",
"references": [
"RC01346"
]
},
{
"pap_id": "96",
"title": "Mechanism of inhibition by ubicidin: inhibitor with piericidin ring structure and ubiquinone side chain.",
"authors": "Gutman, M; Kliatchko, S",
"chapter": "",
"pages": "348-353",
"journal": "FEBS Letters",
"pub_date": "1976-09-01",
"pub_year": 1976,
"volume": "67",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1016/0014-5793(76)80562-5",
"doi": "10.1016/0014-5793(76)80562-5",
"pmid": "986952.0",
"pmcid": "",
"abstract": "",
"references": [
"RC01350"
]
},
{
"pap_id": "97",
"title": "New 4-hydroxypyridine and 4-hydroxyquinoline derivatives as inhibitors of NADH-ubiquinone reductase in the respiratory chain.",
"authors": "Chung, K H; Cho, K Y; Asami, Y; Takahashi, N; Yoshida, S",
"chapter": "",
"pages": "609-616",
"journal": "Zeitschrift fur Naturforschung. C, Journal of Biosciences",
"pub_date": "1989-08-01",
"pub_year": 1989,
"volume": "44",
"issue": "7-8",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1515/znc-1989-7-811",
"doi": "10.1515/znc-1989-7-811",
"pmid": "2505785.0",
"pmcid": "",
"abstract": "Many derivatives of 2,3-dimethoxy-4-hydroxypyridine, which were designed from examination of the structure-activity relationship of piericidins, were tested for inhibition of NADH-UQ reductase. The lipophilic side chain of those compounds was indicated to be a key part for activity and its optimal length was conjectured. By the use of two different phases of assay material, intact mitochondria and submitochondria, the size of a membrane effect was shown to depend on the structure of the side chain. 4-Hydroxyquinoline derivatives were also tested for an analogous role in relation to the electron transport function of menaquinone, and they were proven to be inhibitors of NADH-UQ reductase as good as the pyridine derivatives.",
"references": []
},
{
"pap_id": "98",
"title": "Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I).",
"authors": "Degli Esposti, M; Ghelli, A; Ratta, M; Cortes, D; Estornell, E",
"chapter": "",
"pages": "161-167",
"journal": "The Biochemical Journal",
"pub_date": "1994-07-01",
"pub_year": 1994,
"volume": "301 ( Pt 1)",
"issue": "",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1042/bj3010161",
"doi": "10.1042/bj3010161",
"pmid": "8037664.0",
"pmcid": "PMC1137156",
"abstract": "Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria. The properties of five of such acetogenins are compared with those of rotenone and piericidin, classical potent inhibitors of Complex I. Rolliniastatin-1 and rolliniastatin-2 are more powerful than piericidin in terms of both their inhibitory constant and the protein-dependence of their titre in bovine submitochondrial particles. These acetogenins could be considered therefore the most potent inhibitors of mammalian Complex I. Squamocin and otivarin also have an inhibitory constant lower than that of piericidin, but display a larger protein-dependence of the titre. Squamocin and otivarin, contrary to the other acetogenins, behave qualitatively like rotenone. Rolliniastatin-2 shows unique properties as its interaction, although mutually exclusive to that of piericidin, appears to be mutually non-exclusive to that of rotenone. It is the first time that a potent inhibitor of Complex I is found not to overlap the active site of rotenone.",
"references": [
"RC01354",
"RC01353",
"RC01352"
]
},
{
"pap_id": "99",
"title": "Complex I and complex III of mitochondria have common inhibitors acting as ubiquinone antagonists.",
"authors": "Degli Esposti, M; Ghelli, A; Crimi, M; Estornell, E; Fato, R; Lenaz, G",
"chapter": "",
"pages": "1090-1096",
"journal": "Biochemical and Biophysical Research Communications",
"pub_date": "1993-02-15",
"pub_year": 1993,
"volume": "190",
"issue": "3",
"Issn": "",
"Isbn": "",
"url": "http://dx.doi.org/10.1006/bbrc.1993.1161",
"doi": "10.1006/bbrc.1993.1161",
"pmid": "8439309.0",
"pmcid": "",
"abstract": "Mitochondrial complex I and complex III have common inhibitors with ubiquinone-like structure. The tridecyl analog of stigmatellin, which inhibits mitochondrial complex III at nanomolar concentrations, also inhibits the NADH:ubiquinone reductase activity of complex I at micromolar concentrations. The inhibitor titer depends upon the concentration of the mitochondrial particles and extrapolates to 0.2 microM at zero particle concentration. The stigmatellin analog is more powerful than its parent compound and is noncompetitive with exogenous ubiquinones, rotenone and piericidin. Myxothiazol, which is another potent inhibitor of complex III, is also found to inhibit the activity of complex I with a titer comparable to that of the tridecyl analog of stigmatellin. Additionally, piericidin, which is the most powerful inhibitor of complex I, inhibits the ubiquinol:cytochrome c reductase activity of complex III at micromolar concentrations in mitochondrial particles and at submicromolar concentrations in the isolated enzyme complex.",
"references": [
"RC01365",
"RC01362",
"RC01361",
"RC01360"
]
}
]
}
