title: Mitochondrial electron transport inhibitors cause lipid peroxidation-dependent and -independent cell death: protective role of antioxidants.
abstract: Mitochondrial electron transport inhibitors induced two distinct pathways for acute cell death: lipid peroxidation-dependent and -independent in isolated rat hepatocytes. The toxic effects of mitochondrial complex I and II inhibitors, rotenone (ROT) and thenoyltrifluoroacetone (TTFA), respectively, were dependent on oxidative stress and lipid peroxidation, while cell death induced by inhibitors of complexes III and IV, antimycin A (AA) and cyanide (CN), respectively, was caused by MMP collapse and loss of cellular ATP. Accordingly, cellular and mitochondrial antioxidant depletion or supplementation, in general, resulted in a dramatic potentiation or prevention, respectively, of toxic injury induced by complex I and II inhibitors, with little or no effect on complex III and IV inhibitor-induced toxicity. ROT-induced oxidative stress was prevented by the addition of d-alpha-tocopheryl succinate (TS) but surprisingly TS did not afford hepatocytes protection against TTFA-induced oxidative damage. TS treatment prevented ROT-induced mitochondrial lipid hydroperoxide formation but had no effect on the loss of mitochondrial GSH or cellular ATP, suggesting a mitochondrial lipid peroxidation-mediated mechanism for ROT-induced acute cell death. In contrast, only fructose treatment provided excellent cytoprotection against AA- and CN-induced toxicity. Our findings indicate that complex III and IV inhibitors cause a rapid and severe depletion of cellular ATP content resulting in acute cell death that is dependent on cellular energy impairment but not lipid peroxidation. In contrast, inhibitors of mitochondrial complex I or II moderately deplete cellular ATP levels and thus cause acute cell death via a lipid peroxidation pathway.
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164-6534, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Zhang
authors.forename: M A
authors.initials: MA
authors.lastname: Tirmenstein
authors.forename: F A
authors.initials: FA
authors.lastname: Nicholls-Grzemski
authors.forename: M W
authors.initials: MW
authors.lastname: Fariss
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D003486:Cyanides / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008298:Maleates / Q000633:toxicity; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D012402:Rotenone / Q000633:toxicity; D013804:Thenoyltrifluoroacetone / Q000633:toxicity; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D003486:Cyanides; D008298:Maleates; D012402:Rotenone; D014810:Vitamin E; D013804:Thenoyltrifluoroacetone; D000968:Antimycin A; D000255:Adenosine Triphosphate; C014476:diethyl maleate; D005978:Glutathione; D024505:Tocopherols