title: Coenzyme Q cytoprotective mechanisms for mitochondrial complex I cytopathies involves NAD(P)H: quinone oxidoreductase 1(NQO1).
abstract: The commonest mitochondrial diseases are probably those impairing the function of complex I of the respiratory electron transport chain. Such complex I impairment may contribute to various neurodegenerative disorders e.g. Parkinson's disease. In the following, using hepatocytes as a model cell, we have shown for the first time that the cytotoxicity caused by complex I inhibition by rotenone but not that caused by complex III inhibition by antimycin can be prevented by coenzyme Q (CoQ1) or menadione. Furthermore, complex I inhibitor cytotoxicity was associated with the collapse of the mitochondrial membrane potential and reactive oxygen species (ROS) formation. ROS scavengers or inhibitors of the mitochondrial permeability transition prevented cytotoxicity. The CoQ1 cytoprotective mechanism required CoQ1 reduction by DT-diaphorase (NQO1). Furthermore, the mitochondrial membrane potential and ATP levels were restored at low CoQ1 concentrations (5 microM). This suggests that the CoQ1H2 formed by NQO1 reduced complex III and acted as an electron bypass of the rotenone block. However cytoprotection still occurred at higher CoQ1 concentrations (>10 microM), which were less effective at restoring ATP levels but readily restored the cellular cytosolic redox potential (i.e. lactate: pyruvate ratio) and prevented ROS formation. This suggests that CoQ1 or menadione cytoprotection also involves the NQO1 catalysed reoxidation of NADH that accumulates as a result of complex I inhibition. The CoQ1H2 formed would then also act as a ROS scavenger.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Ont, Canada.
authors.forename: Tom S
authors.initials: TS
authors.lastname: Chan
authors.forename: Shirley
authors.initials: S
authors.lastname: Teng
authors.forename: John X
authors.initials: JX
authors.lastname: Wilson
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Galati
authors.forename: Sumsallah
authors.initials: S
authors.lastname: Khan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D014451:Ubiquinone / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000633:toxicity; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D009243:NAD; D014451:Ubiquinone; D024483:Vitamin K 3; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione; C025203:Ubiquinone Q1