title: Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement.
abstract: Incubation of 10 mM 1-methyl-4-phenylpyridinium (MPP+) with sonicated beef heart mitochondria caused an irreversible time-dependent decrease in NADH-ubiquinone-1 (CoQ1) reductase activity (52% inhibition after 1 h). Inclusion of glutathione, ascorbate, or catalase in the incubation mixture protected the NADH-CoQ1 reductase activity. These results suggest that the interaction of MPP+ with complex I induces free radical generation, which in turn leads to the irreversible inhibition of complex I activity. The generation of free radicals by neurotoxin-induced inhibition of complex I has important implications for our interpretation of the increased oxidative stress observed in Parkinson's disease substantia nigra and for our understanding of the cause(s) of dopaminergic cell death in this disorder.
authors.affiliation: Department of Neuroscience, Royal Free Hospital School of Medicine, London, England.
authors.forename: M W
authors.initials: MW
authors.lastname: Cleeter
authors.forename: J M
authors.initials: JM
authors.lastname: Cooper
authors.forename: A H
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002417:Cattle; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration
chemical_list: D005609:Free Radicals; D002374:Catalase; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione; D001205:Ascorbic Acid; D015655:1-Methyl-4-phenylpyridinium