Irreversible Inhibition of Mitochondrial Complex I by 1-Methyl-4-Phenylpyridinium: Evidence for Free Radical Involvement |
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| Authors: | M W J Cleeter† J M Cooper† A H V Schapira‡ |
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| Institution: | Department of Neuroscience, London, England;Department of Protein and Molecular Biology, Royal Free Hospital School of Medicine, London, England;University Department of Clinical Neurology, Institute of Neurology, London, England |
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| Abstract: | Abstract: Incubation of 10 m M I-methyl-4-phenylpyridinium (MPP+) with sonicated beef heart mitochondria caused an irreversible time-dependent decrease in NADH-ubiquinone-l (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. |
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| Keywords: | l-Methyl-4-phenylpyridinium Complex I Free radicals Parkinson's disease |
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