| 10908294 |
Nakamura K, Bindokas VP, Marks JD, Wright DA, Frim DM, Miller RJ, Kang UJ: The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited. J Biol Chem. 2004 Jul 23;279(30):31121-30. Epub 2004 May 19.
1-Methyl-4-phenylpyridinium (MPP (+)) is selectively toxic to dopaminergic neurons and has been studied extensively as an etiologic model of Parkinson's disease (PD) because mitochondrial dysfunction is implicated in both MPP (+) toxicity and the pathogenesis of PD. MPP (+) can inhibit mitochondrial complex I activity, and its toxicity has been attributed to the subsequent mitochondrial depolarization and generation of reactive oxygen species. However, MPP (+) toxicity has also been noted to be greater than predicted by its effect on complex I inhibition or reactive oxygen species generation. Therefore, we examined the effects of MPP (+) on survival, mitochondrial membrane potential (DeltaPsim), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP (+) (5 microM) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their DeltaPsim. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP (+) to dopaminergic neurons, depolarized DeltaPsim to a greater extent than MPP (+). In addition, neither rotenone nor MPP (+) increased superoxide in dopaminergic neurons, and MPP (+) failed to alter levels of reduced glutathione. Therefore, we conclude that increased superoxide and loss of DeltaPsim may not represent primary events in MPP (+) toxicity, and complex I inhibition alone is not sufficient to explain the selective toxicity of MPP (+) to dopaminergic neurons. Clarifying the effects of MPP (+) on energy metabolism may provide insight into the mechanism of dopaminergic neuronal degeneration in PD. |
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