The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: The role of mitochondrial complex I and reactive oxygen species revisited

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 (Delta Psi m), and superoxide and reduced glutathione levels in individual dopaminergic and nondopaminergic mesencephalic neurons. MPP+ (5 mu M) selectively induced death in fetal rat dopaminergic neurons and caused a small decrease in their Delta Psi m. In contrast, the specific complex I inhibitor rotenone, at a dose (20 nM) that was less toxic than MPP+ to dopaminergic neurons, depolarized Delta Psi m 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 Delta Psi m 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.