There is evidence that 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) toxicity is mediated through both inhibition of mitochondrial complex I and free radical generation. 7-Nitroindazole protects against MPTP toxicity in vitro and in vivo, and this appears to be related to its inhibition of nitric oxide (NO) synthase. We now show that the NO generator, glutathione-N-oxide, enhances the inhibitory action of 1-methyl-4-phenylpyridinium (MPP+) on complex I activity in brain submitochondrial particles. We propose that the NO-induced reversible inhibition of complex IV (cytochrome oxidase) potentiates the MPP+-induced irreversible free radical-mediated inhibition of complex I. Thus, NO may ‘prime’ the respiratory chain to the effects of MPP+. These data provide evidence for an interaction between NO and MPP+ at the level of the respiratory chain.
