Nitric oxide enhances MPP(+) inhibition of complex I.
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.
Cleeter
M W
MW
University Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK.
Cooper
J M
JM
Schapira
A H
AH
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium