Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases.
Incubation of rat skeletal muscle mitochondria with the nitric oxide generator, S-nitrosoglutathione (GSNO) reversibly inhibited oxygen utilisation with all substrates tested. The visible absorption spectra of the inhibited mitochondria showed that cytochromes c+c1, b and a+a3 were reduced, indicating a block at the distal end of the respiratory chain. Analysis of the respiratory chain enzyme activities in the presence of GSNO localised the site of inhibition of cytochrome c oxidase alone. These results indicate that nitric oxide is capable of rapidly and reversibly inhibiting the mitochondrial respiratory chain and may be implicated in the cytotoxic effects of nitric oxide in the CNS and other tissues.
Cleeter
M W
MW
Department of Neuroscience, Royal Free Hospital School of Medicine, Hampstead, London, UK.
Cooper
J M
JM
Darley-Usmar
V M
VM
Moncada
S
S
Schapira
A H
AH
D000818:Animals; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D026422:S-Nitrosoglutathione
D009603:Nitroso Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D003576:Electron Transport Complex IV; D005978:Glutathione