Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+.
The addition of NADH to submitochondrial particles inhibited by agents which interrupt electron transport from NADH-Q oxidoreductase (Complex I) to Q10 (rotenone, piericidin A, and MPP+) results in superoxide formation and lipid peroxidation. A study of the quantitative relations now shows that oxyradical formation does not appear to be the direct result of the inhibition. Although tetraphenyl boron (TPB) greatly enhances the inhibition by MPP+, it has no effect on O2. formation or lipid peroxidation. When submitochondrial particles completely inhibited by rotenone or piericidin A are treated with bovine serum albumin to remove spuriously bound inhibitor molecules without affecting those bound at the specific inhibition site, NADH-Q activity remains inhibited and lipid peroxidation occurs but superoxide formation ceases. Thus oxyradical formation may be the result of the binding of inhibitors at sites in the membrane other than those related to the inhibition of electron transport.
Ramsay
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RR
Molecular Biology Division, Veterans Affairs Medical Center, San Francisco, CA 94121.
Singer
T P
TP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000323:Adrenochrome / Q000378:metabolism; D000818:Animals; D002417:Cattle; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008315:Malondialdehyde / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology*; D013367:Submitochondrial Particles / Q000187:drug effects / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D009097:Multienzyme Complexes; D011725:Pyridines; D012402:Rotenone; D013481:Superoxides; D008315:Malondialdehyde; D000323:Adrenochrome; C100213:piericidin A; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D015655:1-Methyl-4-phenylpyridinium