Inhibition of mitochondrial electron transport by peroxynitrite.
Mammalian mitochondria are sensitive targets of the cytotoxic effects of superoxide (O.2-) and nitric oxide (.NO). In turn, when superoxide and nitric oxide are simultaneously produced, they rapidly react with each other yielding the highly oxidizing peroxynitrite anion (ONOO-) which may be also toxic to mammalian mitochondria. In this study we report that peroxynitrite exposure to rat heart mitochondria resulted in significant inactivation of electron carriers such as succinate dehydrogenase and NADH dehydrogenase as well as the mitochondrial ATPase. As a result of enzyme inactivation, peroxynitrite lead to a profound inhibition of glutamate/malate- and succinate-supported oxygen consumption but did not cause mitochondrial uncoupling. Secondary to inhibiting mitochondrial electron transport, peroxynitrite induced an enhanced succinate-stimulated hydrogen peroxide formation by heart mitochondria. Most of the damaging effects against mitochondria can be ascribed to peroxynitrite anion itself and not to hydroxyl radical-like oxidant yielded during the proton-catalyzed decomposition of peroxynitrite, as hydroxyl radical scavengers provided a rather modest protection. Our observations indicate that mitochondria may constitute a key intracellular loci for the toxic effects of peroxynitrite under the various pathological conditions in which peroxynitrite appears to play a contributory role.
Radi
R
R
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Rodriguez
M
M
Castro
L
L
Telleri
R
R
D000818:Animals; D004579:Electron Transport / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000138:chemical synthesis / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D009566:Nitrates; C039642:peroxynitric acid; D006861:Hydrogen Peroxide; D013385:Succinate Dehydrogenase