Nitric Oxide and Peroxynitrite Interactions with Mitochondria

An overview of the biochemical mechanisms by which NO and ONOO regulate or alter mitochondrial functions is provided, supporting the concept that mitochondria constitute central loci of the toxic effects of excess reactive nitrogen species. Abstract Nitric oxide (NO) and peroxynitrite (ONOO) avidly interact with mitochondrial components, leading to a range of biological responses spanning from the modulation of mitochondrial respiration, mitochondrial dysfunction to the signaling of apoptotic cell death. Physiological levels of NO primarily interact with cytochrome c oxidase, leading to a competitive and reversible inhibition of mitochondrial oxygen uptake. In turn, this leads to alterations in electrochemical gradients, which affect calcium uptake and may regulate processes such as mitochondrial transition pore (MTP) opening and the release of proapoptotic proteins. Large or persistent levels of NO in mitochondria promote mitochondrial oxidant formation. Peroxynitrite formed either extra or intramitochondrially leads to oxidative damage, most notably at complexes I and II of the electron transport chain, ATPase, aconitase and Mnsuperoxide dismutase. Mitochondrial scavenging systems for peroxynitrite and peroxynitritederived radicals such as carbonate (CO3.) and nitrogen dioxide radicals (NO2) include cytochrome c oxidase, glutathione and ubiquinol and serve to partially attenuate the reactions of these oxidants with critical mitochondrial targets. Detection of nitrated mitochondrial proteins in vivo supports the concept that mitochondria constitute central loci of the toxic effects of excess reactive nitrogen species. In this review we will provide an overview of the biochemical mechanisms by which NO and ONOO regulate or alter mitochondrial functions.

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