Regular ArticleNitric Oxide Inhibits Electron Transfer and Increases Superoxide Radical Production in Rat Heart Mitochondria and Submitochondrial Particles
Abstract
Nitric oxide (·NO) released byS-nitrosoglutathione (GSNO) inhibited enzymatic activities of rat heart mitochondrial membranes. Cytochrome oxidase activity was inhibited to one-half at an effective ·NO concentration of 0.1 μM, while succinate– and NADH–cytochrome-creductase activities were half-maximally inhibited at 0.3 μM·NO. Submitochondrial particles treated with ·NO (either from GSNO or from a pure solution) showed increased[formula]and H2O2production when supplemented with succinate alone, at rates that were comparable to those of control particles with added succinate and antimycin. Rat heart mitochondria treated with ·NO also showed increased H2O2production. Cytochrome spectra and decreased enzymatic activities in the presence of ·NO are consistent with a multiple inhibition of mitochondrial electron transfer at cytochrome oxidase and at the ubiquinone–cytochromebregion of the respiratory chain, the latter leading to the increased[formula]production. Electrochemical detection showed that the buildup of a ·NO concentration from GSNO was interrupted by submitochondrial particles supplemented with succinate and antimycin and was restored by addition of superoxide dismutase. The inhibitory effect of ·NO on cytochrome oxidase was also prevented under the same conditions. Apparently, mitochondrial[formula]reacts with ·NO to form peroxynitrite and, by removing ·NO, reactivates the previously inhibited cytochrome oxidase. It is suggested that, at physiological concentrations of ·NO, inhibition of electron transfer, ·NO-induced[formula]production, and ONOO−formation participate in the regulatory control of mitochondrial oxygen uptake.
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