A Role of Mitochondrial Glutathione Peroxidase in Modulating Mitochondrial Oxidations in Liver

Abstract

The inhibitory effect of t‐butyl hydroperoxide on O2 uptake by perfused rat liver and by isolated hepatocytes was investigated with isolated mitochondria. O2 uptake by mitochondria oxidizing the ketoacids, 2‐oxoglutarate and pyruvate, was substantially decreased upon addition of t‐butyl hydroperoxide, that of isocitrate was only slightly decreased, and that of succinate and of 3‐hydroxybutyrate was practically unchanged. The reduction product of the hydroperoxide, t‐butyl alcohol, showed no effect. The inhibitory effect of the hydroperoxide was reversed upon addition of dithioerythritol, a thiol reductant. The inhibitory effect of the hydroperoxide was mimicked by the penetrant disulfide, cystamine, and by the thiol‐oxidizing agent, diamide. Mitochondrial extracts from rats fed a selenium‐deficient diet were shown to have virtually no measurable GSH peroxidase activity. The hydroperoxide had almost no inhibitory effect on 2‐oxoglutarate‐dependent O2 uptake in mitochondria from selenium‐deficient rats. These observations demonstrate effects of GSH peroxidase activity in the mitochondrial matrix on the pattern of substrate oxidations, possibly with the ketoacid oxidases, dependent on coenzyme A and lipoamide, as main target sites. In view of the known steady‐state formation of mitochondrial O2− and H2O2, a connection between the resulting oxidation of mitochondrial GSH and NADPH and the regulation of mitochondrial substrate oxidations is proposed. Copyright © 1978, Wiley Blackwell. All rights reserved