Inhibition of succinate-linked respiration and complex II activity by hydrogen peroxide

Hydrogen peroxide produced from electron transport chain derived superoxide is a relatively mild oxidant, and as such, the majority of mitochondrial enzyme activities are impervious to physiological concentrations. Previous studies, however, have suggested that complex II (succinate dehydrogenase) is sensitive to H(2)O(2)-mediated inhibition. Nevertheless, the effects of H(2)O(2) on succinate-linked respiration and complex II activity have not been examined in intact mitochondria. Results presented indicate that H(2)O(2) inhibits succinate-linked state 3 mitochondrial respiration in a concentration dependent manner. H(2)O(2) has no effect on complex II activity during state 2 respiration, but inhibits activity during state 3. It was found that conditions which prevent oxaloacetate accumulation during state 3 respiration, such as inclusion of rotenone, glutamate, or ATP, blunted the effect of H(2)O(2) on succinate-linked respiration and complex II activity. It is concluded that H(2)O(2) inhibits succinate-linked respiration indirectly by sustaining and enhancing oxaloacetate-mediated inactivation of complex II.