Manganese ions induce H2O2 generation at the ubiquinone binding site of mitochondrial complex II

Manganese-induced toxicity has been recently associated with an increased ROS generation from mitochondrial complex II (succinate:ubiquinone oxidoreductase). To achieve a deeper mechanistic understanding how divalent manganese ions (Mn2+) could stimulate mitochondrial ROS production we performed investigations with bovine heart submitochondrial particles (SMP). In succinate fueled SMP, the Mn2+ induced hydrogen peroxide (H2O2) production was blocked by the specific complex II ubiquinone binding site (IIQ) inhibitor atpenin A5 while a further downstream block at complex III increased the rate markedly. This suggests that site IIQ was the source of the reactive oxygen species. Moreover, Mn2+ ions also accelerated the rate of superoxide dismutation, explaining the general increase in the measured rates of H2O2 production and an attenuation of direct superoxide detection. (C) 2015 Elsevier Inc. All rights reserved.