TY - JOUR T1 - A common mechanism links differently acting complex II inhibitors to cardioprotection: modulation of mitochondrial reactive oxygen species production JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.070342 SP - mol.110.070342 AU - Stefan Droese AU - Lea Bleier AU - Ulrich Brandt Y1 - 2011/01/28 UR - http://molpharm.aspetjournals.org/content/early/2011/01/28/mol.110.070342.abstract N2 - In this study we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) since ROS seem to be essential for signalling during preconditioning to prevent ischemia/reperfusion injury. Despite different binding sites and concentrations required for halfmaximal inhibition - ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analogue malonate - all inhibitors modulated ROS production in the same ambivalent fashion: they promoted the generation of superoxide at the Qo site of complex III under conditions of 'oxidant-induced reduction' but attenuated ROS generated at complex I due to reverse electron transfer. All inhibitors showed these ambivalent effects independent of the presence of K+. These findings suggest a direct modulation of mitochondrial ROS generation during cardioprotection via complex II inhibition and question the recently proposed role of complex II as a regulatory component of the putative mitochondrial KATP channel. ER -