RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 814
OP 822
DO 10.1124/mol.110.070342
VO 79
IS 5
A1 Stefan Dröse
A1 Lea Bleier
A1 Ulrich Brandt
YR 2011
UL http://molpharm.aspetjournals.org/content/79/5/814.abstract
AB In this study, we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) because ROS seem to be essential for signaling during preconditioning to prevent ischemia/reperfusion injury. Despite different binding sites and concentrations required for half-maximal inhibition—ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analog 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.