title: A common mechanism links differently acting complex II inhibitors to cardioprotection: modulation of mitochondrial reactive oxygen species production.
abstract: 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 Q(o) 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 K(ATP) channel.
authors.affiliation: Molecular Bioenergetics Group, Cluster of Excellence Frankfurt "Macromolecular Complexes," Medical School, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.forename: Lea
authors.initials: L
authors.lastname: Bleier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
mesh_terms: D000818:Animals; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002417:Cattle; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D011728:Pyridones; D017382:Reactive Oxygen Species; C058278:atpenin A5; D013804:Thenoyltrifluoroacetone; D042963:Electron Transport Complex II