The endogenous mitochondrial complex II inhibitor malonate regulates mitochondrial ATP-sensitive potassium channels: implications for ischemic preconditioning.
Ischemic preconditioning (IPC) affords cardioprotection against ischemia-reperfusion (IR) injury, and while the molecular mechanisms of IPC are debated, the mitochondrial ATP-sensitive K(+) channel (mK(ATP)) has emerged as a candidate effector for several IPC signaling pathways. The molecular identity of this channel is unknown, but significant pharmacologic overlap exists between mK(ATP) and mitochondrial respiratory complex II (succinate dehydrogenase). In this investigation, we utilized isolated cardiac mitochondria, Langendorff perfused hearts, and a variety of biochemical methods, to make the following observations: (i) The competitive complex II inhibitor malonate is formed in mitochondria under conditions resembling IPC. (ii) IPC leads to a reversible inhibition of complex II that has likely been missed in previous investigations due to the use of saturating concentrations of succinate. (iii) Malonate opens mK(ATP) channels even when mitochondria are respiring on complex I-linked substrates, suggesting an effect of this inhibitor on the mK(ATP) channel independent of complex II inhibition. Together, these observations suggest that complex II inhibition by endogenously formed malonate may represent an important activation pathway for mK(ATP) channels during IPC.
Wojtovich
Andrew P
AP
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Brookes
Paul S
PS
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D006028:Glycosphingolipids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019194:Ischemic Preconditioning; D054086:KATP Channels / Q000187:drug effects / Q000502:physiology*; D008314:Malonates / Q000378:metabolism / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006028:Glycosphingolipids; D054086:KATP Channels; D008314:Malonates; C477937:inositolphosphorylceramide; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II