The endogenous mitochondrial complex II inhibitor malonate regulates mitochondrial ATP-sensitive potassium channels: Implications for ischemic preconditioning

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• 作者：Andrew P. Wojtovich ; Paul S. Brookes
• 关键词：ATP-sensitive potassium channel ; mK_ATP ; Preconditioning ; Ischemia ; Succinate dehydrogenase ; Diazoxide ; Mitochondria
• 刊名：Biochimica et Biophysica Acta (BBA)/Bioenergetics
• 出版年：2008
• 期刊代码：13_00052728
• 类别：bio
• 出版时间：July-August 2008
• 卷：1777
• 期：7-8
• 页码：882-889
• 文件大小：779 K

摘要

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.