Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection

Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California at Los Angeles, California 90095-1760 Submitted 3 December 2002 ; accepted in final form 27 February 2003 Fatty acids accumulate during myocardial ischemia and are implicated in ischemia-reperfusion injury and mitochondrial dysfunction. Because functional recovery after ischemia-reperfusion ultimately depends on the ability of the mitochondria to recover membrane potential ( m ), we studied the effects of fatty acids on m regulation, cytochrome c release, and Ca 2+ handling in isolated mitochondria under conditions that mimicked aspects of ischemia-reperfusion. Long-chain but not short-chain free fatty acids caused a progressive and reversible (with BSA) increase in inner membrane leakiness (proton leak), which limited mitochondrial ability to support m . In comparison, long-chain activated fatty acids promoted 1 ) a slower depolarization that was not reversible with BSA, 2 ) cytochrome c loss that was unrelated to permeability transition pore opening, and 3 ) inhibition of the adenine nucleotide translocator. Together, these results impaired both mitochondrial ATP production and Ca 2+ handling. Diazoxide, a selective opener of mitochondrial ATP-dependent potassium (K ATP ) channels, partially protected against these effects. These findings indicate that long-chain fatty acid accumulation during ischemia-reperfusion may predispose mitochondria to cytochrome c loss and irreversible injury and identify a novel cardioprotective action of diazoxide. calcium; adenine nucleotide translocator; membrane potential; cytochrome c ; ATP-dependent channel; palmitic acid; palmitoyl-coenzyme A Address for reprint requests and other correspondence: P. Korge, Dept. of Physiology, 3641 MRL Bldg., UCLA School of Medicine, Los Angeles, CA 90095 (E-mail: pkorge{at}mednet.ucla.edu ).