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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 Ca²⁺ 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 Ca²⁺ 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

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