Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection.
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 (DeltaPsim), we studied the effects of fatty acids on DeltaPsim 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 DeltaPsim. 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 (KATP) 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.
Korge
Paavo
P
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California 90095-17690, USA. pkorge@mednet.ucla.edu
Honda
Henry M
HM
Weiss
James N
JN
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002462:Cell Membrane / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004579:Electron Transport / Q000502:physiology; D005227:Fatty Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008929:Mitochondria, Heart / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000473:pathology* / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D010539:Permeability; D016062:Porosity; D011817:Rabbits; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D002614:Chelating Agents; D003574:Cytochrome c Group; D005227:Fatty Acids; D014475:Uncoupling Agents; D012710:Serum Albumin, Bovine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D003981:Diazoxide; D002118:Calcium