Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance.
Modest depolarization of the mitochondrial inner membrane potential is known to attenuate mitochondrial reactive oxygen species generation. Transient pharmacologic uncoupling of mitochondrial oxidative phosphorylation results in modest depolarization of the mitochondrial membrane potential and confers protection against subsequent cardiac ischemia-reperfusion injury. Whether cardiac mitochondria have an innate capacity to temporally self-modulate their membrane potential as a possible adaptive mechanism in the context of cardiac ischemia and early reperfusion is supported by emerging data and is an intriguing concept that warrants further investigation. The objective of this review is to explore the various mechanisms whereby mitochondrial depolarization can be evoked in the context of both cardiac ischemia and reperfusion and in response to the cardioprotective program of ischemic preconditioning. The potential regulatory pathways orchestrating this biological perturbation of mitochondrial function are explored from the level of signal transduction to potential transcription-mediated modulations of nuclear-encoded mitochondrial inner membrane proteins, emphasizing the potential function of the mitochondrial uncoupling proteins.
Sack
Michael N
MN
Cardiology Branch, NHLBI, National Institutes of Health, Building 10-CRC, Room 5-3150, 10 Center Drive, Bethesda, MD 20892-1454, USA. sackm@nhlbi.nih.gov
D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008564:Membrane Potentials / Q000502:physiology; D008929:Mitochondria, Heart / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D014475:Uncoupling Agents / Q000378:metabolism*
D014475:Uncoupling Agents