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1 Medicine, Case Western Reserve University, Cleveland, Ohio, United States
2 Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Anesthesiology, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States; Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, United States; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
4 Pharmacology, Case Western Reserve University, United States; Medicine, Case Western Reserve University, Cleveland, Ohio, United States
5 Medical Service, Louis Stokes Veterans Affairs Medical Center, Cleveland, Ohio, United States; Medicine, Case Western Reserve University, Cleveland, Ohio, United States
* To whom correspondence should be addressed. E-mail: exl9{at}cwru.edu.
Mitochondria are increasingly recognized as lynchpins in the evolution of cardiac injury during ischemia and reperfusion. This review addresses the emerging concept that modulation of mitochondrial respiration during and immediately following an episode of ischemia can attenuate the extent of myocardial injury. The blockade of electron transport or the partial uncoupling of respiration are two mechanisms whereby manipulation of mitochondrial metabolism during ischemia decreases cardiac injury. Although protection by inhibition of electron transport or uncoupling of respiration initially appears to be counterintuitive, the continuation of mitochondrial oxidative phosphorylation in the pathologic milieu of ischemia generates reactive oxygen species, mitochondrial calcium overload, and the release of cytochrome c. The initial target of these deleterious mitochondrial-driven processes is the mitochondria themselves. Consequences to the cardiomyocyte, in turn, include oxidative damage, the onset of mitochondrial permeability transition, and activation of apoptotic cascades, all favoring cardiomyocyte death. Ischemia-induced mitochondrial damage carried forward into reperfusion further amplifies these mechanisms of mitochondrial-driven myocyte injury. Interruption of mitochondrial respiration during early reperfusion by pharmacologic blockade of electron transport or even recurrent hypoxia or brief ischemia paradoxically decreases cardiac injury. It increasingly appears that the cardioprotective paradigms of ischemic preconditioning and post-conditioning utilize modulation of mitochondrial oxidative metabolism as a key effector mechanism. The initially counterintuitive approach to inhibit mitochondrial respiration provides a new cardioprotective paradigm to decrease cellular injury during both ischemia and reperfusion.
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