Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion

Abstract

Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol 292: C137-C147, 2007. First published September 13, 2006; doi:10.1152/ajpcell.00270.2006.-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 and 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 pathological 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 postconditioning 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.cardiolipin; cytochrome c; complex I; cytochrome oxidase MITOCHONDRIA are both targets and sources of injury during cardiac ischemia and reperfusion. This review addresses the emerging concept that modulation of mitochondrial oxidative metabolism during ischemia or early reperfusion protects mitochondrial function and decreases myocardial cell death. Mitochondria contribute to their own damage during ischemia, since blockade of electron transport immediately before ischemia dramatically attenuates damage to mitochondrial electron transport, with preserved oxidative phosphorylation, retention of cytochrome c, and decreased release of reactive oxygen species (ROS). Ischemic preconditioning (IPC) leads to a partial uncoupling of mitochondrial respiration, resulting in decreased mitochondrial injury following subsequent sustained ischemia. A substantial portion of damage to mitochondrial electron transport and oxi...

The effect of crataegus fruit extract and some of its flavonoids on mitochondrial oxidative phosphorylation in the heart

“…In contrast, the treatment of isolated, perfused rabbit heart with rotenone (mitochondrial complex I inhibitor) decreased the production of ROS in mitochondria and preserved the contents of cardiolipin and cytochrome c measured after 45 min of ischemia (Chen et al, 2007). Interestingly, in isolated rat cardiocytes, antimycin A-caused ROS production was abolished by the mitochondrial uncoupler (Kabir et al, 2006).…”

“…Thus, some inhibition of mitochondrial respiration observed at the highest CE concentration can be beneficial in some circumstances and may complement the effect of uncoupling. The blockade of electron transport and the partial uncoupling of respiration were regarded as two mechanisms whereby manipulation of mitochondrial metabolism during ischemia decreases cardiac injury (Chen et al, 2007).…”

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…However, it has recently been shown that complex I inhibition may underlie the cardioprotective effects of agents such as amobarbital [29,30], volatile anesthetics [60], and ranolazine [61]. Complex II inhibitors such as diazoxide [60] and 3-nitropropionic acid [62,63] are also cardioprotective, as are complex IV inhibitors such as hydrogen sulfide [64,65] and carbon monoxide [66].…”

“…Considering several reports of reversible complex I inhibition by S-nitrosation [27,28,47,48], with the recent finding that complex I inhibition is cardioprotective [29,30], and the known importance of NO • in IPC [16], we hypothesized that complex I S-nitrosation may be an endogenous cardioprotective mechanism [27]. While ischemic conditions (acidic pH) can favor SNO formation from nitrite [21,50], and hypoxia has been proposed to enhance complex I Snitrosation [51], it is known that typical laboratory lighting conditions can degrade SNOs.…”

“…Recently, we suggested that mitochondrial S-nitrosation is a potential mechanism of NO • signaling in IPC [27], with one particular example being the S-nitrosation and reversible inhibition of mitochondrial respiratory complex I [27,28]. Notably, it has been demonstrated that reversible complex I inhibition by amobarbital is cardioprotective [29,30], and this led us to hypothesize that mitochondrial S-nitrosation and subsequent reversible inhibition of the respiratory chain could be a therapeutic avenue for cardioprotection.…”