Mitochondrial Metabolic Inhibition and Cardioprotection

Reperfusion is needed to initiate reflow of blood in cardiac arrest triggered by surgical intervention or pathologically-induced cardiac ischemia. However, subsequent reperfusion may lead not only to the recovery of ischemic cardiac tissue, but also to the paradoxical phenomenon of myocardial ischemia/reperfusion (IR) injury, including protracted organ recovery, myocardial stunning, and acute myocardial infarction (MI). Mortality due to acute MI remains substantial, and the prevalence of MI-associated heart failure is increasing worldwide. The year 2016 is the 30th anniversary of the first report of ischemic preconditioning (IPC) by Murry, Jennings, and Reimer, and elucidation of the signaling pathways underlying IPC has led to the discovery of various therapeutic targets for pharmacological cardioprotection. It is increasingly evident that the cardioprotective paradigms of IPC and ischemic post-conditioning employ modulation of mitochondrial oxidative metabolism as a key effector mechanism because mitochondria can act as inducers of reperfusion injury or effectors of cardioprotection. 1)2) Mitochondria are specialized organelles that generate adenosine triphosphate (ATP) via the electron transport chain and the oxidative phosphorylation system and are essential for maintaining energy homeostasis in cardiomyocytes. Therefore, mitochondria are major determinants of cell survival or death. During reperfusion, ischemically damaged mitochondria further increase oxidative damage, calcium-driven myocyte injury, and the activation of apoptotic programs. The cardioprotective effects observed following pharmacological blockade of mitochondrial respiration during IR clearly show the contribution of ischemic mitochondrial damage to myocardial injury after reperfusion. 2) Given that mitochondrial respiration is already inhibited during hypoxia or ischemia, it is surprising that several respiratory inhibitors 3) or IPC can improve recuperation from IR injury (Fig. 1). Reversible inhibition of mitochondrial metabolism may offer protection during reperfusion by facilitating a gradual restoration of mitochondrial function, i.e., a slow reintroduction of electrons into the respiratory chain following reperfusion. 3) In strategies modulating mitochondrial respiration, pharmacological agents such as amobarbital, rotenone, and s-nitrothiols can offer protection against IR injury by inhibiting mitochondrial Complex I (nicotinamide adenine dinucleotide phosphate ubiquinone oxidoreductase). However, unlike the direct association of cardioprotection with the inhibition of Complex I, the cardioprotective effect of some agents, including ranolazine, capsaicin, volatile anesthetics (halothane and isoflurane), menadione, and metformin may be dependent on their effect on Complex I (Fig. 1). There are two suggested modes of cardioprotection via Complex II. The first is direct inhibition of Complex II by 3-nitropropionic acid, malonate, and nitric oxide. The second mode involves the opening of a putative mitochondrial ATP-sensitive potassium …