Abstract
The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes—a phenomenon referred to as ‘lethal myocardial ischemia-reperfusion (IR) injury’. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion.
Highlights
Cardiovascular disease (CVD), comprising coronary heart disease (CHD), heart failure, stroke, and hypertension, is the leading global cause of death and disability, with roughly 18 million deaths attributed to CVD annually [1]
Despite the wealth of evidence obtained in preclinical models for the contribution of these mitochondria-centric mechanisms to the pathogenesis of lethal IR injury, efforts to translate these insights into clinical therapies for the treatment of acute myocardial infarction (MI) have been unsuccessful: i.e., pharmacologic therapies aimed at scavenging reactive oxygen species (ROS) and preventing mitochondrial permeability transition pore (mPTP) opening at the time of reperfusion have failed to improve outcomes [50,51,52,53,54]
Calcium overload activates proteases and phosphatases that modify components of the electron transport chain as well as key molecular GTPases involved in mitochondrial morphosis [99,165,166,167,168], effectively priming the ischemic myocardium for the hyperpolarization of mitochondrial membranes, burst of ROS production, disruption of the outer mitochondrial membrane and opening of the mPTP that occurs upon reperfusion and reintroduction of oxygen (Figure 2) [164,169,170]
Summary
Cardiovascular disease (CVD), comprising coronary heart disease (CHD), heart failure, stroke, and hypertension, is the leading global cause of death and disability, with roughly 18 million deaths attributed to CVD annually [1]. The increased efficacy of this combination therapy paired with improved control of patient risk factors, has produced significant reductions in acute mortality rates from MI and coronary heart disease [7,8] Despite this progress, MI continues to be a significant medical burden, as the prevalence of post-MI heart failure and long-term deleterious cardiac sequelae continue to rise [7,8]. The myocardium is highly dependent on aerobic metabolism to generate sufficient amounts of ATP for maintenance of both cell viability and contractile function and, is sensitive to ischemic injury This dependency on mitochondrial metabolic processes is reflected in the significant mitochondrial content of myocardial tissue, which accounts for >30% of the total volume of cardiomyocytes [12]. Our goals in this review are to: (1) briefly summarize the current understanding of the pathogenesis of lethal IR injury and, (2) focus on current and emerging evidence regarding the contribution of mitochondrial quality control (including mitochondrial morphosis and mitophagy) to ischemia-reperfusion-induced cardiomyocyte death
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