Review articleCyclophilin D and myocardial ischemia–reperfusion injury: A fresh perspective
Introduction
Myocardial infarction (MI) remains the most common debilitating disease and important cause of death in developed world [1], [2]. Following coronary occlusion, deprivation of oxygen and nutrient metabolites is the primary cause of damage to the myocardium and its severity depends on the scale and duration of artery obstruction. Reoxygenation of hypoxic tissue, referred to as ischemia–reperfusion (IR), exacerbates injury experienced during the ischemic episode. Experimental evidence suggests that reperfusion per se contributes to up to half of the myocardial infarct size and it diminishes the beneficial effects of myocardial reflow [2], [3]. For many years various pre- and post-conditioning (PreC and PostC) modalities are extensively being tested to improve usefulness of reperfusion therapy. Although ischemic PreC, a potent endogenous protective strategy, was first reported many decades ago [4], its utility in MI patients with an abrupt onset of disease in clinical settings undermines its implementation. Therefore, most modern approaches are focusing on the application of pharmacological or ischemic PostC maneuvers to reduce lethal outcomes of IR injury [3], [5].
IR triggers many pro-death signaling pathways which converge on to the mitochondria [6], [7]. Therefore mitochondrial dysfunction is considered to be one of the major mechanisms responsible for IR-induced cell death in ischemic heart. Reoxygenation of cardiomyocytes after an ischemic insult leads to accumulation of superfluous calcium and reactive oxygen species (ROS) in the mitochondrial matrix. It triggers mitochondrial permeability transition (PT) which is associated with the opening of the so-called mitochondrial permeability transition pore (mPTP). The subsequent swelling of mitochondria due to influx of water and ions leads to dissipation of mitochondrial membrane potential (mΔΨ), uncoupling of oxidative phosphorylation, loss of ATP and finally rupture of mitochondrial membranes, thus activating necrotic signaling cascades. Although mild PT can be recovered by autophagic degradation of damaged mitochondria, disseminated PT may lead to irreversible tissue/organ damage [7], [8], [9], [10]
Section snippets
IR-mediated cell death
In addition to their role in cellular metabolism and calcium homeostasis, mitochondria have also been established as major players in triggering cell death signaling cascades resulting in necrosis and/or apoptosis which contributes to pathogenesis of many diseases. Mitochondria harbor molecular machineries both for the execution of apoptosis and regulated necrosis in response to a variety of stimuli [6], [11], [12]. Although apoptosis has been reported to contribute to IR injury, mPTP-mediated
Mitochondrial permeability transition pore
The mPTP, a non-specific channel formed in the inner mitochondrial membrane (IMM), contributes to the pathogenesis of many diseases including (but not limited to) myocardial IR injury [17], [18]. It is suggested as an equivalent of the electrophysiologically sought mitochondrial mega-channel that allows the passage of molecules of < 1500 Da to pass through the IMM which is normally impermeable to most solutes [8], [18]. A number of stress agents trigger formation of the mPTP making it a common
Historical overview
CypD belongs to a family of proteins which have been named as ‘cyclophilins’ due to their affinity to an immunosuppressant drug: cyclosporin A (CsA). Found both in prokaryotes and eukaryotes, cyclophilins are characterized by an evolutionarily conserved peptidyl-prolyl cis-trans isomerase (PPIase) activity [46]. First cyclophilin was discovered in 1984 as a cytosolic target of CsA [49]. Later it was observed that cyclophilin and PPIase are identical proteins and PPIase activity, which is
Conflict of interest
None.
Acknowledgments
We would like to thank Lukas N. Groschner (University of Oxford, UK) and Dr. Salma Malik (HCL, Lyon) for critically reading the manuscript and for providing valuable suggestions.
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