Splice variants are then subject to proteolytic processing in order to generate cell-specific profiles of OPA1 peptides (i.e., FX1 OPA1 forms). death in the setting of ischemia-reperfusion. ischemia-reperfusion (IR) injury [9,10,11] (Figure 1). Open in FX1 a separate window Figure 1 Myocardial ischemia-reperfusion injury. Schematic representation of myocardial cell death as a function of increasing duration of ischemia. In the absence of reperfusion, all cardiomyocytes will die: i.e., ~100% of cells are irreversibly injured (red curve). In theory, timely reintroduction of blood flow would salvage all remaining, previously ischemic cardiomyocytes (dotted line). However, reintroduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic myocytesthe phenomenon of is determined by both the magnitude of the Rabbit Polyclonal to MARCH3 deficit in oxygen supply and the duration of the ischemic insult . After the onset of ischemia, there are two populations of cardiomyocytes in the ischemic territory: (1) injured myoyctes that have undergone necrosis, and (2) injured myocytes that remain viable and have the potential to be salvaged upon reperfusion [9,29]. These two distinct injury populations are the result of spatial heterogeneity in both the sensitivity to ischemia and the severity of the ischemic insult (arising, for example, from varying degrees of collateral flow from adjacent coronary vessels) . Moreover, and as expected, the proportion of irreversibly versus reversibly injured myocardium displays temporal variation and increases as the duration of ischemia is prolonged (Figure 1). The transition from reversible to irreversible injury during ischemia is the consequence of cellular events initiated by the ischemia-induced mismatch between myocardial oxygen supply and demand. These deleterious sequelae include (but are not limited to) the resultant shift from aerobic metabolism to anaerobic glycolysis, and subsequent inability to generate sufficient ATP to maintain ionic homeostasis and integrity of mitochondrial and sarcolemmal membranes [9,10,11,12,30,31,32,33,34,35,36,37,38,39,40,41] (Figure 2). Open in a separate window Figure 2 Cellular consequences of ischemia-reperfusion in cardiomyocytes. Under conditions of ischemia (left), mitochondria are depolarized (i.e., m is decreased) and ATP stores are depleted. This is accompanied by acidosis secondary to lactate accumulation, and an increase in intracellular calcium concentration. However, the OMM remains intact and the mPTP remains closed. Reintroduction of oxygen (right), results in the raid normalization of pH and increase in m, and precipitates multiple deleterious sequelae including generation of FX1 ROS, exacerbated calcium overload, disruption of the OMM and opening of the mPTP. OMM = outer mitochondrial membrane; IMM = inner mitochondrial membrane; MOMP = mitochondrial outer membrane permeabilization; mPTP = mitochondrial permeability transition pore; m = mitochondrial membrane potential; ROS = reactive oxygen species. Adapted from reference . 2.2. Reintroduction of Oxygen: A Double-Edged Sword As discussed previously, reperfusion of the ischemic myocardium and the attendant reintroduction of oxygen and nutrients is required to salvage reversibly injured myocardium and limit infarct progression. However, for sub-populations of reversibly injured cardiomyocytes, re-instatement of blood flow paradoxically precipitates (rather than prevents) necrotic and apoptotic cell death [11,14,42]. The mechanisms of lethal IR injury are FX1 complex and multi-factorial and, despite decades of investigation, remain incompletely resolved [12,31,43,44,45]. There are, however, two recurring themes. First, mitochondria, and loss of mitochondrial integrity, have been identified to play a pivotal role, with emphasis to date focusing largely on the well-documented cytotoxic consequences of mitochondrial ROS production and opening of the mPTP at the time of reoxygenation [12,16,43,46,47,48,49] (Figure 2). Second, 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 MI have been unsuccessful: i.e., pharmacologic therapies aimed at scavenging ROS and preventing mPTP opening at the time of reperfusion have failed to improve outcomes [50,51,52,53,54]. These data underscore the importance of expanding our understanding of the molecular mechanisms of lethal IR injury, with the goal of identifying novel and rationally designed pharmacologic approaches to attenuate the deleterious component of reperfusion. In this regard, increasing attention has focused on the possible role of mitochondrial morphosis and mitophagy in IR-induced cell death, and manipulation of the key protein mediators of inner and outer mitochondrial membrane integrity as targets for intervention. 3. Mitochondrial Morphosis 3.1. Definitions and Key Players A wealth of evidence over the past two decades has demonstrated that mitochondria are FX1 not discrete and static organelles. Rather, mitochondria.