Mitochondrial Membrane Permeabilization and Cell Death During Myocardial Infarction: Roles of Calcium and Reactive Oxygen Species

Abstract

Excess generation of reactive oxygen species (ROS) and cytosolic calcium accumulation play major roles in the initiation of programmed cell death during acute myocardial infarction. Cell death may include necrosis, apoptosis and autophagy, and combinations thereof. During ischemia, calcium handling between the sarcoplasmic reticulum and myofilament is disrupted and calcium is diverted to the mitochondria causing swelling. Reperfusion, while essential for survival, reactivates energy transduction and contractility and causes the release of ROS and additional ionic imbalance. During acute ischemia–reperfusion, the principal death pathways are programmed necrosis and apoptosis through the intrinsic pathway, initiated by the opening of the mitochondrial permeability transition pore and outer mitochondrial membrane permeabilization, respectively. Despite intense investigation, the mechanisms of action and modes of regulation of mitochondrial membrane permeabilization are incompletely understood. Extrinsic apoptosis, necroptosis and autophagy may also contribute to ischemia–reperfusion injury. In this review, the roles of dysregulated calcium and ROS and the contributions of Bcl-2 proteins, as well as mitochondrial morphology in promoting mitochondrial membrane permeability change and the ensuing cell death during myocardial infarction are discussed.

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“…13,14 Ciddi Ca +2 dengesizliği, nekroz ve nekroptozis gibi diğer tip hücre ölümlerine de neden olabilmektedir. 15,16 Endomembran ağ aracılığı ile ER, golgi cismi, mitokondri, lizozom, peroksizom gibi diğer organeller ile yakın bir ilişki içindedir. ER, golgi cismi ve lizozomal kompartmanlar sitokimyasal yaklaşımlar kullanılarak tanınmıştır ve bu organel ağı golgi-endoplazmik retikulum-ribozom-lizozom olarak adlandırılmıştır.…”

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“…SMAC and HtrA2 serve to counteract the caspase inhibitory functions of X-linked inhibitor of apoptosis protein (XIAP) allowing for downstream activation of caspases and initiation of apoptosis (31). Regulation of mitochondrial mediated apoptosis during MI is essential in salvaging viable myocardium, thereby limiting cardiac injury (14).…”

“…The lack of oxygen of during ischemia results in cardiomyocyte cell death via apoptosis and necrosis (13). Apoptosis is a programmed cell death pathway characterized by membrane blebbing, cell shrinkage, nuclear fragmentation and chromatin condensation (14). Apoptosis is activated via two distinct pathways: the extrinsic and intrinsic pathway.…”

“…The intrinsic pathway is mediated by release of mitochondrial death factors including cytochrome c, high temperature requirement A2 (HtrA2) apoptosis inducing factor and second mitochondrial derived activator of caspase (SMAC). The downstream target of both the intrinsic and extrinsic pathways is caspase-3, a cysteine protease, which degrades proteins and activates deoxyribonucleases (DNases) to degrade deoxyribonucleic acid (DNA) (14). Apoptosis is an energy requiring process so cardiomyocytes within the border zone of the infarct undergo apoptosis and cardiomyocytes within the infarct zone undergo necrosis due to depletion of adenosine triphosphate (ATP).…”

“…Necrosis involves whole cell swelling and loss of plasma membrane integrity (14) resulting from decreased ATP levels needed to maintain ionic gradients at the plasma membrane. Upon plasma membrane rupture cellular contents initiate an inflammatory response within the myocardium resulting in migration of macrophages, monocytes, and neutrophils into the infarct zone (16).…”