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Abstract
Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial‐independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled ‘Mitochondria as targets of acute cardioprotection’ and emerged as part of the discussions of the European Union (EU)‐CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
Highlights
Ischaemic heart disease remains a major cause of morbidity and mortality throughout the world, and is responsible for ~20% of deaths in the European Union in both men and women.[1]
Cardiomyocytes begin to die during exposure to prolonged ischaemia, and while reperfusion is necessary to limit this process, it causes a spike of further cell death that contributes to final infarct size.[3]
The involvement of mitochondria in extrinsic and intrinsic apoptotic pathways is undeniable, and their role in necroptosis and pyroptosis is being elucidated, the degree to which mitochondria are involved in other, more newly recognized, forms of cell death has just begun to be disentangled. In this respect, ‘parthanatos’ entails cell death characterized by excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1).[117]
Summary
Ischaemic heart disease remains a major cause of morbidity and mortality throughout the world, and is responsible for ~20% of deaths in the European Union in both men and women.[1]. In combination with oxidative stress and calcium overload, ATP levels may decrease to a critical level at which the ability of the cardiac cell to remain viable becomes compromised, and the cell undergoes uncontrolled death through a process of oncosis and necrosis, which is described in detail below. Even before this step, programmed cell death pathways may be activated including apoptosis, necroptosis or pyroptosis. This review aims to provide insight into the different types of cell death which myocardial cells may undergo during IR, with special emphasis on the role of mitochondria in those processes, in order to understand how these processes can be targeted to protect the heart.[6]
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