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Review
. 2020 Apr;24(7):3795-3806.
doi: 10.1111/jcmm.15127. Epub 2020 Mar 10.

Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury

Sean M Davidson  1 , Adriana Adameová  2   3 , Lucio Barile  4 , Hector Alejandro Cabrera-Fuentes  5   6   7   8   9 , Antigone Lazou  10 , Pasquale Pagliaro  11   12 , Kåre-Olav Stensløkken  13 , David Garcia-Dorado  14   15   16 ; EU-CARDIOPROTECTION COST Action (CA16225)
Affiliations
Review

Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury

Sean M Davidson et al. J Cell Mol Med. 2020 Apr.

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.

Keywords: apoptosis; autophagy; cardiac; cell death; ischaemia; myocardial infarction; necroptosis; necrosis; pyroptosis; reperfusion.

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Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Figures

Figure 1
Figure 1
The major pathways of cell death that contribute to myocardial ischaemia and reperfusion injury. During initial oncosis, cells swell—this is reversible but can proceed to necrosis. Non‐cardiomyocytes can die via a processes of apoptosis or necrosis/necroptosis, in addition to other types of cell death described herein. Cardiomyocytes die primarily via a process of necrosis/necroptosis in addition to other cell‐death processes such as pyroptosis, but there is a little evidence for any contribution of apoptosis. Plasma membrane rupture is the terminal event, and this is mediated either by MLKL channels during necroptosis or by GSDMD pores during pyroptosis. Multiple cell‐death pathways can eventuate in plasma membrane permeabilization, as detected by dyes such as propodium iodide (resulting in red nuclei as shown) or trypan blue
Figure 2
Figure 2
Possible mitochondrial pathways of necroptosis. Ischaemia and reperfusion causes an increase in levels or phosphorylation and activation of RIP1 and RIP3 (receptor‐interacting serine/threonine‐protein kinase 1 and 3), MLKL (mixed‐lineage kinase domain‐like pseudokinase) and PGAM5 (phosphoglycerate mutase family member 5). RIP3 translocates to the mitochondria and interacts with PGAM5 and DRP1. PGAM5 dephosphorylates and activates DRP1 leading to mitochondrial fission and dysfunction. Additionally, RIP3‐mediated activation of CaMKII (Ca2+‐calmodulin‐dependent protein kinase) may trigger necroptosis via the MPTP. Mitochondrial dysfunction leads ultimately the formation of the necroptosome consisting of activated RIP1, RIP3 and MLKL, and necroptotic cell death ensues.
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