Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond

Abstract

Excessive death of cardiac myocytes leads to many cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of many organs, including the heart. The recognition of necrosis as a regulated process mandates a re-examination of cell death in the heart together with the mechanisms and therapy of cardiac diseases. In this study, we summarize the regulatory mechanisms of the programmed necrosis of cardiomyocytes, that is, the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Furthermore, the role of this programmed necrosis in various heart diseases is also delineated. Finally, we describe the currently known pharmacological inhibitors of several of the key regulatory molecules of regulated cell necrosis and the opportunities for their therapeutic use in cardiac disease. We intend to systemically summarize the recent progresses in the regulation and pathological significance of programmed cardiomyocyte necrosis along with its potential therapeutic applications to cardiac diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

Figure 1

Main signalling pathways of programmed necrosis in cardiomyocytes. Association of TNFR1 with the TNF trimer leads to the formation of complex I, consisting of TRADD, TRAF2, RIP1, CYLD and cIAP1/cIAP2, at the cytoplasmic membrane. K63‐linked polyubiquitination of RIP1 by cIAP1/cIAP2 leads to the recruitment of critical proteins and the activation of survival pathways. In the absence of cIAP1/cIAP2, RIP1, FADD and caspase‐8 form cytosolic complex IIa, which activates the caspase cascade and induces apoptosis. Under conditions in which caspase‐8 activity is inhibited genetically or pharmacologically (zVAD), RIP1 interacts with RIP3 and MLKL to form complex IIb, which is involved in the mediation of necroptosis. The kinase activity of RIP1 is essential for complex IIb action. RIP3 and MLKL are phosphorylated in complex IIb and translocate to the plasma membrane or to mitochondria‐associated membranes, where the complex mediates membrane permeabilization. Phosphorylated MLKL changes the permeability of the plasma membrane, resulting in ion exchange (Na⁺ and Ca²⁺) across the membrane. RIP1 and RIP3 undergo a complex set of phosphorylation events, and necrosis ensues through unclear mechanisms. One potential mechanism, as shown, may involve the activation of catabolic pathways and ROS production. A second necrotic pathway involves the mPTP in the IMM and its regulation by CypD. mPTP may be opened by increased Ca²⁺ concentration, oxidative stress, decreased ATP levels and other stimuli that occur during I/R and HF. Furthermore, mitochondrial protein kinases such as PKC‐1, Akt/HKII and GSK‐3β have been suggested to be recruited from the cytosol to mitochondria in response to the activation of GPCR receptors. As described in the text, mPTP opening results in profound alterations in mitochondrial structure and function; these changes result in decreased ATP levels and loss of ΔΨm. Furthermore, ischaemia leads to increased [Na⁺], which directly induces necrosis, and reperfusion leads to increased [Ca²⁺], which induces mPTP opening. No definitive connection between death receptors and mitochondrial necrosis pathways has been delineated. A possible connection is RIP3‐induced ROS generation (see text for details).

Figure 2

Chemical structures of inhibitors of regulated necrosis. The mechanisms of action and key functions of the inhibitors, along with relevant references are provided in Table 1.