Targeting mitochondrial fusion and fission proteins for cardioprotection

Abstract

New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded protein response. In this article, we review how targeting these inter-related processes may provide novel treatment targets and new therapeutic strategies for reducing MI size, preventing the onset of HF following AMI.

Keywords: acute myocardial ischaemia/reperfusion injury; cardioprotection; mitochondrial morphology; mitochondrial unfolded protein response; mitophagy cardioprotection.

FIGURE 1

Mitochondrial fission and fusion proteins as targets for cardioprotection. Mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury can be targeted by mdivi‐1 and Drpitor, pharmacological inhibitors of Drp1 and P110, a peptide inhibitor of the interaction between Drp1 and hFis1 to confer cardioprotection. A number of other factors (such as SB203580, PKA activators, succinate, erythropoietin and melatonin) have also been shown to confer cardioprotection by targeting the fusion and fission proteins. Inset upper box: This scheme shows the mitochondrial fission machinery, comprising Drp1 and its outer mitochondrial membrane receptors, MiD49/MiD51, Mff and hFis1. Pre‐constriction by the endoplasmic reticulum (ER) via INF2, actin and Spire1C initiates the Drp1‐driven mitochondrial fission process. Inset lower box: This scheme shows the pleiotropic non‐fusion effect of Mfn2 in tethering mitochondria to the ER

FIGURE 2

Mitophagy as a target for cardioprotection. The mitochondrial fusion and fission comments have been demonstrated to participate in 2 different mitophagy pathways—(A) the PINK‐Parkin mitophagy pathway and (B) the Ulk1 mitophagy pathway (modified from Ref. 121)

FIGURE 3

The mitochondrial unfolded protein response and cardioprotection. Schematic model of the mitochondrial unfolded protein response (UPRmt). Nicotinamide ribose, ischaemic preconditioning (IPC), oligomycin and doxycycline are therapeutic strategies that have been shown to reduce acute myocardial ischaemia/reperfusion injury (IRI) by enhancing the UPRmt, and Mfn2 has been shown to play a key role in the UPR