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.
Highlights
Targeting mitochondrial fusion and fission proteins for cardioprotectionSauri Hernandez-Resendiz1,2,3 | Fabrice Prunier4 | Henrique Girao5,6,7 | Gerald Dorn8 | Derek J
The mitochondrial fission and fusion proteins which play key roles in process involved in mitochondrial quality control, act to preserve normal mitochondrial respiratory function in the setting of acute myocardial ischaemia/reperfusion injury (IRI), positioning them as key targets of cardioprotection
It is important to note that chronic inhibition of mitochondrial fission is detrimental to both susceptibility to acute IRI and cardiac function, as it suppresses mitophagy and results in the accumulation of damaged mitochondria
Summary
Sauri Hernandez-Resendiz1,2,3 | Fabrice Prunier4 | Henrique Girao5,6,7 | Gerald Dorn8 | Derek J. The mechanisms through which IR induces mitochondrial fission are not clear but a number of factors may play a role: (a) oxidative stress—this is increased in acute myocardial IRI and is known to be an inducer of mitochondrial fission[59]; (b) p38 MAPK—pharmacological inhibition of p38 MAPK at reoxygenation in HL-1 cells has been shown to reverse hypoxia-induced mitochondrial fragmentation, suggesting that p38 MAPK activation may in part contribute to hypoxia/reoxygenation-induced mitochondrial fission[58]; (c) Cdk[1] and PKC-δ—these have been shown to increase during IRI and associate with Drp[1], thereby inducing mitochondrial fission[59]; (d) calcium overload—this occurs in IRI and has been shown to induce mitochondrial fission[60]; (e) calcineurin— IRI has been shown to induce calcineurin activation, which is known to dephosphorylate Drp[1] at Ser[637], thereby promoting translocation of Drp[1] to mitochondria to induce fission.[59,61] Wang et al[61] have demonstrated that miRNA499 was shown to confer cardioprotection by preventing IR-induced calcineurin activation and inhibiting Drp1-mediated fission; (f) SUMOylation of Drp1—it has been reported that Sentrinspecific protease 3 (SENP3)-mediated deSUMOylation of Drp[1] facilitated its binding to Mff and promoted cell death following simulated IRI62,63; (g) succinate—it has been shown that extracellular succinate produced during acute myocardial IRI activated GPR91 and promoted
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