Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

Abstract

Optic atrophy 1 (OPA1)‐related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1‐related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia‐reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1‐related mitochondrial fusion/mitophagy. At the molecular level, OPA1‐related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase‐9‐involved mitochondrial apoptosis. However, genetic approaches with a cardiac‐specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1‐related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK‐OPA1‐mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

“…11 Furthermore, there is evidence suggesting that Mel is able to reduce the infarct area, sustain myocardial function and suppress cardiomyocyte death during cardiac ischaemia-reperfusion injury. 12,13 Mel also abrogates diabetic cardiomyopathy, by reducing ROS level and rescuing impaired mitophagy activity. 14,15 Additional studies also showed Mel being involved in alleviating mitochondrial oxidative damage and apoptosis caused by Dox in cardiomyocytes.…”

“…Studies have shown that Mel alleviates post‐infarct cardiac remodelling and dysfunction through up‐regulating autophagy, decreasing apoptosis and modulating mitochondrial integrity and biogenesis . Furthermore, there is evidence suggesting that Mel is able to reduce the infarct area, sustain myocardial function and suppress cardiomyocyte death during cardiac ischaemia‐reperfusion injury . Mel also abrogates diabetic cardiomyopathy, by reducing ROS level and rescuing impaired mitophagy activity .…”

MCU Up‐regulation contributes to myocardial ischemia‐reperfusion Injury through calpain/OPA‐1–mediated mitochondrial fusion/mitophagy Inhibition

“…Recently, Zhang et al reported OPA1 down-regulation associated with mitochondrial fusion and mitophagy inhibition in cardiac I/R model 15. Although OPA1 could be modulated by calpain in experimental neural cell,16 the relationship between calpain, OPA1 and MCU upon I/R injury remains unclear.Therefore, this study investigated the role of MCU expression in I/R and its impact on mitochondrial fission, fusion and mitophagy via modulating calpain/OPA1 expression.…”

The protective effort of GPCR kinase 2–interacting protein‐1 in neurons via promoting Beclin1‐Parkin induced mitophagy at the early stage of spinal cord ischemia‐reperfusion injury

“…5 Mitophagy acts as mitochondria-specific autophagy that specifically phagocytoses mitochondria during mitochondrial damage 6,7 and has been reported to protect against ischemia-reperfusion injury in many organs. [8][9][10] ROS are produced during mitochondrial metabolism. They act as a regulator of signaling molecules in autophagy and regulates cell apoptosis and death.…”