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However, no study has confirmed whether OPA1\u2010related mitochondrial fusion\/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia\u2010reperfusion (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\u2010related mitochondrial fusion\/mitophagy. At the molecular level, OPA1\u2010related 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\u20109\u2010involved mitochondrial apoptosis. However, genetic approaches with a cardiac\u2010specific 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\u2010related mitochondrial fusion\/mitophagy is actually modulated by melatonin in the setting of cardiac I\/R injury. Moreover, manipulation of the AMPK\u2010OPA1\u2010mitochondrial fusion\/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I\/R injury.<\/jats:p>","DOI":"10.1111\/jpi.12542","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T07:54:10Z","timestamp":1543996450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":376,"title":["Melatonin attenuates myocardial ischemia\u2010reperfusion injury via improving mitochondrial fusion\/mitophagy and activating the AMPK\u2010OPA1 signaling pathways"],"prefix":"10.1111","volume":"66","author":[{"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology Chinese PLA General Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Ninth People\u2019s 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