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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.

journal_name

J Pineal Res

journal_title

Journal of pineal research

authors

Zhang Y,Wang Y,Xu J,Tian F,Hu S,Chen Y,Fu Z

doi

10.1111/jpi.12542

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

e12542

issue

eissn

0742-3098

issn

1600-079X

journal_volume

pub_type

杂志文章

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