Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Pineal Res. 2019 Mar;66(2):e12542. doi: 10.1111/jpi.12542. Epub 2019 Jan 31.
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.
视神经萎缩 1 (OPA1)-相关的线粒体融合和自噬对于维持应激条件下的线粒体稳态至关重要。然而，尚无研究证实 OPA1 相关的线粒体融合/自噬是否被褪黑素激活，从而减轻心脏缺血再灌注 (I/R) 损伤中的心肌细胞死亡和线粒体应激。我们的结果表明，OPA1、线粒体融合和自噬在 I/R 损伤后受到显著抑制，伴随着梗死面积扩大、心功能障碍、心肌炎症和心肌细胞氧化应激。然而，褪黑素治疗维持了心肌功能和心肌细胞活力，这些作用高度依赖于 OPA1 相关的线粒体融合/自噬。在分子水平上，褪黑素可使 OPA1 相关的线粒体融合/自噬正常化，从而显著纠正过度的线粒体分裂，促进线粒体能量代谢，维持线粒体功能，并阻断心肌细胞 caspase-9 参与的线粒体凋亡。然而，心脏特异性 OPA1 基因敲除的遗传方法消除了褪黑素对体内和体外心肌细胞存活和线粒体稳态的有益作用。此外，我们证明褪黑素通过 AMPK 信号通路影响 OPA1 的稳定性，而 AMPK 的阻断会抑制 OPA1 的表达并损害褪黑素的心脏保护作用。总的来说，我们的研究结果证实了在心脏 I/R 损伤中，OPA1 相关的线粒体融合/自噬确实受到褪黑素的调节。此外，通过褪黑素对 AMPK-OPA1-线粒体融合/自噬轴的操纵可能是减轻心脏 I/R 损伤的一种新的治疗方法。
