Abstract：
Dysregulated autophagy/mitophagy is one of the major causes of cardiac injury in ischemic conditions. Glycogen synthase kinase-3alpha (GSK-3α) has been shown to play a crucial role in the pathophysiology of cardiac diseases. However, the precise role of GSK-3α in cardiac mitophagy remains unknown. Herein, we investigated the role of GSK-3α in cardiac mitophagy by employing AC16 human cardiomyocytes under the condition of acute hypoxia. We observed that the gain-of-GSK-3α function profoundly induced mitophagy in the AC16 cardiomyocytes post-hypoxia. Moreover, GSK-3α overexpression led to increased ROS generation and mitochondrial dysfunction in cardiomyocytes, accompanied by enhanced mitophagy displayed by increased mt-mKeima intensity under hypoxia. Mechanistically, we identified that GSK-3α promotes mitophagy through upregulation of BNIP3, caused by GSK-3α-mediated increase in expression of HIF-1α and FOXO3a in cardiomyocytes post-hypoxia. Moreover, GSK-3α displayed a physical interaction with BNIP3 and, inhibited PINK1 and Parkin recruitment to mitochondria was observed specifically under hypoxia. Taken together, we identified a novel mechanism of mitophagy in human cardiomyocytes. GSK-3α promotes mitochondrial dysfunction and regulates FOXO3a -mediated BNIP3 overexpression in cardiomyocytes to facilitate mitophagy following hypoxia. An interaction between GSK-3α and BNIP3 suggests a role of GSK-3α in BNIP3 recruitment to the mitochondrial membrane where it enhances mitophagy in stressed cardiomyocytes independent of the PINK1/Parkin.
摘要：
自噬/线粒体自噬失调是缺血性心脏损伤的主要原因之一。糖原合成酶激酶3α（GSK-3α）已被证明在心脏病的病理生理学中起着至关重要的作用。然而,GSK-3α在心脏线粒体自噬中的确切作用尚不清楚。在这里，我们通过在急性缺氧条件下使用AC16人心肌细胞研究了GSK-3α在心脏线粒体自噬中的作用。我们观察到，缺氧后AC16心肌细胞中GSK-3α功能的获得深刻诱导了线粒体自噬。此外，GSK-3α过表达导致心肌细胞中ROS生成增加和线粒体功能障碍,伴随着缺氧下mt-mKeima强度增加的线粒体自噬增强。机械上,我们发现GSK-3α通过上调BNIP3促进线粒体自噬，这是由GSK-3α介导的缺氧后心肌细胞中HIF-1α和FOXO3a表达增加引起的。此外，GSK-3α显示与BNIP3的物理相互作用，在缺氧下观察到抑制PINK1和Parkin对线粒体的募集。一起来看,我们在人心肌细胞中发现了一种新的线粒体自噬机制。GSK-3α促进线粒体功能障碍并调节FOXO3a介导的BNIP3在心肌细胞中的过表达以促进缺氧后的线粒体自噬。GSK-3α和BNIP3之间的相互作用表明GSK-3α在BNIP3募集到线粒体膜中的作用，在线粒体膜中它增强了应激心肌细胞中的线粒体自噬，而与PINK1/Parkin无关。
