OPA1缺失介导的线粒体自噬水平降低促发慢性心力衰竭及机制

心力衰竭是严重威胁人类健康和寿命的重大慢病，近年国人心衰患病率持续上升，亟需阐明其分子病因学机制以探寻新的防控措施。线粒体自噬是线粒体质控途径的关键环节，然而其在心衰中的变化、作用及上游机制尚未阐明。OPA1是核编码的线粒体蛋白，可介导线粒体融合、防止线粒体途径引发的凋亡等。申请者新近预实验发现，压力负荷性心衰小鼠心肌线粒体自噬水平降低、OPA1蛋白下调，更重要的是，心肌特异性OPA1敲除小鼠线粒体结构功能异常、线粒体自噬水平降低并出现心力衰竭。提示，线粒体自噬水平与心衰进程存在密切联系；OPA1参与线粒体自噬的调控，但其与心衰的关系及机制尚不清楚。本课题拟在前期发现基础上，阐明OPA1下调介导的线粒体自噬水平降低可促发慢性心衰、并进一步研究其机制，期望为深入认识心衰发生的线粒体机理提供实验依据，并为防控心衰提供分子靶点。

Mortality and morbidity in patients with chronic heart failure (HF) are increasing each year and survival estimates only 50% at 5 years after the diagnosis of HF. So, HF is one of the major causes of human death and disability. Mitochondrial defects reduce the amount of cardiomyocytes energy and relate to many cardiac disorders, which exist in the beginning of hypertrophy and HF. Alteration of mitochondrial function is considered an origin of HF, as well as a target. However, what causes mitochondrial dysfunction in the development of HF has not been fully understood. OPA1 is a dynamic-related protein and mediates the mitochondrial fusion, maintains mitochondrial cristae morphology and prevents mitochondria-related apoptosis. In our latest preliminary study, mice with transverse aortic constriction-induced HF showed decreased mitophagy and OPA1 protein level. On the other hand, deficiency of OPA1 in cardiac-specific OPA1 knockout mice caused mitochondrial dysfunction and HF, meanwhile with lower level of mitophagy. These data suggest that mitophagy possibly plays a role in the development of HF and OPA1 may regulate mitophagy. However, the mechanisms remain largely unknown. Based on these data, we hypothesized that downregulation of mitophagy induced by OPA1 deficiency in cardiomyocytes contributes to development of HF. The present study was designed to clarify this hypothesis and investigate the underlying mechanisms. Proving this hypothesis might gain further insight into the pathogenesis of HF and provide theoretical basis and novel possible targets for preventing mitochondrial dysfunction in HF.