慢性压力负荷型心力衰竭心肌保护新机制：TBC1D15/RAB7调控的线粒体-溶酶体轴

Heart failure is characterized by cardiac remodeling and contractile dysfunction, while the underlying molecular mechanism(s) remains to be clarified. Finding new target is critical for the management of heart failure. Research from our and others has been demonstrated that impaired mitophagy contribute to the onset and development of heart failure. More evidence from our lab has revealed reduced TBC1D15 expression, increased abnormal mitochondria–lysosome contacts, depressed mitophagy in heart failure. TBC1D15 overexpression in vitro inhibited heart failure-induced cardiomyocyte apoptosis and mitochondrial dysfunction, which means that the cardio-protection of TBC1D15 may be associated with mitochondria–lysosome contacts and mitophagy. This project will take advantage of TAC induced heart failure and TBC1D15 overexpression transgenic mice combined with TBC1D15, Fis1, RAB7 mutant virus transfection to examine the detrimental role of abnormal mitochondria–lysosome contacts in heart failure, to explore the mechanism(s) of cardio-protection for heart failure exerted by mitochondria-lysosome axis and subsequent mitophagy regulation induced by TBC1D15/Fis1/RAB7 signaling pathway, which provides new target for the clinical management of heart failure.

心力衰竭患者心肌重构及心功能损害的机制亟待明确，对于寻找心力衰竭新的干预靶点具有重要的意义。国内外及本课题组研究证实线粒体自噬受损是心力衰竭的关键机制。前期工作证实，心力衰竭时心肌细胞内TBC1D15表达下调，线粒体与溶酶体异常结合增多，线粒体自噬抑制，体外过表达TBC1D15能够明显降低心力衰竭时心肌细胞凋亡及线粒体功能异常，提示TBC1D15的心肌保护作用可能与线粒体-溶酶体结合轴及线粒体自噬有关。本项目结合前期工作拟采用主动脉缩窄诱导慢性压力超负荷型心力衰竭模型及TBC1D15过表达转基因小鼠，体外转染TBC1D15、Fis1、RAB7突变病毒，明确线粒体与溶酶体异常结合在心力衰竭中的心肌损伤作用，探讨TBC1D15/Fis1/RAB7介导的线粒体-溶酶体轴及后续的线粒体自噬调控发挥心肌保护的机制，为临床心力衰竭的防治提供新的干预靶点。

心力衰竭患者心肌重构及心功能损害的机制亟待明确，对于寻找心力衰竭新的干预靶点具有重要的意义。国内外及本课题组研究证实线粒体自噬受损是心力衰竭的关键机制。本项目采用心力衰竭模型及TBC1D15心肌特异性过表达或敲除小鼠，发现TBC1D15通过Fis1/RAB7轴调控线粒体-溶酶体结合进而调节溶酶体相关的线粒体自噬流激活，减轻急性心肌梗死诱导心肌损伤；发现TBC1D15通过Fis1/RAB7轴调控线粒体-溶酶体结合促进TBC1D15/Drp1介导的线粒体不均等分裂，维持线粒体稳态，减轻缺血再灌注时心肌损伤；发现TBC1D15过表达后进一步加重TAC诱导的心力衰竭，其机制正在深入研究；以上发现提示TBC1D15在急性和慢性心力衰竭中作用不同，TBC1D15介导的线粒体-溶酶体互作及线粒体稳态在急性心力衰竭中具有重要作用，为临床治疗相关心力衰竭提供了一个新的靶点。