线粒体外膜蛋白Sam50在线粒体动力学及线粒体自噬调控中的作用及分子机制研究

Mitochondrial dynamics is required for maintenance of mitochondrial morphology, structure and functions. Mitophagy (mitochondrial autophagy) is effective regulation to clearance of damaged or unneeded mitochondria. The abnormal mitochondrial dynamics or mitophagy is closely associated with lots of human diseases such as neurodegenerative diseases, diabetes and tumors, but the molecular mechanisms of mitochondrial dynamics or mitophagy and the relationship between mitochondrial dynamics and mitophagy still remain unclear. The current project will focus on mitochondrial outer membrane protein Sam50, will study the role of Sam50 in regulation of mitochondrial dynamics and mitophagy; and explore the function of Sam50 in linking mitochondrial dynamics and mitophagy. In addition, we will create Sam50 conditional knockout mice, and check the role of Sam50 in the development of mouse embryos and organs, and study the role and molecular mechanism of Sam50 in regulation of cardiovascular function. In summary, this project will facilitate the understanding of mitochondrial dynamics and mitophagy, and will benefit to the diagnosis and treatment of some mitochondrial related human diseases.

线粒体动力学对于线粒体形态结构的维持及功能发挥具有重要作用；线粒体自噬是受损伤及不需要的线粒体被清除的有效调控机制。线粒体动力学或线粒体自噬异常与神经退行性疾病、糖尿病和肿瘤等多种人类疾病发生发展密切相关，但线粒体动力学和线粒体自噬的具体分子机制及两者之间的内在联系仍不清楚。本项目将以线粒体外膜蛋白Sam50为出发点，利用建立的线粒体研究平台系统研究Sam50在线粒体动力学及线粒体自噬调控中作用及分子机制，探索Sam50在衔接线粒体动力学与线粒体自噬的桥梁作用及相关生物学功能。此外，还将建立Sam50条件性敲除小鼠，从个体水平研究Sam50调控胚胎和器官发育, 并重点研究Sam50在心血管功能发挥中的作用及机制。此项目的实施将加深人们对于线粒体动力学及线粒体自噬的认识，对于线粒体相关疾病的病理机制的阐明及诊治具有重要意义。

线粒体动力学对于线粒体形态结构维持及功能发挥具有重要作用，线粒体自噬是受损伤及不需要的线粒体被清除的有效调控机制，线粒体动力学或线粒体自噬异常与神经退行性疾病、糖尿病和肿瘤等多种人类疾病发生发展密切相关，但线粒体动力学和线粒体自噬的具体分子机制及两者之间的内在联系仍不清楚。本项目利用建立的线粒体研究平台系统研究Sam50在线粒体动力学及线粒体自噬调控中作用及分子机制，发现Sam50缺失导致线粒体形态结构异常并直接诱导PINK1-Parkin介导的线粒体自噬。此外，构建了Sam50肝特异性敲除小鼠，发现Sam50 肝特异性敲除可导致小鼠肝炎的发生。此项目的研究成果阐明了Sam50在线粒体动力学及线粒体自噬调控中的作用，并初步解析了Sam50 肝特异性敲除小鼠的病理功能。此项目的研究结果对于加深人们对于线粒体动力学及线粒体自噬的认识，对于线粒体相关疾病的病理机制的阐明及诊治具有重要意义。