线粒体嵴形成机制及生物学功能研究

The mitochondrial cristae are subcompartments of mitochondrial inner membrane, they are arranged orderly and are main sites of ATP production in mitochondria, but the mechanism of cristae formation is poorly known.We and other groups found that Mitofilin complex is the key regulator in the cristae formation and morphology. Based on our previous works, we will identify the composition of the mitochondrial cristae formation complex,then study the molecular mechanism of the cristae formation and morphology; study the molecular mechanism of quality control of Mitofilin complex and its subunits; check how mitochondrial dynamics link to cristae formation by electronic microscope, confocal microscope, photo-activable and other molecular and cellular technologies. Additionally, the CHCHD3 (the key factor of cristae formation complex) conditional knockout mouse will be created, and the role of CHCHD3 in the development of mouse embryos and the physiological function of organs will be checked; importantly, we will explore the role of mitochondrial cristae in the occurrence and development of some human severe diseases. In summary, this project will facilitate the understanding of mitochondrial cristae's function and its role in human diseases.

线粒体内膜结构嵴,在线粒体内整齐有序地排列，是线粒体内产生ATP的重要场所，但关于嵴的形成机制和生物学功能知之甚少。目前国际上及我们前期的研究结果发现Mitofilin复合物是嵴形成和形态调控的关键。本项目将在已有工作基础上，筛选和鉴定Mitofilin复合物的组成蛋白，并研究Mitofilin复合物调控嵴形成及形态的分子机理；探索复合物及其组成蛋白的质量控制机理；将利用电子和激光共焦显微镜、光激活及实时摄影等技术研究Mitofilin复合物与线粒体动力学的内在联系；还将通过建立复合物核心蛋白CHCHD3条件性基因敲除小鼠，检验CHCHD3在小鼠胚胎发育、器官组织发育和生理功能中的作用；并且将通过检测与线粒体功能异常相关的一些人类重大疾病患者的组织细胞内线粒体嵴的结构形态变化，探索线粒体嵴在这些疾病发生和发展中的作用。希望通过这些研究提高我国对于线粒体嵴功能以及相关疾病的认识和研究水平。

线粒体是半自主性的双层膜细胞器, 包括内膜和外膜，主要功能是为细胞各种生命活动提供能量。线粒体内膜结构嵴是线粒体氧化磷酸化并产生ATP的重要场所。MICOS是介导线粒体内膜系统组装的关键复合物，调控嵴的形态及嵴连接点的形成。本项目研究结果阐明了MICOS复合物的分子组装及质量控制机制；揭示了Sam50-Mic19-Mic60轴线在线粒体嵴形态调控中的关键作用；发现线粒体嵴调控蛋白Sam50在PINK-Parkin介导的线粒体自噬中发挥重要的调控作用；构建了Mic19（CHCHD3）肝特异性敲除小鼠，发现Mic19肝特异性敲除可导致小鼠脂肪肝的形成。此项目对于线粒体嵴形成及形态调控机制的阐明以及线粒体嵴相关生理和病理功能的揭示等方面具有重要进展，并作出了重要的贡献。