细胞代谢调控线粒体稳态及其与细胞器互作的机制研究

线粒体是细胞的能量工厂，是分解代谢和合成代谢的中心。线粒体处于持续的融合-分裂和与其他细胞器互作的动态平衡中，与细胞稳态、组织器官发育、衰老及疾病发生紧密相关。但线粒体稳态及其与其他细胞器互作的调控机制远未明晰。本项目致力于揭示细胞代谢调控线粒体稳态及与其他细胞器互作的机制、线粒体稳态在遗传代谢性疾病中的作用。利用已建立的独特的线虫线粒体稳态研究体系，我们将重点开展以下研究：1）筛选影响线粒体稳态的突变体，克隆基因，发现影响线粒体稳态的关键因子；2）利用高分辨活细胞成像、透射电镜分析、代谢组学及生化方法等，揭示参与代谢的关键因子对线粒体代谢、结构和功能的影响； 3) 揭示它们参与的代谢和信号通路对线粒体融合-分裂的作用及机制；4）揭示它们对线粒体-内质网、线粒体-溶酶体互作的影响和机制；5)研究相应小鼠模型中线粒体结构、功能异常及组织器官发育，揭示相关遗传代谢性疾病与线粒体稳态之间的关系。

Mitochondria are central to cell metabolism by coordinating multiple catabolic and anabolic pathways and coupling the tricarboxylic acid cycle with ATP production via oxidative phosphorylation. Mitochondria dynamically interact with other organelles, and undergo constant fusion and fission, thus homeostatically maintaining their normal functions. However, the mechanisms that maintain mitochondrial homeostasis are not well understood. In this project, we aim to explore the effects of metabolism on mitochondrial homeostasis and to elucidate the underlying mechanisms by exploiting the unique C. elegans-based in vivo system for studying mitochondrial homeostasis. We will: 1) uncover major factors that are important for mitochondrial homeostasis by screening C. elegans mutants that are defective in mitochondrial morphologies and cloning the affected genes; 2) elucidate the role of the newly identified metabolic factors in mitochondrial metabolisms, structures and functions by means of high-resolution live-cell imaging, transmission electron microscopy analysis, metabolic analysis and biochemical studies; 3) understand the regulatory roles of these metabolic factors in mitochondrial fusion and fission; 4) understand the regulatory roles of these metabolic factors in mitochondrion-ER and mitochondria-lysosome interactions; and 5) study mitochondrial structures and functions, tissue and organ development in mouse models of metabolic factors identified in C. elegans, and demonstrate the contribution of impaired mitochondrial homeostasis to corresponding genetic metabolic diseases.