线粒体炫和活性氧信号调控细胞能量代谢平衡的机制研究

线粒体是细胞能量代谢的中枢和活性氧（ROS）的主要产生位点，ROS作为高反应活性的化学分子，在细胞信号转导中发挥重要作用。本课题组发现了新形式的线粒体功能信号，即线粒体炫，发现线粒体炫是单个线粒体水平ROS产生和能量代谢的复合信号，而且在细胞能量代谢过程中发挥重要作用。同时，我们前期研究发现包括三羧酸循环和呼吸链蛋白在内的530多个线粒体蛋白的半胱氨酸位点能够被ROS氧化修饰，提示ROS所介导的蛋白氧化还原修饰是线粒体能量代谢调控的重要机制。本课题将利用线粒体蛋白质氧化还原组学和代谢组学技术，结合线粒体代谢功能检测，研究长时程本底ROS和瞬时线粒体炫信号对线粒体能量代谢蛋白的氧化还原修饰作用，从蛋白质翻译后修饰新视角解析线粒体能量代谢的调控机制。进一步鉴定受氧化还原修饰的关键代谢蛋白，建立突变小鼠模型，揭示它们在糖脂代谢稳态平衡调控中的生理、病理功能，为治疗代谢相关疾病提供新策略、新靶点。

Mitochondria are not only the center of energy metabolism but also the major site of ROS production. ROS are active to react with cellular molecules and play important roles in signal transduction. We focus on studying the signal transduction and biological functions of mitochondrial flash (mitoflash) which was discovered by our group and find the mitoflash is a multiplexed signal interwined with ROS production and energy metabolism. Importantly, it participates in regulating energy metabolism. Our preliminary data show that about 530 mitochondrial proteins including subunits of respiratory chain and enzymes in Kreb’s cycle are modified by ROS at their cysteine sites, suggesting that the ROS-mediated mitochondrial protein redox modifications might take part in regulating energy metabolism. In the present study, we will study the roles of basal ROS and transient bursting ROS in mitoflash in redox modification of mitochondrial key metabolic proteins using mitochondrial oxidation-reduction proteomics profiling, metabolic flux analysis, and mitochondrial functional assays. We aim to illustrate the underlined mechanism of mitochondrial metabolism from the new angle of protein post-translational modifications. Further, we will identify the key metabolic proteins modified by redox and reveal their physiological and pathological functions in the balance of glucose and fatty acid metabolism. Our study will not only identify new mechanism of energy metabolism, but also provide new targets and strategies for the therapeutics of metabolic diseases.