代谢应激因素促进SENP1磷酸化并调控线粒体功能的作用与机制研究

我们前期研究证实SUMO化特异性蛋白酶SENP1能够去除线粒体去乙酰化酶Sirt3的SUMO化修饰，从而影响线粒体蛋白的乙酰化修饰和线粒体的代谢活性；同时发现一些代谢应激因素能够促进SENP1进入线粒体，并且SENP1进入线粒体与其S180位点的磷酸化有密切关系，S180的突变能够抑制SENP1进入线粒体并影响线粒体的代谢活性。基于这些前期工作，我们推测代谢应激因素通过促进SENP1磷酸化修饰调控了其进入线粒体，并影响线粒体的代谢和功能。在本课题中，我们拟将研究：1.代谢应激因素调控SENP1磷酸化和进入线粒体的分子机制；2.SENP1磷酸化修饰对线粒体功能的调控作用及分子基础；3.调控SENP1磷酸化的小分子化合物的筛选。通过本项研究，我们期望更深入的阐明SENP1-Sirt3信号通路对线粒体的调控作用及生理病理意义。

Our studies find that the SUMO-specific protease 1 (SENP1) can deSUMOylate the mitochondrial deacetylase Sirt3, regulate the mitochondrial proteins acetylation level and then affect the stress induced mitochondrial adaptation. Upon certain metabolic stress, it is found that SENP1 can translocate into mitochondria and initiate the process of mitochondrial proteins deSUMOylation. Importantly, we find that SENP1 S180 is a key phosphorylation site to carry out its translocation. Based on these previous works, we propose that metabolic stress factors may promote SENP1 S180 phosphorylation and translocation, and then affect the mitochondrial metabolism and function. In this project, we will focus on the following points: 1. The molecular mechanism of SENP1 S180 phosphorylation and translocation into mitochondria upon metabolic stress; 2. The regulation and molecular basis of SENP1 S180 phosphorylation on mitochondrial function; 3. Screening and application of small molecule compounds that regulate SENP1 S180 phosphorylation. In this study, we expect to further elucidate the roles of SENP1-Sirt3 signaling pathway in the regulation of mitochondrial functions and its physiological and pathological significance.