Drp1 SUMO化修饰对线粒体自噬的调节在糖尿病心肌病中的作用研究

Cardiovascular diseases are the most severe complications in diabetes mellitus. It has been suggested that mitochondrial damage and dysfunction contribute to diabetic cardiomyopathy. Drp1 is a small GTPase translocating from cytosol to mitochondria that mediates mitochondrial fission. Recent findings also indicated that Drp1 plays a pivotal role in mitochondrial autophagy in cardiomyocytes in response to energy stress. Drp1 is regulated by a variety of post-translational modification (PTM), including phosphorylation, S-nitrosylation, small ubiquitin-like modifier(SUMO)-ylation, and ubiqutination. SUMOylation is a versatile and dynamic PTM, regulating several important cellular functions, including transcription, cell division, protein stability and translocation, signal transduction, protein-protein interactions, and chromatin segregation. Drp1 has been reported to be a substrate for both SUMO-1 and SUMO-2/3 conjugation. It is also suggested that SUMOylation may regulate translation of Drp1 from cytosol to mitochondria, as well as stabilize the conjunction of Drp1 with mitochondria. Nonetheless, it still remains elusive with regards to the role of Drp1 and its SUMOlyation in diabetic cardiomyopathy. Our earlier evidence failed to note any change of Drp1 expression in cardiac tissue from type 1 diabetic mouse model, while Drp1-/- deteriorated diabetes-induced cardiac dysfunction as well as destroyed mitochondria autophagy. In the present study, we aim to test the following hypothesis: diabetes inhibited SUMOylation of Drp1 in murine myocardium and further decreased the stability of the conjunction of Drp1 with mitochondria, resulting in translational inhibition of Drp1 from cytosol to mitochondria and aberrant mitophagy, en route to cardiac dysfunction. Through this work, we will take a step to reveal the mechanism behind diabetic cardiomyophathy and identify possible link between mitochondia fission and mitochondrial autophagy. Completion of this work should help to identify new therapeutic target for diabetic cardiomyopathy.

心血管疾病是糖尿病患者最严重、最致命的并发症。糖尿病心肌病发病机制与线粒体损伤及功能密切相关。Drp1是调节线粒体分裂的小分子GTP酶，最新研究提示，在能量应激时Drp1在线粒体募集促进线粒体自噬的发生。Drp1 SUMO化可稳定其与线粒体的结合。然而在糖尿病心肌病中Drp1及其SUMO化的作用目前尚不明了。课题组前期研究发现糖尿病小鼠心肌中Drp1水平并未发生变化，但Drp1-/-可进一步恶化心功能，同时伴有线粒体自噬水平的下降。提示Drp1可能通过促进线粒体自噬改善心肌损伤。本项目拟进一步验证糖尿病抑制心肌中Drp1的 SUMO修饰，降低Drp1与线粒体结合的稳定性，减少Drp1向线粒体的转位，抑制线粒体自噬，最终导致心肌收缩舒张功能障碍。通过本研究进一步探明糖尿病心肌病的发病机制，为线粒体自噬抑制和线粒体分裂寻找可能的衔接蛋白，为糖尿病心肌损伤寻找可能的治疗靶点。

心血管疾病是糖尿病患者最严重、最致命的并发症。糖尿病心肌病发病机制与线粒体损伤及功能密切相关。Drp1是调节线粒体分裂的小分子GTP酶，在能量应激时Drp1在线粒体募集促进线粒体自噬的发生。本项目通过研究证实：Drp1过表达可显著改善高糖导致的线粒体自噬钝化、膜电位下降及心肌细胞凋亡。高糖导致SUMO2/3水平下调及线粒体融合，证实DRP1 SUMO化促进了线粒体自噬小体的形成。同时证实了Drp1作为关键分子调控线粒体与溶媒体的融合，诱导线粒体的不均等分裂，而这一过程受到TBC1D15的调控。TBC1D15不仅仅与Drp1相结合，也与Fis1相结合，调控线粒体不均等分裂，同时也调控线粒体与溶酶体的融合，影响线粒体自噬的发生。通过本研究进一步探明糖尿病心肌病的发病机制，为线粒体自噬抑制和线粒体分裂寻找可能的衔接蛋白，为糖尿病心肌损伤寻找可能的治疗靶点。项目共发表SCI论文16篇，其中IF>10分的5篇，受邀撰写综述2篇。申请人获得树兰医学奖青年奖、上海市优秀学术带头人，主编英文专著2部。见附件部分。培养博士后2名，毕业博士研究生3名，2名博士后均获得国家自然科学青年项目，其中1人入选2020年中华医学会心血管分会年优胜奖。期间课题负责人2018年11月应邀参加美国休斯顿the annual Houston Methodist George P. Noon Transplant Conference并进行大会特邀发言，并进行大会特邀发言，2018年10月受邀参加韩国The Korean Society of Cardiology会议，并进行大会发言。