线粒体质量失衡在严重创伤多器官功能损害中的作用及ER-MITO 接触调控机制

Multiple organ damage was major reason of death after severe trauma. Several organs such as heart, blood vessel and intestine are vulnable to severe trauma and play critical roles in MODS, their mechanisms need further investigation. Our previous study found that mitochondrial fission, fusion and biogenesis were disorder, and the contact of endoplasmtic reticulum and mitochondrial (ER-MITO contact) was increased after severe trauma. We hypothesize that mitochondrial quality inbalance is a key mechanism in the occurrence of multiple organ damage suffering from severe trauma, ER-MITO contact is the key knot that disturbs the balance of mitochondrial fission, fusion, mitophagy and biogenesis. With severe trauma model, the characterastic and role of mitochondrial quality inbalance in cardiac myocyte, vascular endothelial cell and vascular smooth muscle cell, intestinal cell are observed, the mechanisms of ER-MITO contact inducing mitochondrial fission, fusion, mitophagy and biogenesis and its key passways are explored. The study will provide a new mechanism for the occurrence of multiple organ damage suffering from severe trauma and provide new targets and measures for the treatments of multiple organ dysfunction after severe trauma.

多器官功能损害是严重创伤死亡的重要原因。心脏、血管、肠道功能损害是严重创伤致多器官功能损害的关键和启动器官，但机制有待深入阐明。本实验前期研究发现严重创伤后心肌细胞、血管内皮细胞、血管平滑肌细胞和肠粘膜上皮细胞线粒体分裂、融合以及生成出现明显紊乱，与内质网与线粒体接触（ER-MITO contact）增加密切相关。据此推测：严重创伤致线粒体质量失衡即线粒体分裂、融合、自噬和生成动态平衡失调可能是导致多器官功能损害的关键机制，ER-MITO contact增加可能是导致线粒体质量失衡的枢纽环节。项目拟采用严重创伤失血模型，以心脏、血管和肠道为靶器官，研究线粒体质量失衡在严重创伤多器官功能损害中的作用，以及ER-MITO contact增多致线粒体分裂、融合、自噬和生成动态平衡紊乱的机制及关键通路。研究将从全新角度解释严重创伤致多器官功能损害的机制，为其防治提供全新靶点和措施。

多器官功能损害是严重创伤死亡的重要原因。心脏、血管、肠道功能损害是严重创伤致多器官功能损害的关键和始动器官，但其机制有待进一步阐明。本研究发现，严重创伤后心肌细胞、血管内皮细胞、血管平滑肌细胞和肠粘膜上皮细胞线粒体分裂和融合出现明显紊乱，线粒体功能受损。线粒体质量的失衡与内质网和线粒体接触（ER-MITO contact）增加密切相关。机制研究发现，缺血缺氧后细胞质活化的Drp1通过与细胞骨架蛋白Shroom4结合，引起肌动蛋白丝成束，拉动内质网包裹线粒体，引起线粒体预收缩，启动ER-MITO接触。ER-MITO接触后，线粒体分裂的机制主要与Calnexin/FUNDC1有关。进一步研究发现，Drp1抑制剂可以通过恢复线粒体质量来保护缺血缺氧损伤后的器官功能。严重创伤致线粒体质量失衡是导致多器官功能损害的关键机制，ER-MITO contact增加是导致线粒体质量失衡的枢纽环节。该研究将从一个新的角度解释严重创伤致多器官功能损害的机制，并为其防治提供新的靶点和措施。