Mst1抑制线粒体自噬参与糖尿病心肌病进展的分子机制研究

Diabetes has become a worldwide epidemic disease. Cardiovascular complications accounts for more than 2/3 of diabetic mortality. However, the specific mechanism is unknown. Our previous study has suggested that mitophagy is the core pathogenesis of diabetic cardiomyopathy. Removing injured mitochondria, while improving the function and biogenesis of mitochondria, are the key routes to prevent diabetic cardiomyopathy and reduce the cardiovascular mortality in diabetic patients. Our previous study also demonstrated that the phosphorylation of mammalian STE20 like kinase 1 (Mst1) was increased in the diabetic cardiomyocytes. In diabetic Mst1 knockout mice, mitochondrial damage was alleviated. Typical double membrane autophagosomes with injured mitochondria were also observed in the cardiomyocytes. These results suggest that Mst1 inhibits mitophagy and participates in the development of diabetic cardiomyopathy. However, the molecular mechanism by which Mst1 regulates mitophagy is not clear. In the present research project, diabetic cardiomyopathy model will be constructed. Animal studies and signaling detecting will be used to elucidate the role of Mst1 modulated mitophagy in the pathogenesis of diabetic cardiomyopathy and the underlying mechanisms. The present study will provide new treatment targets for diabetic cardiomyopathy and provide new strategies for the prevention and treatment of diabetes.

糖尿病是世界范围内的流行病，大于三分之二的糖尿病患者死于糖尿病心血管并发症，具体机制不明。本课题组前期研究提示，线粒体自噬可能是糖尿病心肌病发病机制的核心。有效清除损伤线粒体，改善线粒体生物合成及线粒体功能，才能从根本上延缓糖尿病心肌病的进展，降低糖尿病患者心源性死亡率。课题组进一步研究提示，糖尿病小鼠心肌细胞哺乳动物STE20样激酶1（Mst1）磷酸化上调。Mst1敲除小鼠构建糖尿病模型后，线粒体损伤减轻，心肌细胞内可见包裹损伤线粒体的典型自噬小体。上述结果提示Mst1可能抑制线粒体自噬并参与糖尿病心肌病的进展。然而，Mst1调控线粒体自噬的分子机制如何？目前尚不清楚。课题组拟构建糖尿病心肌病模型，采用动物实验、信号通路检测等在体、离体手段，从整体、细胞、分子水平揭示Mst1调控线粒体自噬在糖尿病心肌病发生发展中的作用及分子机制，寻找糖尿病心肌病治疗的新靶点，为该疾病的防治提供新的思路。

糖尿病心肌病是糖尿病相关的心肌慢性进行性损害，表现为心功能不全。阐明糖尿病心肌病损伤的机制，是糖尿病心肌病防治领域中亟待解决的重要问题。作为能量供应细胞器，线粒体占胞浆容积35-40%，并为心肌提供95%的ATP，参与心肌细胞收缩及舒张功能、电稳态、细胞存活与死亡等系列过程。线粒体损伤是糖尿病心肌病发病的中心环节，然而具体机制尚需阐明。我们课题组前期研究发现Mst1参与多种心血管疾病的凋亡与自噬调控，抑制Mst1表达，促进糖尿病心肌自噬活性，改善心肌活性。损伤线粒体聚集是1型和2型糖尿病心肌病的病理特征，损伤线粒体不仅合成ATP障碍，而且是氧化应激损伤、诱导凋亡的重要参与者，清除受损线粒体是改善线粒体质量和细胞稳态的有效途径。因此，我们从Mst1参与糖尿病心肌病线粒体自噬调控角度进一步探索。.本课题主要发现如下：(1)Mst1敲除减少糖尿病小鼠心肌线粒体数量，但不抑制线粒体生源学相关蛋白表达，说明Mst1敲除促进糖尿病心肌病中损伤线粒体的消除；(2)在高糖处理下，抑制Mst1表达增强心肌细胞的线粒体自噬活性；(3)PINK1/Parkin, BNIP3, BNIP3L, FUNDC1四种途径在多种疾病中参与线粒体自噬调控。但我们只观察到Parkin与线粒体自噬水平变化趋势一致，因此我们推测，抑制Mst1可能主要通过Parkin通路调控线粒体自噬。进一步我们用Parkin 敲除小鼠模型证实Parkin参与Mst1调控线粒体自噬过程；(4)Mst1敲除通过促进Parkin介导线粒体自噬，改善糖尿病心肌病表型；(5)在糖尿病心肌病模型中，Mst1通过抑制Parkin依赖的线粒体自噬，加重线粒体形态损伤和功能障碍；(6)抑制Mst1表达后，促进Parkin从胞浆到线粒体的募集，进一步证实Mst1通过调控Parkin参与线粒体自噬。.本课题阐明内源性Mst1对线粒体数量和功能的调控作用和机制，在此基础上阐明Mst1过表达与糖尿病心肌病受损线粒体聚集相关，抑制Mst1表达通过上调Parkin介导线粒体自噬活性，为糖尿病心肌线粒体的损伤修复机制提供了新的认识，并为临床糖尿病性心脏损伤的线粒体稳态治疗的靶向性和特异性提供了重要的临床指导。

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