60-80%糖尿病患者死于心血管并发症，糖尿病心肌病是糖尿病心血管严重并发症，其发病机制尚未完全清楚、防治措施有限。线粒体异常是糖尿病心肌病重要机制，而蛋白酶YME1L是维护线粒体蛋白稳态的关键因素之一，但是它在糖尿病心肌病中的作用从未见报道。我们预实验首次发现糖尿病条件下氧化应激介导心肌细胞YME1L蛋白的下调，因此提出“YME1L下调损害线粒体蛋白稳态，从而促进线粒体片段化及线粒体膜通透性转换孔开放，最终导致糖尿病心肌病变”的假说。为此，我们拟使用糖尿病小鼠模型和高糖刺激培养心肌细胞模型、腺病毒载体、基因沉默技术等阐明线粒体氧化应激下调糖尿病心肌细胞YME1L蛋白表达的机制，明确YME1L维持心肌细胞线粒体稳态、减轻糖尿病心肌病，和探索YME1L防止线粒体内非正常折叠蛋白聚积、线粒体片段化及线粒体膜通透转换孔开放等维持心肌细胞线粒体稳态的机制，为治疗糖尿病心肌病提供新的思路和靶点。

60-80% patients with diabetes die of cardiovascular complications and diabetic cardiomyopathy is one of cardiovascular complications. So far, the mechanisms underlying diabetic cardiomyopathy remain incompletely understood and therapeutic approaches are limited. Mitochondrial abnormalities contribute to the development of diabetic cardiomyopathy and a protease YME1L keeps mitochondrial protein homeostasis; however, it remains unknown if YME1L plays any roles in diabetic cardiomyopathy. Our preliminary study found that diabetic conditions-mediated oxidative stress induced a reduction of YME1L protein levels in the heart and cultured cardiomyocytes. Thus, we hypothesized that decreased YME1L impairs mitochondrial protein homeostasis thereby promoting mitochondrial fragmentation and membrane permeability transition pore opening, leading to diabetic cardiomyopathy. To examine this hypothesis, we propose to utilize mouse models of diabetes, cultured cardiomyocytes stimulated with high glucose, recombinant adenoviral vectors and gene silencing technologies to investigate how oxidative stress reduces YME1L expression under diabetic conditions, to define the role of YME1L in diabetic cardiomyopathy and to explore the mechanism of YME1L maintaining mitochondrial homeostasis in cardiomyocytes under diabetic conditions. This study may provide new mechanism and new therapeutic targets for cardiovascular complications of diabetes.