糖尿病患者心肌缺血再灌注（I/R）损伤敏感，是导致患者死亡的主要危险因素之一。申请人前期研究提示，糖尿病小鼠心肌酮体β-羟丁酸（βOHB）氧化利用减少，并且生酮饮食可减轻糖尿病小鼠心肌I/R损伤，但具体机制不明。本申请将延续课题组研究方向，通过动物、细胞模型，结合13C-NMR同位素分析、代谢组学、蛋白翻译后修饰、内质网-线粒体互作、线粒体生物学等多个研究层面和技术，系统验证酮体βOHB代谢是调控糖尿病心肌I/R敏化的潜在靶点，并层层揭示酮体βOHB通过下调FUNDC1表达，减少ER-Mito Contact，干预FUNDC1-Calnexin-Drp1线粒体分裂信号通路，激活ULK1相关线粒体自噬信号通路，从而优化线粒体功能，改善心肌I/R敏化的分子机制。这种针对线粒体能量底物代谢的研究方案，有望从源头找到糖尿病心肌I/R损伤敏化的路径，为临床糖尿病心肌保护提供新的思路和药物作用靶点。

The diabetic heart is more sensitive to ischemia/reperfusion (I/R) injury, which is one of the leading risk factors for the death of diabetic patients. Our preliminary data suggested that the oxidation of ketone body β-hydroxybutyrate (βOHB) is reduced in diabetic heart. Also, the diabetic mice under ketogenic diet showed ameliorated cardiac I/R injury, but the underlying mechanism is elusive. Based on previous findings, the proposed project will utilize in vivo/vitro animal model, cell culture and multiple methods, such as 13C-NMR isotope analysis, targeted metabolomics, protein post-translational modification, endoplasmic reticulum (ER)-mitochondria interaction, and mitochondrial biology, to test our hypothesis that ketone body metabolism is the therapeutic target for the ischemia-sensitive phenotype of diabetic heart. This project will demonstrate that βOHB can attenuate FUNDC1 gene expression, reduce ER-Mito Contact, inhibit the FUNDC1-Calnexin-Drp1 signaling pathway mediated mitochondrial fission, and activate ULK1-initiated mitophagy, thereby improving mitochondrial function and ameliorating cardiac I/R injury in diabetic heart. Optimizing mitochondrial energy metabolism is a promising way to protect diabetic heart against I/R injury, which will also provide new thought and novel therapeutic target for diabetic heart protection.