线粒体不仅是细胞的能量工厂，也参与重要的信号转导过程。其蛋白乙酰化能够感应细胞能量状态，同时又能调控代谢酶的活性，反馈调控糖、脂和氨基酸代谢等。线粒体功能的正常与否与胰岛素抵抗和2型糖尿病的发生过程密切相关。作为细胞感受能量的手段，线粒体蛋白乙酰化在肥胖和胰岛素抵抗发生过程中是否通过影响线粒体和内质网之间的信号传递来协同调控代谢等细胞过程并不清楚。肝脏是机体的代谢中枢且富含线粒体，其线粒体功能是否影响胰岛素敏感性也不清楚。本项目将利用GCN5L1肝脏特异性敲除小鼠这一优化的线粒体蛋白乙酰化调节模型，结合高脂饮食诱导的小鼠胰岛素抵抗模型，研究线粒体蛋白乙酰化和内质网钙离子平衡的关系在糖脂代谢和胰岛素抵抗中的功能，从而揭示线粒体蛋白乙酰化在细胞能量代谢平衡中的作用并阐明这种细胞器间的协作机制。以期通过本项目的研究发现糖脂代谢调控与细胞能量感应的新规律，为糖尿病的预防和临床治疗提供全新的策略。

Mitochondria are not only the energy factories of cell, but also participate in important cell signal transduction. Mitochondrial protein acetylation senses energy status of cells and regulates metabolic enzyme activities, which manipulate metabolism of glucose, lipid and amino acids in feedback way. The development of insulin resistance and type 2 diabetes are tightly determined by mitochondrial function. Though mitochondrial protein acetylation is a nutrient sensor, it is still not clear that whether the acetylation cooperatively regulates cellular process (e.g. metabolism) through affecting signal transduction between mitochondria and ER during the development of obesity and insulin resistance. It is well known that liver is critical to maintain energy homeostasis, but whether its mitochondrial function affects insulin sensitivity is not well understood. In this proposed research, we will develop a new mouse model for mitochondrial protein acetylation by specifically knocking out GCN5L1 in mouse liver, and then use this mouse model to investigate the relationship between mitochondria protein acetylation and ER calcium balance in glucose and lipid metabolism and insulin resistance, thus unveil the regulatory function of mitochondrial protein acetylation in maintaining energy homeostasis and the underlying mechanism of cooperative signaling transduction between mitochondria and ER. This study will figure out new machinery of energy sensing in regulation of glucose and lipid metabolism and provide potential novel strategy for diabetes prevention and clinical treatment.