Biomaterial Database

Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy. 2024

Hua Qu, and Xiufei Liu, and Jiaran Zhu, and Niexia He, and Qingshan He, and Linlin Zhang, and Yuren Wang, and Xiaoli Gong, and Xin Xiong, and Jinbo Liu, and Chuan Wang, and Gangyi Yang, and Qingwu Yang, and Gang Luo, and Zhiming Zhu, and Yi Zheng, and Hongting Zheng

Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, China.

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.