The incidence of type 2 diabetes is increasing globally and has become a major public health problem endangering human health. Insulin resistance is the foundation and core link of type 2 diabetes. Although the mechanism of epigenetic modification of nuclear DNA involved in insulin resistance has been extensively studied, the mechanism of mitochondrial DNA epigenetic modification is rarely reported.

Recently, teams led by Liu Jiankang and Feng Zhihui, professors of a mitochondrial biomedical research institute at the School of Life Science and Technology (SLST), Xi'an Jiaotong University (XJTU), together with a team led by professor Zang Weijin from XJTU Health Science Center and a team led by professor Gao Feng from Air Force Medical University, made important progress in research of mitochondrial epigenetics involved in insulin resistance. 

The study found that the increase of intracellular free fatty acids can promote mitochondrial translocation of DNA’s DNMT1 by activating AMP-activated protein kinase (AMPK), and induce hypermethylation of the key gene MT-ND6 of respiratory chain complex I encoded by mitochondrial DNA. This can result in transcription inhibition of MT-ND6 and impaired mitochondrial oxidative phosphorylation, which eventually leads to insulin resistance. 

From a new perspective of mitochondrial epigenetics, the study reveals the molecular mechanism of imbalanced mitochondrial homeostasis in insulin resistance, and provides a new intervention target and prevention strategy for the prevention and treatment of type 2 diabetes. The judges said, “This finding is a milestone in the field of mitochondrial gene regulation and metabolic diseases.”

The results, entitled “Hypermethylation of hepatic mitochondrial ND6 provokes systemic insulin resistance”, were published by Advanced Science. Associate professor Cao Ke, doctoral students Lyu Weiqiang and Wang Xueqiang from the SLST are the co-first authors of the paper. 

Professor Liu and Feng are the corresponding authors. Joint authors are professors Long Jiangang and Yang Tielin, associate professor Dong Shanshan and assistant researcher Xu Jie from SLST, doctors Ma Qingqing and Lin Mu from Guizhou Aerospace Hospital, assistant researcher Zou Xuan from the Second Affiliated Hospital of XJTU (Xibei Hospital), Professor Zang from XJTU Health Science Center and professor Gao Feng from Air Force Medical University.

The Mitochondrial Biomedical Research Institute at the SLST is the first author and communication unit of the paper. 

Paper link: https://onlinelibrary.wiley.com/doi/10.1002/advs.202004507