Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity
Tingting Fu,
Zhisheng Xu,
Lin Liu,
Qiqi Guo,
Hao Wu,
Xijun Liang,
Danxia Zhou,
Liwei Xiao,
Lei Liu,
Yong Liu,
Min-Sheng Zhu,
Quan Chen,
Zhenji Gan
Affiliations
Tingting Fu
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Zhisheng Xu
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Lin Liu
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Qiqi Guo
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Hao Wu
The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Xijun Liang
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Danxia Zhou
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Liwei Xiao
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Lei Liu
The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Yong Liu
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan 430072, China
Min-Sheng Zhu
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China
Quan Chen
The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Zhenji Gan
The State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing 210061, China; Corresponding author
Summary: The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, we demonstrate that FUNDC1, a mediator of mitophagy, plays a critical role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Skeletal-muscle-specific ablation of FUNDC1 in mice resulted in LC3-mediated mitophagy defect, leading to impaired mitochondrial energetics. This caused decreased muscle fat utilization and endurance capacity during exercise. Interestingly, mice lacking muscle FUNDC1 were protected against high-fat-diet-induced obesity with improved systemic insulin sensitivity and glucose tolerance despite reduced muscle mitochondrial energetics. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality control in mediating the muscle-adipose dialog to regulate systemic metabolism. : Mitochondrial quality is essential to muscle function. How muscle mitochondrial quality is regulated and its physiological impacts remain unclear. Fu et al. show that loss of FUNDC1-dependent mitochondrial quality control in muscle alleviates high-fat-diet-induced obesity and improves systemic glucose homeostasis through promoting exercise-independent fat burning in adipose tissue. Keywords: muscle, mitochondrial quality control, mitophagy, adaptive thermogenesis, metabolic homeostasis
