Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity
Juan Xu,
Qiqi Zhang,
Xinyu Yang,
Qiqi Tang,
Yitong Han,
Jiahui Meng,
Jiaqi Zhang,
Xin Lu,
Danni Wang,
Jing Liu,
Bo Shan,
Xue Bai,
Kai Zhang,
Longhao Sun,
Lingdi Wang,
Lu Zhu
Affiliations
Juan Xu
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Qiqi Zhang
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Xinyu Yang
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Qiqi Tang
Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Yitong Han
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Jiahui Meng
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Jiaqi Zhang
Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Xin Lu
Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Danni Wang
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Jing Liu
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
Bo Shan
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Xue Bai
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Kai Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
Longhao Sun
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Corresponding author
Lingdi Wang
Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Corresponding author
Lu Zhu
Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China; Corresponding author
Summary: The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.
