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  3. AMPKα2 signals amino acid insufficiency to inhibit protein synthesis

AMPKα2 signals amino acid insufficiency to inhibit protein synthesis

  • Cell Metab. 2025 Oct 7:S1550-4131(25)00389-4. doi: 10.1016/j.cmet.2025.09.004.
Yunzi Mao 1,  Mei Cui 2,  Yanfeng Jiang 3,  Haowen Yu 1,  Meng Wang 1,  Gang Li 1,  Haihui Zhang 1,  Cheng Zhao 1,  Yanxin Shen 1,  Yupeng Hu 1,  Yanpeng An 1,  Yan Lin 1,  Yiyuan Yuan 1,  Pengcheng Lin 4,  Xingdong Chen 5,  Wei Xu 6,  Shi-Min Zhao 7
Affiliations

Affiliations

  • 1 The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai Key Laboratory of Metabolic Remodeling and Health, and State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai 200433, China.
  • 2 Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai 200040, China.
  • 3 The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai Key Laboratory of Metabolic Remodeling and Health, and State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai 200433, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China; Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Shanghai 201203, China; Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China.
  • 4 Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, Qinghai, China.
  • 5 The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai Key Laboratory of Metabolic Remodeling and Health, and State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai 200433, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China; Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Shanghai 201203, China; Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China. Electronic address: xingdongchen@fudan.edu.cn.
  • 6 Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 201100, China. Electronic address: xuwei_0706@fudan.edu.cn.
  • 7 The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai Key Laboratory of Metabolic Remodeling and Health, and State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai 200433, China; Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, Qinghai, China. Electronic address: zhaosm@fudan.edu.cn.
PMID: 41061696 DOI: 10.1016/j.cmet.2025.09.004
Abstract

The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.

Keywords

AMPK; Alzheimer’s disease; amino acids; translation.

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