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Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.
Mao, Yunzi; Zhang, Jiaojiao; Zhou, Qian; He, Xiadi; Zheng, Zhifang; Wei, Yun; Zhou, Kaiqiang; Lin, Yan; Yu, Haowen; Zhang, Haihui; Zhou, Yineng; Lin, Pengcheng; Wu, Baixing; Yuan, Yiyuan; Zhao, Jianyuan; Xu, Wei; Zhao, Shimin.
Affiliation
  • Mao Y; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Zhang J; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Zhou Q; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • He X; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Zheng Z; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Wei Y; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Zhou K; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Lin Y; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Yu H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Zhang H; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Zhou Y; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Lin P; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Wu B; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China.
  • Yuan Y; Shanghai Fifth People's Hospital of Fudan University, Fudan University, Shanghai, China.
  • Zhao J; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Xu W; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
  • Zhao S; The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetic Engineering, School of Life Sciences, Children's Hospital of Fudan University, and Institutes of Biomedical Sciences, Fudan University, Shanghai,
Cell Res ; 34(1): 13-30, 2024 01.
Article in En | MEDLINE | ID: mdl-38163844
ABSTRACT
Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
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Full text: 1 Database: MEDLINE Main subject: Oxidative Phosphorylation / Mitochondrial Proteins Limits: Animals Language: En Journal: Cell Res Year: 2024 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Oxidative Phosphorylation / Mitochondrial Proteins Limits: Animals Language: En Journal: Cell Res Year: 2024 Type: Article