Volume 34, No 1, Jan 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 1, January 2024: 13-30   |  Open Access

ORIGINAL ARTICLES

Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation

Yunzi Mao^1,† , Jiaojiao Zhang^1,† , Qian Zhou^1,† , Xiadi He^1,2,3,† , Zhifang Zheng¹ , Yun Wei^1,2,3 , Kaiqiang Zhou¹ , Yan Lin^1,4,5 , Haowen Yu¹ , Haihui Zhang¹ , Yineng Zhou¹ , Pengcheng Lin⁶ , Baixing Wu⁷ , Yiyuan Yuan^1,4 , Jianyuan Zhao^1,4 , Wei Xu^1,4,5,* , Shimin Zhao^1,4,6,*

¹The 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, China
²Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
³Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
⁴NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, China
⁵Shanghai Fifth People’s Hospital of Fudan University, Fudan University, Shanghai, China
⁶Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, Qinghai, China
⁷Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, RNA Biomedical Institute, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
^†These authors contributed equally: Yunzi Mao, Jiaojiao Zhang, Qian Zhou, Xiadi He
Correspondence: Wei Xu(xuwei_0706@fudan.edu.cn)Shimin Zhao(zhaosm@fudan.edu.cn)

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.

https://doi.org/10.1038/s41422-023-00864-6

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