Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation

被引:68
作者
Mao, Yunzi [1 ,2 ]
Zhang, Jiaojiao [1 ,2 ]
Zhou, Qian [1 ,2 ]
He, Xiadi [1 ,2 ,3 ,4 ]
Zheng, Zhifang [1 ,2 ]
Wei, Yun [1 ,2 ,3 ,4 ]
Zhou, Kaiqiang [1 ,2 ]
Lin, Yan [1 ,2 ,5 ,6 ]
Yu, Haowen [1 ,2 ]
Zhang, Haihui [1 ,2 ]
Zhou, Yineng [1 ,2 ]
Lin, Pengcheng [7 ]
Wu, Baixing [8 ]
Yuan, Yiyuan [1 ,2 ,5 ]
Zhao, Jianyuan [1 ,2 ,5 ]
Xu, Wei [1 ,2 ,5 ,6 ]
Zhao, Shimin [1 ,2 ,5 ,7 ]
机构
[1] Fudan Univ, Shanghai Key Lab Metab Remodeling & Hlth, Sch Life Sci,Childrens Hosp, State Key Lab Genet Engn,Obstet & Gynecol Hosp, Shanghai, Peoples R China
[2] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China
[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA
[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA
[5] Shanghai Inst Planned Parenthood Res, NHC Key Lab Reprod Regulat, Shanghai, Peoples R China
[6] Fudan Univ, Shanghai Peoples Hosp 5, Shanghai, Peoples R China
[7] Qinghai Nationalities Univ, Coll Pharm, Key Lab Tibet Plateau Phytochem Qinghai Prov, Xining, Qinghai, Peoples R China
[8] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangdong Hong Kong Joint Lab RNA Med,RNA Biomed I, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
TRANSFER-RNA SYNTHETASES; HUMAN SKELETAL-MUSCLE; PYRUVATE-DEHYDROGENASE; HIF-ALPHA; METABOLISM; EXPRESSION; ENDURANCE; SIRT3; DIET; PERFORMANCE;
D O I
10.1038/s41422-023-00864-6
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:13 / 30
页数:18
相关论文
共 57 条
  • [1] The Lactate Receptor HCAR1 Modulates Neuronal Network Activity through the Activation of Gα and Gβγ Subunits
    Abrantes, Haissa de Castro
    Briquet, Marc
    Schmuziger, Celine
    Restivo, GLeonardo
    Puyal, Julien
    Rosenberg, Nadia
    Rocker, Anne-Berengere
    Offermanns, Stefan
    Chatton, Jean-Yves
    [J]. JOURNAL OF NEUROSCIENCE, 2019, 39 (23) : 4422 - 4433
  • [2] Limiting factors for maximum oxygen uptake and determinants of endurance performance
    Bassett, DR
    Howley, ET
    [J]. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, 2000, 32 (01) : 70 - 84
  • [3] Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2
    Baumann, Fusun
    Leukel, Petra
    Doerfelt, Anett
    Beier, Christoph P.
    Dettmer, Katja
    Oefner, Peter J.
    Kastenberger, Michael
    Kreutz, Marina
    Nickl-Jockschat, Thomas
    Bogdahn, Ulrich
    Bosserhoff, Anja-Katrin
    Hau, Peter
    [J]. NEURO-ONCOLOGY, 2009, 11 (04) : 368 - 380
  • [4] Comparative NMR and NIRS analysis of oxygen-dependent metabolism in exercising finger flexor muscles
    Bendahan, David
    Chatel, Benjamin
    Jue, Thomas
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2017, 313 (06) : R740 - R753
  • [5] Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction
    Bergersen, Linda Hildegard
    [J]. JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2015, 35 (02) : 176 - 185
  • [6] Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex
    Bowker-Kinley, MM
    Davis, WI
    Wu, PF
    Harris, RA
    Popov, KM
    [J]. BIOCHEMICAL JOURNAL, 1998, 329 : 191 - 196
  • [7] A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans
    Bricker, Daniel K.
    Taylor, Eric B.
    Schell, John C.
    Orsak, Thomas
    Boutron, Audrey
    Chen, Yu-Chan
    Cox, James E.
    Cardon, Caleb M.
    Van Vranken, Jonathan G.
    Dephoure, Noah
    Redin, Claire
    Boudina, Sihem
    Gygi, Steven P.
    Brivet, Michele
    Thummel, Carl S.
    Rutter, Jared
    [J]. SCIENCE, 2012, 337 (6090) : 96 - 100
  • [8] The Science and Translation of Lactate Shuttle Theory
    Brooks, George A.
    [J]. CELL METABOLISM, 2018, 27 (04) : 757 - 785
  • [9] Orai1 enhances muscle endurance by promoting fatigue-resistant type I fiber content but not through acute store-operated Ca2+ entry
    Carrell, Ellie M.
    Coppola, Aundrea R.
    McBride, Helen J.
    Dirksen, Robert T.
    [J]. FASEB JOURNAL, 2016, 30 (12) : 4109 - 4119
  • [10] Chen YJ, 2016, NAT CHEM BIOL, V12, P937, DOI [10.1038/NCHEMBIO.2172, 10.1038/nchembio.2172]