The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation
Open accessAbstract
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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The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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Metabolic regulation of gene expression by histone lactylation
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Regulation of angiogenesis by hypoxia: role of the HIF system
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Limiting factors for maximum oxygen uptake and determinants of endurance performance
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Regulation of cellular metabolism by protein lysine acetylation
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Self-citationHypoxia, HIF1 and glucose metabolism in the solid tumour
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The Science and Translation of Lactate Shuttle Theory
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Cited by
Wang, N., Zhu, S., Chen, S., Zou, J., Zeng, P., & Tan, S. (2025) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0147 · Cited by 12
Metadata
- Authors
- Mao, Y., Zhang, J., Zhou, Q., He, X., Zheng, Z., Wei, Y., Zhou, K., Lin, Y., Yu, H., Zhang, H., Zhou, Y., Lin, P., Wu, B., Yuan, Y., Zhao, J., Xu, W., & Zhao, S.
- Venue
- Cell Research
- Published
- 2024-01-02
- Volume
- 34
- Issue
- 1
- Pages
- 13-30
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- OpenAlex
- W4390487565
- Cited by
- 359
- References
- 56
- FWCI
- 55.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Mao, Y., Zhang, J., Zhou, Q., He, X., Zheng, Z., Wei, Y., Zhou, K., Lin, Y., Yu, H., Zhang, H., Zhou, Y., Lin, P., Wu, B., Yuan, Y., Zhao, J., Xu, W., & Zhao, S. (2024). Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation. Cell Research. https://doi.org/10.1038/s41422-023-00864-6
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