| Accession |
PRJCA027447 |
| Title |
Hypoxia Induces Mitochondria Protein Lactylation to Limit Oxidative Phosphorylation |
| Relevance |
Model organism |
| Data types |
Phenotype or Genotype
Proteomics sequencing
|
| Organisms |
Mus musculus
Homo sapiens
|
| Description |
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 mitochondria 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 oxygen-sensing PHD2-catalyzed proline 377 hydroxylation. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 of the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 lysine 457/8, inactivates both enzymes and inhibits 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 manipulations that decrease or increase lactylation levels, accordingly. We reveal that protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS. |
| Sample scope |
Synthetic |
| Release date |
2024-06-27 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
|
|
Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation
|
Cell Research
|
Doi.org/10.1038/s41422-023-00864-6
|
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
|
2018YFA0800300
|
|
| Ministry of Science and Technology of the People's Republic of China (MOST)
|
|
2018YFA0801300
|
|
| National Natural Science Foundation of China (NSFC)
|
|
31821002
|
|
| National Natural Science Foundation of China (NSFC)
|
|
92253305
|
|
|
|
| Submitter |
Yunzi
Mao (maoyz@fudan.edu.cn)
|
| Organization |
Obstetrics and Gynecology Hospital of Fudan University |
| Submission date |
2024-06-27 |
