| 项目编号 |
PRJCA027447 |
| 项目标题 |
Hypoxia Induces Mitochondria Protein Lactylation to Limit Oxidative Phosphorylation |
| 涉及领域 |
Model organism |
| 数据类型 |
Phenotype or Genotype
Proteomics sequencing
|
| 物种名称 |
Mus musculus
Homo sapiens
|
| 描述信息 |
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. |
| 样品范围 |
Synthetic |
| 发布日期 |
2024-06-27 |
| 出版信息 |
|
| 项目资金来源 |
| 机构 |
项目类型 |
授权项目ID |
授权项目名称 |
| 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
|
|
|
|
| 提交者 |
Yunzi
Mao (maoyz@fudan.edu.cn)
|
| 提交单位 |
Obstetrics and Gynecology Hospital of Fudan University |
| 提交日期 |
2024-06-27 |
