Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation

氧化磷酸化 生物 生物化学 线粒体 细胞内 β氧化 肉碱 丙酮酸脱氢酶复合物 化学 细胞生物学 新陈代谢
作者
Yun-Zi Mao,Jiaojiao Zhang,Qian Zhou,Xinlei He,Zhifang Zheng,Ying Wei,Kaiqiang Zhou,Yan Lin,Hai Yu,Haihui Zhang,Yifei Zhou,Peng-Cheng Lin,Baixing Wu,Yiyuan Yuan,Jianyuan Zhao,Wei Xu,Shimin Zhao
出处
期刊:Cell Research [Springer Nature]
卷期号:34 (1): 13-30 被引量:6
标识
DOI:10.1038/s41422-023-00864-6
摘要

Abstract 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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