Yunzi Mao, Jiaojiao Zhang, Qian Zhou, Xiadi He, Zhifang Zheng, Yun Wei, Kaiqiang Zhou, Yan Lin, Haowen Yu, Haihui Zhang, Yineng Zhou, Pengcheng Lin, Baixing Wu, Yiyuan Yuan, Jianyuan Zhao, Wei Xu, Shimin Zhao
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...
January 2024: Cell Research