Hypoxia Induces Mitochondrial Protein Lactylation to Limit Oxidative Phosphorylation

Overview

Journal Cell Res

Specialty Cell Biology

Date 2024 Jan 1

PMID 38163844

Authors

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

Affiliations

Soon will be listed here.

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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