Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation

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…

• NN
  National Natural Science Foundation of China

  Awards: 92157001, 92253305, 2018YFA0801300, 32171298, 31930062, 31821002, 81971449, 82171672, 32230054, 91857000
• PO
  Program of Shanghai Academic Research Leader

  Award: 21XD1423000