复旦大学Shimin Zhao和Wei Xu共同合作，近期取得重要工作进展。他们研究提出了，缺氧能够诱导线粒体蛋白乳酸化以限制氧化磷酸化。相关研究成果2024年1月2日在线发表于《细胞研究》杂志上。

据介绍，氧化磷酸化（OXPHOS）消耗氧气来产生ATP。然而，平衡OXPHOS活性和细胞内氧气供应的机制仍然还不清楚。

研究人员报道了线粒体蛋白乳酸化是由细胞内缺氧诱导的，以抑制OXPHOS。研究人员发现，线粒体丙氨酰tRNA合成酶（AARS2）是一种蛋白质赖氨酸乳酰转移酶，其蛋白酶体降解通过氧感应羟化酶PHD2催化的脯氨酸377羟基化而增强。缺氧诱导AARS2积累为丙酮酸脱氢酶复合物中的乳酸PDHA1赖氨酸336和肉碱棕榈酰转移酶2（CPT2）赖氨酸457/8，分别通过限制丙酮酸和脂肪酸氧化的乙酰辅酶A流入来灭活这两种酶并抑制OXPHOS。

PDHA1和CPT2的乳酰化可以被SIRT3逆转以激活OXPHOS。在小鼠肌肉细胞中，运动时乳酸氧化诱导的细胞内缺氧诱导乳酸化，以限制高强度耐力跑疲劳时间，可通过降低或增加乳酸化水平分别增加或减少乳酸化时间。

总之，这一研究结果表明，线粒体蛋白乳酸化整合了细胞内缺氧和乳酸信号来调节OXPHOS。

附：英文原文

Title: Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation

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

Issue&Volume: 2024-01-02

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.

DOI: 10.1038/s41422-023-00864-6

Source: https://www.nature.com/articles/s41422-023-00864-6