cdk1介导的LDHA磷酸化通过ldhb依赖性乳酸氧化促进有丝分裂。

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-09-12 DOI:10.1038/s44319-025-00573-8

Mengting Liu, Aoxing Cheng, Weiyi You, Jiaxin Wu, Chenxu Dai, Ting Wang, Ying Wu, Fumei Zhong, Jue Shi, Yingying Du, Zhonghuai Hou, Ping Gao, Ke Ruan, Yi Yang, Yuzheng Zhao, Kaiguang Zhang, Zhenye Yang, Jing Guo

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引用次数: 0

摘要

虽然癌细胞过度表达乳酸脱氢酶A （LDHA）以支持糖酵解通量和乳酸生成，但ldhb优先催化乳酸氧化的作用尚不清楚。在这里，我们证明了LDHB，而不是LDHA，在癌症的有丝分裂过程中是必不可少的。在有丝分裂过程中，CDK1磷酸化LDHA的苏氨酸18，减少其与乳酸脱氢酶（LDH）四聚体的结合。这导致富含ldhb的四聚体将催化活性转向乳酸氧化，将乳酸和NAD⁺转化为丙酮酸和NADH。产生的NADH为氧化磷酸化和ATP的产生提供燃料，从而维持有丝分裂。值得注意的是，LDHA-T18磷酸化仅发生在肿瘤组织中。我们的研究结果揭示了一种肿瘤特异性机制，其中CDK1重编程LDH同工酶的组成，以指导乳酸生成NADH，确保有丝分裂期间的能量稳态。这强调了靶向LDHA和LDHB治疗癌症的必要性。

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CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.

While cancer cells overexpress lactate dehydrogenase A (LDHA) to support glycolytic flux and lactate production, the role of LDHB-which preferentially catalyzes lactate oxidation-remains unclear. Here, we demonstrate that LDHB, but not LDHA, is essential for mitotic progression in cancers. During mitosis, CDK1 phosphorylates LDHA at threonine 18, reducing its incorporation into the lactate dehydrogenase (LDH) tetramer. This results in LDHB-enriched tetramers that shift catalytic activity toward lactate oxidation, converting lactate and NAD⁺ into pyruvate and NADH. The generated NADH fuels oxidative phosphorylation and ATP production, thereby sustaining mitosis. Notably, LDHA-T18 phosphorylation occurs exclusively in tumor tissues. Our findings reveal a tumor-specific mechanism in which CDK1 reprograms LDH isoenzyme composition to direct lactate toward NADH production, ensuring energy homeostasis during mitosis. This underscores the therapeutic necessity of targeting both LDHA and LDHB in cancer.

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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