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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月12日

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  • 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

摘要

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.