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.
Authors
- Yuzheng Zhao (ORCID: https://orcid.org/0000-0001-5400-0135)
- Daisy Dai (ORCID: https://orcid.org/0000-0003-2950-036X)
- Yi Yang (ORCID: https://orcid.org/0000-0001-7896-1184)
- Zhenye Yang (ORCID: https://orcid.org/0000-0001-7797-5891)
- Ke Ruan (ORCID: https://orcid.org/0000-0001-9358-0451)
- Mengting Liu
- Jue Shi (ORCID: https://orcid.org/0000-0003-4061-3496)
- Kaiguang Zhang (ORCID: https://orcid.org/0000-0001-9462-6335)
- Ping Gao (ORCID: https://orcid.org/0000-0002-6930-7989)
- Zhonghuai Hou (ORCID: https://orcid.org/0000-0003-1241-7041)
- Weiyi You
- Fumei Zhong
- Aoxing Cheng (ORCID: https://orcid.org/0000-0001-9143-2199)
- Ting Wang (ORCID: https://orcid.org/0000-0003-4334-6522)
- Ying Wu (ORCID: https://orcid.org/0000-0002-0510-7208)
- Jiaxin Wu
- Jing Guo (ORCID: https://orcid.org/0000-0002-0470-5417)
- Yingying Du (ORCID: https://orcid.org/0000-0002-6318-9256)
Institutions
- University of Science and Technology of China (CN)
- Hong Kong Baptist University (HK)
- East China University of Science and Technology (CN)
- Anhui Medical University (CN)
- Hefei National Center for Physical Sciences at Nanoscale (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-09-12
- DOI
- https://doi.org/10.1038/s44319-025-00573-8
- Citations
- 2
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- National Science Foundation
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Innovation and Technology Commission
- University of Science and Technology of China
- Fundamental Research Funds for the Central Universities