PKM1 is required for embryonic cardiomyocyte proliferation through energetic regulation of NFYa stability
Pyruvate kinase M1 (PKM1) is a critical enzyme in glycolysis, particularly in high-energy-demand tissues like the heart. However, previous knockout strategies for PKM1 were confounded by compensatory upregulation of its low-activity splice variant, PKM2. Here, we generated a <i>Pkm1</i> mutant mouse model using a point mutation that eliminates PKM1 without compensatory PKM2 upregulation. Homozygous <i>Pkm1</i> mutants exhibited perinatal lethality associated with cardiac dysfunction, characterized by thin myocardium and reduced cardiomyocyte proliferation during mid-to-late gestation. We found that PKM1 sustains ATP levels to inhibit AMPK, which otherwise promotes NFYa phosphorylation and destabilization. NFYa, a transcription factor essential for cardiomyocyte proliferation, has been identified as a key mediator linking metabolic status to cell cycle. These findings identify the PKM1-AMPK-NFYa axis in energetic regulation of cardiomyocyte proliferation in the embryonic heart, offering new insights into the function of PKM1 and the broader impact of energy metabolism on cardiac development, while also shedding light on the potential metabolic underpinnings of congenital heart diseases.
Authors
- Lan Kang (ORCID: https://orcid.org/0000-0003-4525-5923)
- Rongrong Huang (ORCID: https://orcid.org/0000-0003-4045-5299)
- Guangzheng Shi (ORCID: https://orcid.org/0000-0001-8722-2199)
- Nan Su (ORCID: https://orcid.org/0000-0002-0653-923X)
- Shaorong Gao (ORCID: https://orcid.org/0000-0003-1041-3928)
- Ke Wei (ORCID: https://orcid.org/0000-0001-8542-2146)
- Yanhong Zhao (ORCID: https://orcid.org/0000-0002-1216-8420)
- Shengtang Qin (ORCID: https://orcid.org/0000-0003-2128-3217)
- Dachun Xu (ORCID: https://orcid.org/0000-0002-4123-6613)
- Xiaochen Kou (ORCID: https://orcid.org/0009-0007-9137-8373)
- Dandan Zhang (ORCID: https://orcid.org/0000-0001-7649-7605)
- Wen Ye (ORCID: https://orcid.org/0000-0001-7933-1838)
- Juntao Liu (ORCID: https://orcid.org/0000-0002-6259-9157)
- Danli Yang (ORCID: https://orcid.org/0000-0003-2346-6404)
- Hong Wang
- Yansong Tang (ORCID: https://orcid.org/0000-0002-8768-8498)
Institutions
- Tongji University (CN)
- Dalian Medical University (CN)
- Shanghai East Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- Shanghai First Maternity and Infant Hospital (CN)
- Shanghai Cell Therapy Research Institute (CN)
Publication Details
- Journal
- National Science Review
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1093/nsr/nwaf408
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Fundamental Research Funds for the Central Universities