α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells

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作   者：

Yin, Mengran;  Li, Yan;  Sun, Zhenzhu;  Wu, Xinyu;  Ding, Liang;  Zhang, Qiang;  Zhou, Hai;  Zhang, Man;  Qin, Dajiang;  Qin, Baoming;  Wang, Lulu; 

作者机构：

BGI Shenzhen;  Guangzhou Natl Lab;  Chinese Acad Sci;  Guangzhou Med Univ; 

关键词：

succinate;  TET;  DMM;  alpha-ketoglutarate;  totipotency;  α‐ketoglutarate; 

期刊名称：

The FEBS journal

i s s n：

1742-464X

年卷期：

2025 年 292 卷 9 期

页   码：

2398-2409

页   码：

摘   要：

In early mouse embryogenesis, the distinct enrichment of alpha-ketoglutarate (alpha KG) in blastocysts and L-2-hydroxyglutarate (L-2HG) in 2-cell (2C) embryos serves as a key metabolic signature. While elevated L-2HG levels inhibit the resolution of totipotency during the transition from the 2C stage to the blastocyst, the role of alpha KG remains elusive. Mouse embryonic stem cells (mESCs) cultured in vitro naturally harbor a subpopulation that transitions dynamically into a 2C-like totipotent state, providing a convenient model to investigate the role of alpha KG in totipotency reprogramming. This study demonstrates that alpha KG significantly inhibits the pluripotency to totipotency transition through upregulating ten-eleven translocation (TET) DNA hydroxylases. We further show that reducing endogenous alpha KG levels via glutamine withdrawal or inhibiting alpha KG-dependent dioxygenases by blocking succinate dehydrogenase (SDH) markedly enhances the induction of 2C-like cells (2CLCs). Finally, leveraging the potent SDH inhibitor dimethyl malonate (DMM), we have developed a highly efficient protocol for 2CLC induction, producing cells that transcriptionally resemble mid-to-late 2C embryos. Our findings deepen the understanding of the metabolic regulation of totipotency and provide a previously undescribed approach for capturing totipotent-like stem cells in vitro.