Metabolic adaptations direct cell fate during tissue regeneration

Almudena Chaves-Perez, Scott E. Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J. A. Barthet, John P. Morris, Francisco M. Barriga, Jose Reyes, Aye Kyaw, H. Amalia Pasolli, Dana Pe’er, Craig B. Thompson, Lydia W. S. Finley, Justin R. Cross and Scott W. Lowe ()
Additional contact information
Almudena Chaves-Perez: Memorial Sloan Kettering Cancer Center
Scott E. Millman: Memorial Sloan Kettering Cancer Center
Sudha Janaki-Raman: Memorial Sloan Kettering Cancer Center
Yu-Jui Ho: Memorial Sloan Kettering Cancer Center
Clemens Hinterleitner: Memorial Sloan Kettering Cancer Center
Valentin J. A. Barthet: Memorial Sloan Kettering Cancer Center
John P. Morris: Memorial Sloan Kettering Cancer Center
Francisco M. Barriga: Memorial Sloan Kettering Cancer Center
Jose Reyes: Memorial Sloan Kettering Cancer Center
Aye Kyaw: Memorial Sloan Kettering Cancer Center
H. Amalia Pasolli: The Rockefeller University
Dana Pe’er: Memorial Sloan Kettering Cancer Center
Craig B. Thompson: Memorial Sloan Kettering Cancer Center
Lydia W. S. Finley: Memorial Sloan Kettering Cancer Center
Justin R. Cross: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 643, issue 8071, 468-477

Abstract: Abstract Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1–3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4–6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

Date: 2025
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DOI: 10.1038/s41586-025-09097-6

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