2. Academic Validation
  3. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells

Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells

  • Nat Metab. 2025 Jul;7(7):1344-1357. doi: 10.1038/s42255-025-01325-7.
Simon Andersson 1 2,  Hien Bui 1 2,  Arto Viitanen # 1 2,  Daniel Borshagovski # 3,  Ella Salminen 1 2,  Sami Kilpinen 1,  Angelika Gebhart 1 2,  Emilia Kuuluvainen 1 2,  Swetha Gopalakrishnan 1 2,  Nina Peltokangas 1 2,  Martyn James 2,  Kaia Achim 1,  Eija Jokitalo 2,  Petri Auvinen 2,  Ville Hietakangas 1 2,  Pekka Katajisto 4 5 6
Affiliations

Affiliations

  • 1 Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
  • 2 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 3 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
  • 4 Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. pekka.katajisto@helsinki.fi.
  • 5 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland. pekka.katajisto@helsinki.fi.
  • 6 Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. pekka.katajisto@helsinki.fi.
  • # Contributed equally.
PMID: 40659911 DOI: 10.1038/s42255-025-01325-7
Abstract

Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.

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