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

Abstract Cellular metabolism is a key regulator of cell fate 1 , raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues 2,3 . In the small intestine, intestinal stem cells (ISCs) 4 produce metabolically distinct progeny 5 , including their Paneth cell (PC) niche 6 . Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISC mito-O ), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISC mito-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.