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NAC regulates metabolism and cell fate in intestinal stem cells

Ramalho, S.
; 
Alkan, F.
; 
Prekovic, S.
; 
Jastrzebski, K.
; 
BarberĆ , E. P.
; 
Hoekman, L.
; 
Altelaar, M.
; 
de Heus, C.
; 
Liv, N.
; 
RodrĆ­guez-Colman, M. J.
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Abstract
Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACĪ± is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
Authors
Ramalho, S.
Alkan, F.
Prekovic, S.
Jastrzebski, K.
BarberĆ , E. P.
Hoekman, L.
Altelaar, M.
de Heus, C.
Liv, N.
RodrĆ­guez-Colman, M. J.
Yilmaz, M.
van der Kammen, R.
Fedry, J.
de Gooijer, M. C.
Suijkerbuijk, S. J. E.
Faller, W. J.
Silva, J.
Affiliation
Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, Netherlands. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands. Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands. Oncode Institute, Utrecht, Netherlands. MRC Laboratory of Molecular Biology, Cambridge, UK. Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. The Christie NHS Foundation Trust, Manchester, UK. Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, Netherlands.
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2025
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All Christie Publications
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Ramalho S, Alkan F, Prekovic S, Jastrzebski K, BarberĆ  EP, Hoekman L, et al. NAC regulates metabolism and cell fate in intestinal stem cells. Science advances. 2025 Jan 10;11(2):eadn9750. PubMed PMID: 39772672. Pubmed Central PMCID: PMC11708876. Epub 2025/01/08. eng.
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https://christie.openrepository.com/handle/10541/627918
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