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SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis

The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell pro...

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Bibliographic Details
Main Authors: Tucker, Sarah A. (Author) , Hu, Song-Hua (Author) , Vyas, Sejal (Author) , Park, Albert (Author) , Joshi, Shakchhi (Author) , Inal, Aslihan (Author) , Lam, Tiffany (Author) , Tan, Emily (Author) , Haigis, Kevin M. (Author) , Haigis, Marcia C. (Author)
Format: Article (Journal)
Language:English
Published: April 23, 2024
In: Cell reports
Year: 2024, Volume: 43, Issue: 4, Pages: 113975-1-113975-22
ISSN:2211-1247
DOI:10.1016/j.celrep.2024.113975
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2024.113975
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124724003036
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Author Notes:Sarah A. Tucker, Song-Hua Hu, Sejal Vyas, Albert Park, Shakchhi Joshi, Aslihan Inal, Tiffany Lam, Emily Tan, Kevin M. Haigis, Marcia C. Haigis
Description
Summary:The intestine is a highly metabolic tissue, but the metabolic programs that influence intestinal crypt proliferation, differentiation, and regeneration are still emerging. Here, we investigate how mitochondrial sirtuin 4 (SIRT4) affects intestinal homeostasis. Intestinal SIRT4 loss promotes cell proliferation in the intestine following ionizing radiation (IR). SIRT4 functions as a tumor suppressor in a mouse model of intestinal cancer, and SIRT4 loss drives dysregulated glutamine and nucleotide metabolism in intestinal adenomas. Intestinal organoids lacking SIRT4 display increased proliferation after IR stress, along with increased glutamine uptake and a shift toward de novo nucleotide biosynthesis over salvage pathways. Inhibition of de novo nucleotide biosynthesis diminishes the growth advantage of SIRT4-deficient organoids after IR stress. This work establishes SIRT4 as a modulator of intestinal metabolism and homeostasis in the setting of DNA-damaging stress.
Item Description:Gesehen am 14.11.2024
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2024.113975

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