SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis.
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DOI：
10.1016/j.celrep.2024.113975
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发表时间：
2024-03
期刊：
影响因子：
8.8
通讯作者：
Sarah A Tucker;Song-Hua Hu;Sejal Vyas;Albert Park;Shakchhi Joshi;Aslihan Inal;Tiffany Lam;Emily Tan;Kevin M Haigis;Marcia C. Haigis
中科院分区：
文献类型：
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作者：
Sarah A Tucker;Song-Hua Hu;Sejal Vyas;Albert Park;Shakchhi Joshi;Aslihan Inal;Tiffany Lam;Emily Tan;Kevin M Haigis;Marcia C. Haigis
肠道是一个高度代谢的组织，但影响肠隐窝增殖、分化和再生的代谢程序仍在出现。在这里，我们研究线粒体sirtuin 4 （SIRT4）如何影响肠道内稳态。肠SIRT4丢失促进肠电离辐射（IR）后的细胞增殖。SIRT4在小鼠肠癌模型中发挥抑瘤作用，SIRT4缺失导致肠腺瘤中谷氨酰胺和核苷酸代谢失调。缺乏SIRT4的肠道类器官在IR应激后显示增殖增加，同时谷氨酰胺摄取增加，并向新核苷酸生物合成的转变而不是挽救途径。抑制新核苷酸的生物合成会降低sirt4缺陷类器官在IR胁迫后的生长优势。本研究确立了SIRT4在dna损伤应激环境下作为肠道代谢和体内平衡的调节剂。
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 towardde novonucleotide biosynthesis over salvage pathways. Inhibition ofde novonucleotide 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.