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 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.