SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis
Sarah A. Tucker,
Song-Hua Hu,
Sejal Vyas,
Albert Park,
Shakchhi Joshi,
Aslihan Inal,
Tiffany Lam,
Emily Tan,
Kevin M. Haigis,
Marcia C. Haigis
Affiliations
Sarah A. Tucker
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Song-Hua Hu
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Sejal Vyas
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Albert Park
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Shakchhi Joshi
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Aslihan Inal
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Tiffany Lam
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Emily Tan
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Kevin M. Haigis
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Marcia C. Haigis
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
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.
