SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724003036 |
| _version_ | 1797253958553567232 |
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| author | Sarah A. Tucker Song-Hua Hu Sejal Vyas Albert Park Shakchhi Joshi Aslihan Inal Tiffany Lam Emily Tan Kevin M. Haigis Marcia C. Haigis |
| author_facet | Sarah A. Tucker Song-Hua Hu Sejal Vyas Albert Park Shakchhi Joshi Aslihan Inal Tiffany Lam Emily Tan Kevin M. Haigis Marcia C. Haigis |
| author_sort | Sarah A. Tucker |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-24T21:42:20Z |
| format | Article |
| id | doaj.art-26040fd746924c7981ec50c9a0b98a5a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-24T21:42:20Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-26040fd746924c7981ec50c9a0b98a5a2024-03-21T05:36:35ZengElsevierCell Reports2211-12472024-04-01434113975SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasisSarah A. Tucker0Song-Hua Hu1Sejal Vyas2Albert Park3Shakchhi Joshi4Aslihan Inal5Tiffany Lam6Emily Tan7Kevin M. Haigis8Marcia C. Haigis9Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment 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, USADepartment of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724003036CP: Cancer |
| spellingShingle | Sarah A. Tucker Song-Hua Hu Sejal Vyas Albert Park Shakchhi Joshi Aslihan Inal Tiffany Lam Emily Tan Kevin M. Haigis Marcia C. Haigis SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis Cell Reports CP: Cancer |
| title | SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| title_full | SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| title_fullStr | SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| title_full_unstemmed | SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| title_short | SIRT4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| title_sort | sirt4 loss reprograms intestinal nucleotide metabolism to support proliferation following perturbation of homeostasis |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724003036 |
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