SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells

Marcia C. Haigis, Raul Mostoslavsky, Kevin M. Haigis, Kamau Fahie, Danos C. Christodoulou, Andrew J J. Murphy, David M. Valenzuela, George D. Yancopoulos, Margaret Karow, Gil Blander, Cynthia Wolberger, Tomas A. Prolla, Richard Weindruch, Frederick W. Alt, Leonard Guarente

Research output: Contribution to journalArticlepeer-review

Abstract

Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.

Original languageEnglish (US)
Pages (from-to)941-954
Number of pages14
JournalCell
Volume126
Issue number5
DOIs
StatePublished - Sep 8 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells'. Together they form a unique fingerprint.

Cite this