Gene Symbol: Sirt4
Description: sirtuin 4
Alias: 4930596O17Rik, NAD-dependent protein lipoamidase sirtuin-4, mitochondrial
Species: mouse
Products:     Sirt4

Top Publications

  1. Haigis M, Mostoslavsky R, Haigis K, Fahie K, Christodoulou D, Murphy A, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126:941-54 pubmed
    ..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...
  2. Laurent G, German N, Saha A, de Boer V, Davies M, Koves T, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 2013;50:686-98 pubmed publisher
    ..In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis...
  3. Csibi A, Fendt S, Li C, Poulogiannis G, Choo A, Chapski D, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013;153:840-54 pubmed publisher
    ..This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH...
  4. Jeong S, Xiao C, Finley L, Lahusen T, Souza A, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 2013;23:450-63 pubmed publisher
    ..This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid ..
  5. Nasrin N, Wu X, Fortier E, Feng Y, Bare O, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem. 2010;285:31995-2002 pubmed publisher
    b>SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of metabolism in other tissues is unknown...
  6. Kawamura Y, Uchijima Y, Horike N, Tonami K, Nishiyama K, Amano T, et al. Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J Clin Invest. 2010;120:2817-28 pubmed publisher
    ..These results indicate that Sirt3 plays a protective role in preimplantation embryos against stress conditions during in vitro fertilization and culture...
  7. Lombard D, Alt F, Cheng H, Bunkenborg J, Streeper R, Mostoslavsky R, et al. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol. 2007;27:8807-14 pubmed
    ..contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5...
  8. Shih J, Liu L, Mason A, Higashimori H, Donmez G. Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid. J Neurochem. 2014;131:573-81 pubmed publisher
    ..Loss of SIRT4 leads to a more severe reaction to kainic acid and decreased glutamate transporter expression and function in the ..
  9. Jeong S, Lee A, Lee J, Haigis M. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem. 2014;289:4135-44 pubmed publisher
    ..Recently, the mitochondrial sirtuin SIRT4 has been reported to function as a tumor suppressor by regulating glutamine metabolism, suggesting that it might ..

More Information


  1. Mahlknecht U, Voelter Mahlknecht S. Fluorescence in situ hybridization and chromosomal organization of the sirtuin 4 gene (Sirt4) in the mouse. Biochem Biophys Res Commun. 2009;382:685-90 pubmed publisher
    ..b>SIRT4 is a mitochondrial protein that lacks deacetylase activities but efficiently works as an ADP-ribosyltransferase...
  2. Xiao Y, Zhang X, Fan S, Cui G, Shen Z. MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4. PLoS ONE. 2016;11:e0168078 pubmed publisher
    ..In addition, luciferase reporter assays demonstrated that Sirt4 was a direct target gene of miR-497...
  3. Martin J, Balmer M, Rajendran S, Maurhofer O, Dufour J, St Pierre M. Nutritional stress exacerbates hepatic steatosis induced by deletion of the histidine nucleotide-binding (Hint2) mitochondrial protein. Am J Physiol Gastrointest Liver Physiol. 2016;310:G497-509 pubmed publisher
    ..The absence of Hint2 deregulates the posttranslational modification of several mitochondrial proteins, which impedes the adaptation to episodes of nutritional stress. ..
  4. Argmann C, Auwerx J. Insulin secretion: SIRT4 gets in on the act. Cell. 2006;126:837-9 pubmed
    ..In this issue of Cell, Haigis et al. (2006) demonstrate that the mammalian Sir2 homolog SIRT4 acts in the mitochondria of pancreatic beta cells to repress the activity of glutamate dehydrogenase through ADP-..
  5. Mathias R, Greco T, Oberstein A, Budayeva H, Chakrabarti R, Rowland E, et al. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell. 2014;159:1615-25 pubmed publisher
    ..Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive...
  6. Laurent G, de Boer V, Finley L, Sweeney M, Lu H, Schug T, et al. SIRT4 represses peroxisome proliferator-activated receptor ? activity to suppress hepatic fat oxidation. Mol Cell Biol. 2013;33:4552-61 pubmed publisher
    ..We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability...
  7. Drew J, Farquharson A, Horgan G, Williams L. Tissue-specific regulation of sirtuin and nicotinamide adenine dinucleotide biosynthetic pathways identified in C57Bl/6 mice in response to high-fat feeding. J Nutr Biochem. 2016;37:20-29 pubmed publisher
    ..Regulation of the SIRT/NAD system was associated with early (SIRT4, SIRT7, NAPRT1 and NMNAT2) and late phases (NMNAT3, NMRK2, ABCA1 and CD38) of glucose intolerance...
  8. Du J, Jiang H, Lin H. Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD. Biochemistry. 2009;48:2878-90 pubmed publisher the ADP-ribosyltransferase activity of several different sirtuins, including yeast Sir2, human SirT1, mouse SirT4, and mouse SirT6...
  9. Ho L, Titus A, Banerjee K, George S, Lin W, Deota S, et al. SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging (Albany NY). 2013;5:835-49 pubmed
    ..Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis...
  10. Nakamura Y, Ogura M, Tanaka D, Inagaki N. Localization of mouse mitochondrial SIRT proteins: shift of SIRT3 to nucleus by co-expression with SIRT5. Biochem Biophys Res Commun. 2008;366:174-9 pubmed
    ..information regulator 2 (SIR2) is involved in extension of yeast longevity by calorie restriction, and SIRT3, SIRT4, and SIRT5 are mammalian homologs of SIR2 localized in mitochondria...
  11. Witt O, Deubzer H, Milde T, Oehme I. HDAC family: What are the cancer relevant targets?. Cancer Lett. 2009;277:8-21 pubmed publisher
    ..The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease. ..
  12. Nakagawa T, Lomb D, Haigis M, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009;137:560-70 pubmed publisher
    ..Similar effects occur during long-term calorie restriction or a high protein diet. These findings demonstrate SIRT5 plays a pivotal role in ammonia detoxification and disposal by activating CPS1. ..
  13. Anderson K, Huynh F, Fisher Wellman K, Stuart J, Peterson B, Douros J, et al. SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017;25:838-855.e15 pubmed publisher
    ..In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic...