SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells
Open accessAbstract
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 beta 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 beta 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.
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SIRT4 and SIRT6 also function as ADP-ribosyltransferases.
“SIRT4 and SIRT6 also function as ADP-ribosyltransferases, indicating that sirtuins contribute to cell regulation also through mechanisms beyond modulation of protein acetylation, which require further investigation17,18.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [17]
GLUD1 is inhibited by SIRT4 and by acetylation that can be reversed by SIRT3.
“GLUD1 is inhibited by SIRT4 ((Haigis et al. 2006)) and by acetylation which can be reversed by SIRT3 ((Schlicker et al. 2008)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Haigis et al. 2006
ADP-ribosylation of glutamate dehydrogenase limits TCA cycle anaplerosis and NAD[P]H generation.
“ADP-ribosylation of glutamate dehydrogenase limits TCA cycle anaplerosis and NAD[P]H generation ((Haigis et al. 2006)), and SIRT4’s delipoylation activity ((Mathias et al. 2014)) also suggests the potential for inhibitory delipoylation of the downstream oxoglutarate dehydrogenase complex, which functions similarly to pyruvate dehydrogenase (discussed above).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Haigis et al. 2006
SIRT4 inhibits GLUD1 function in pancreatic β cells.
“SIRT4 inhibits GLUD1 function in pancreatic β cells ((Haigis et al. 2006)), raising the possibility that mitochondrial sirtuins might oppose each other to fine tune the activity of urea cycle via modulating different post-translational modifications on various enzymes in this pathway.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Haigis et al. 2006
In mammals, SIRT1, SIRT6, and SIRT7 are nuclear proteins; SIRT1 is found mainly in the cytoplasm; and SIRT3, SIRT4, and SIRT5 are found in the mitochondria.
“In mammals, this family has several members of which SIRT1, SIRT6, and SIRT7 are nuclear proteins; SIRT1 is found mainly in the cytoplasm; and the SIRT3, SIRT4, and SIRT5 are found in the mitochondria (165, 295, 389).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [165]
Cites
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · see citing works
Self-citationStress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239 · see citing works
Self-citationNutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005) · Nature · doi:10.1038/nature03354 · Cited by 3,160 · see citing works
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,653 · see citing works
Self-citationKaeberlein, M., McVey, M., & Guarente, L. (1999) · Genes & Development · doi:10.1101/gad.13.19.2570 · Cited by 2,253 · cited 2× · see citing works
“An extra copy of the yeast SIR2 gene extends replicative life span of mother cells compared to wild-type, while a deletion of SIR2 reduces life span (Kaeberlein et al., 1999).”
BackgroundSelf-citationNegative Control of p53 by Sir2α Promotes Cell Survival under Stress
Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081 · see citing works
Self-citationSirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ
Picard, F., Kurtev, M. V., Chung, N., Topark‐Ngarm, A., Senawong, T., de Oliveira, R. M., Leid, M. E., McBurney, M. W., & Guarente, L. (2004) · Nature · doi:10.1038/nature02583 · Cited by 1,943 · see citing works
Self-citationSirtuin activators mimic caloric restriction and delay ageing in metazoans
Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004) · Nature · doi:10.1038/nature02789 · Cited by 1,868 · see citing works
Lin, S.-J., Defossez, P.-A., & Guarente, L. (2000) · Science · doi:10.1126/science.289.5487.2126 · Cited by 1,775 · see citing works
Self-citationGenomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637 · see citing works
Self-citationThe Human Sir2 Ortholog, SIRT2, Is an NAD+-Dependent Tubulin Deacetylase
North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M., & Verdin, E. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00038-8 · Cited by 1,542 · see citing works
Extrachromosomal rDNA circles—a cause of aging in yeast
Sinclair, D. A., & Guarente, L. (1997) · Cell · doi:10.1016/s0092-8674(00)80493-6 · Cited by 1,500 · see citing works
Self-citationThe Sir2 Family of Protein Deacetylases
Blander, G., & Guarente, L. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073651 · Cited by 1,496 · see citing works
Self-citationPhylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
Frye, R. A. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3000 · Cited by 1,409 · see citing works
Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C., & Horikawa, I. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-01-0033 · Cited by 1,364 · see citing works
Sir2 mediates longevity in the fly through a pathway related to calorie restriction
Rogina, B., & Helfand, S. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404184101 · Cited by 1,361 · see citing works
Mammalian SIRT1 Represses Forkhead Transcription Factors
Motta, M. C., Divecha, N., Lemieux, M. E., Kamel, C., Chen, D., Gu, W. J., Bultsma, Y., McBurney, M. W., & Guarente, L. (2004) · Cell · doi:10.1016/s0092-8674(04)00126-6 · Cited by 1,351 · see citing works
Self-citationThe silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases
Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., & Sternglanz, R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110148297 · Cited by 970 · see citing works
Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells
Bordone, L., Motta, M. C., Picard, F., Robinson, A., Jhala, U. S., Apfeld, J., McDonagh, T., Lemieux, M., McBurney, M., Szilvasi, A., et al. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0040031 · Cited by 715 · see citing works
Self-citationShi, T., Wang, F., Stieren, E., & Tong, Q. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414670200 · Cited by 712 · see citing works
Stanley, C. A., Lieu, Y. K., Hsu, B. Y. L., Burlina, A., Greenberg, C. R., Hopwood, N. J., Perlman, K., Rich, B. H., Zammarchi, E., & Poncz, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199805073381904 · Cited by 676 · see citing works
Calorie restriction extends yeast life span by lowering the level of NADH
Lin, S.-J., Ford, E., Haigis, M., Liszt, G., & Guarente, L. (2004) · Genes & Development · doi:10.1101/gad.1164804 · Cited by 632 · see citing works
Self-citationMoynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal‐Mizrachi, E., Ford, E. L., CRAS-MÉNEUR, C. M. H., Permutt, M. A., & Imai, S. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.07.001 · Cited by 630 · see citing works
Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription
Ford, E., Voit, R., Liszt, G., Magin, C., Grummt, I., & Guarente, L. (2006) · Genes & Development · doi:10.1101/gad.1399706 · Cited by 629 · see citing works
Self-citationSchwer, B., North, B. J., Frye, R. A., Ott, M., & Verdin, E. M. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200205057 · Cited by 599 · see citing works
High-throughput engineering of the mouse genome coupled with high-resolution expression analysis
Valenzuela, D. M., Murphy, A. J., Frendewey, D. A., Gale, N. W., Economides, A. N., Auerbach, W., Poueymirou, W. T., Adams, N. C., Rojas, J., Yasenchak, J., et al. (2003) · Nature Biotechnology · doi:10.1038/nbt822 · Cited by 585 · see citing works
Self-citationSIRT3, a human SIR2 homologue, is an NAD- dependent deacetylase localized to mitochondria
Onyango, P. O., Celic, I., McCaffery, J. M., Boeke, J. D., & Feinberg, A. P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222538099 · Cited by 573 · see citing works
FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction
Kitamura, Y., Kitamura, T., Kruse, J.-P., Raum, J. C., Stein, R. W., Gu, W. J., & Accili, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.08.004 · Cited by 552 · see citing works
Mouse Sir2 Homolog SIRT6 Is a Nuclear ADP-ribosyltransferase
Liszt, G., Ford, E., Kurtev, M., & Guarente, L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413296200 · Cited by 548 · see citing works
Self-citationGrozinger, C. M., Chao, E. D., Blackwell, H. E., Moazed, D., & Schreiber, S. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106779200 · Cited by 533 · see citing works
Increase in Activity During Calorie Restriction Requires Sirt1
Chen, D., Steele, A. D., Lindquist, S., & Guarente, L. (2005) · Science · doi:10.1126/science.1118357 · Cited by 419 · see citing works
Self-citationA Role for SIR-2.1 Regulation of ER Stress Response Genes in Determining C. elegans Life Span
Viswanathan, M., Kim, S. K., Berdichevsky, A., & Guarente, L. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.09.017 · Cited by 409 · see citing works
Self-citationC. elegans SIR-2.1 Interacts with 14-3-3 Proteins to Activate DAF-16 and Extend Life Span
Berdichevsky, A., Viswanathan, M., Horvitz, H. R., & Guarente, L. (2006) · Cell · doi:10.1016/j.cell.2006.04.036 · Cited by 393 · see citing works
Self-citationAn Enzymatic Activity in the Yeast Sir2 Protein that Is Essential for Gene Silencing
Tanny, J. C., Dowd, G. J., Huang, J., Hilz, H., & Moazed, D. (1999) · Cell · doi:10.1016/s0092-8674(00)81671-2 · Cited by 391 · see citing works
L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase
Sener, A., & Malaisse, W. J. (1980) · Nature · doi:10.1038/288187a0 · Cited by 354 · see citing works
Chemistry of Gene Silencing: The Mechanism of NAD+-Dependent Deacetylation Reactions
Sauve, A. A., Celic, I., Avalos, J. L., Deng, H., Boeke, J. D., & Schramm, V. L. (2001) · Biochemistry · doi:10.1021/bi011858j · Cited by 301 · see citing works
MacDonald, M. J., Fahien, L. A., Brown, L. J., Hasan, N. M., Buss, J. D., & Kendrick, M. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00218.2004 · Cited by 244 · see citing works
HST2 Mediates SIR2 -Independent Life-Span Extension by Calorie Restriction
Lamming, D. W., Latorre‐Esteves, M., Medvedik, O., Wong, S. N., Tsang, F. A., Wang, C., Lin, S.-J., & Sinclair, D. A. (2005) · Science · doi:10.1126/science.1113611 · Cited by 228 · see citing works
Effect of Age and Diet on Insulin Secretion and Insulin Action in the Rat
REAVEN, E. P., Wright, D. W., Mondon, C. E., Solomon, R., Ho, H., & Reaven, G. M. (1983) · Diabetes · doi:10.2337/diab.32.2.175 · Cited by 178 · see citing works
Controlling caloric consumption: protocols for rodents and rhesus monkeys☆
Pugh, T. D., Klopp, R. G., & Weindruch, R. H. (1999) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00043-3 · Cited by 174 · see citing works
Self-citationRegulation of Leucine-stimulated Insulin Secretion and Glutamine Metabolism in Isolated Rat Islets
Li, C., Najafi, H., Daikhin, Y., Nissim, I. B., Collins, H. W., Yudkoff, M., Matschinsky, F. M., & Stanley, C. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210577200 · Cited by 158 · see citing works
Additive regulation of hepatic gene expression by dwarfism and caloric restriction
Tsuchiya, T., Dhahbi, J. M., Cui, X., Mote, P. L., Bartke, A., & Spindler, S. R. (2004) · Physiological Genomics · doi:10.1152/physiolgenomics.00039.2004 · Cited by 148 · see citing works
Caloric restriction increases gluconeogenic and transaminase enzyme activities in mouse liver
Hagopian, K. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(02)00202-4 · Cited by 135 · see citing works
Regulation of glutamate dehydrogenase by reversible ADP‐ribosylation in mitochondria
Herrero-Yraola, A., Bakhit, S. M. A., Franke, P., Weise, C., Schweiger, M., Jorcke, D., & Ziegler, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.10.2404 · Cited by 129 · see citing works
13C NMR Isotopomer Analysis of Anaplerotic Pathways in INS-1 Cells
Cline, G. W., Pongratz, R. L., Papas, K. K., Kibbey, R. G., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311842200 · Cited by 122 · see citing works
Protein glycation by ADP-ribose: Studies of model conjugates
Cervantes-Laurean, D., Minter, D. E., Jacobson, E. L., et al. (1993) · Biochemistry · doi:10.1021/bi00057a017 · Cited by 110 · see citing works
Caloric restriction alters the feeding response of key metabolic enzyme genes
Dhahbi, J. M., Mote, P. L., Wingo, J., Rowley, B. C., Cao, S. X., Walford, R. L., & Spindler, S. R. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(01)00230-5 · Cited by 104 · see citing works
Disorders of glutamate metabolism
Kelly, A. T., & Stanley, C. A. (2001) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.1040 · Cited by 100 · see citing works
Hagopian, K. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(02)00203-6 · Cited by 77 · see citing works
Meyer, T. F., & Hilz, H. (1986) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1986.tb09471.x · Cited by 56 · see citing works
Armstrong, C. M., Kaeberlein, M. R., Imai, S., & Guarente, L. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-10-0482 · Cited by 55 · see citing works
Self-citationEnzymic, cysteine-specific ADP-ribosylation in bovine liver mitochondria
Jorcke, D., Ziegler, M., Herrero-Yraola, A., & Schweiger, M. (1998) · Biochemical Journal · doi:10.1042/bj3320189 · Cited by 24 · see citing works
Schwab, C. J., Colville, M. J., Fullerton, A. T., et al. (2000) · Proceedings of The Society for Experimental Biology and Medicine · doi:10.1111/j.1525-1373.2000.22355.x · Cited by 14 · see citing works
Serine utilization in mouse liver: Influence of caloric restriction and aging
Hagopian, K., Ramsey, J. J., & Weindruch, R. H. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.02.062 · Cited by 14 · see citing works
Self-citationSchwab, C. J., Colville, M. J., Fullerton, A. T., et al. (2000) · Proceedings of The Society for Experimental Biology and Medicine · doi:10.1046/j.1525-1373.2000.22355.x · Cited by 13 · see citing works
Regulation of acetyl-CoA carboxylase by ADP-ribosylation
Witters, L. A., & McDermott, J. M. (1986) · Biochemistry · doi:10.1021/bi00370a067 · Cited by 7 · see citing works
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Circu, M. L., & Aw, T. Y. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.12.022 · Cited by 3,340 · see citing works
From Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119 · see citing works
Sirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008 · see citing works
The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935 · see citing works
Self-citationCantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
NAD+ metabolism and its roles in cellular processes during ageing
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Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429 · see citing works
A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis
Ahn, B.-H., Kim, H.-S., Song, S., Lee, I. H., Liu, J., Vassilopoulos, A., Deng, C.-X., & Finkel, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803790105 · Cited by 1,291 · see citing works
Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction
Haigis, M. C., & Guarente, L. P. (2006) · Genes & Development · doi:10.1101/gad.1467506 · Cited by 1,295 · see citing works
Self-citationMammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
Lombard, D. B., Alt, F. W., Cheng, H.-L., Bunkenborg, J., Streeper, R. S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01636-07 · Cited by 1,216 · see citing works
Self-citationNutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival
Yang, H., Yang, T., Baur, J. A., Perez, E., Matsui, T., Carmona, J. J., Lamming, D. W., Souza-Pinto, N. C., Bohr, V. A., Rosenzweig, A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.035 · Cited by 950 · see citing works
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0026 · Cited by 899 · see citing works
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.011 · Cited by 865 · see citing works
Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds
Bonkowski, M. S., & Sinclair, D. A. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.93 · Cited by 834 · see citing works
SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle
Nakagawa, T., Lomb, D. J., Haigis, M. C., & Guarente, L. (2009) · Cell · doi:10.1016/j.cell.2009.02.026 · Cited by 787 · see citing works
Self-citationMolecular mechanisms of dietary restriction promoting health and longevity
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Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling
Verdin, E., Hirschey, M. D., Finley, L. W. S., & Haigis, M. C. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.07.003 · Cited by 661 · see citing works
Self-citationThe mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4
Csibi, A., Fendt, S.-M., Li, C., Poulogiannis, G., Choo, A. Y., Chapski, D. J., Jeong, S. M., Dempsey, J. M., Parkhitko, A., Morrison, T., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.023 · Cited by 586 · see citing works
Self-citationRedox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588 · see citing works
Barger, J. L., Kayo, T., Vann, J. M., Arias, E. B., Wang, J., Hacker, T. A., Wang, Y., Raederstorff, D., Morrow, J. D., Leeuwenburgh, C., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002264 · Cited by 580 · see citing works
Self-citationDeconstructing repression: evolving models of co-repressor action
Perissi, V., Jepsen, K., Glass, C. K., & Rosenfeld, M. G. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2736 · Cited by 532 · see citing works
Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
Schlicker, C., Gertz, M., Papatheodorou, P., Kachholz, B., Becker, C. F. W., & Steegborn, C. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.07.048 · Cited by 531 · see citing works
Guarente, L. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1100831 · Cited by 510 · see citing works
Self-citationDiet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle
Palacios, O. M., Carmona, J. J., Michan, S., Chen, K. Y., Manabe, Y., III, J. L. W., Goodyear, L. J., & Tong, Q. (2009) · Aging · doi:10.18632/aging.100075 · Cited by 487 · see citing works
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Sirtuin Functions in Health and Disease
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Sirtuins as potential targets for metabolic syndrome
Guarente, L. (2006) · Nature · doi:10.1038/nature05486 · Cited by 468 · see citing works
Self-citationSirtuins, a promising target in slowing down the ageing process
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Calorie restriction and sirtuins revisited
Guarente, L. (2013) · Genes & Development · doi:10.1101/gad.227439.113 · Cited by 464 · see citing works
Self-citationJeong, S. M., Xiao, C., Finley, L. W. S., Lahusen, T., Souza, A. L., Pierce, K., Li, Y.-H., Wang, X., Laurent, G., German, N. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.024 · Cited by 445 · see citing works
Self-citationSirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity
Mathias, R. A., Greco, T. M., Oberstein, A., Budayeva, H. G., Chakrabarti, R., Rowland, E. A., Kang, Y., Shenk, T., & Cristea, I. M. (2014) · Cell · doi:10.1016/j.cell.2014.11.046 · Cited by 430 · see citing works
Targeting Sirtuin 1 to Improve Metabolism: All You Need Is NAD+?
Cantó, C., & Auwerx, J. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.003905 · Cited by 433 · see citing works
Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase
Ahuja, N., Schwer, B., Carobbio, S., Waltregny, D., North, B. J., Castronovo, V., Maechler, P., & Verdin, E. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705488200 · Cited by 422 · see citing works
Sirtuins: The ‘ <i>magnificent seven</i> ’, function, metabolism and longevity
Dali‐Youcef, N., Lagouge, M., Froelich, S., Koehl, C., Schoonjans, K., & Auwerx, J. (2007) · Annals of Medicine · doi:10.1080/07853890701408194 · Cited by 402 · see citing works
Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction
Hallows, W. C., Yu, W., Smith, B. C., Devires, M. K., Ellinger, J. J., Someya, S., Shortreed, M. R., Prolla, T., Markley, J. L., Smith, L. M., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.01.002 · Cited by 389 · see citing works
Self-citationChemical mechanisms of histone lysine and arginine modifications
Smith, B. C., & Denu, J. M. (2009) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2008.06.005 · Cited by 390 · see citing works
Li, X. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gms108 · Cited by 360 · see citing works
SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion
Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.003 · Cited by 326 · see citing works
Protein acetylation in metabolism – metabolites and cofactors
Menzies, K. J., Zhang, H., Katsyuba, E., & Auwerx, J. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.181 · Cited by 331 · see citing works
Carrico, C., Meyer, J. G., He, W., Gibson, B. W., & Verdin, E. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.016 · Cited by 331 · see citing works
Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells
Nikiforov, A., Dölle, C., Niere, M., & Ziegler, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.213298 · Cited by 326 · see citing works
SIRT3 regulation of mitochondrial oxidative stress
Bause, A. S., & Haigis, M. C. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2012.08.007 · Cited by 311 · see citing works
Self-citationDifferential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells
Coloff, J. L., Murphy, J. P., Braun, C. R., Harris, I. S., Shelton, L. M., Kami, K., Gygi, S. P., Selfors, L. M., & Brugge, J. S. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.03.016 · Cited by 288 · see citing works
SIRT6 protects against pathological damage caused by diet‐induced obesity
Kanfi, Y., Peshti, V., Gil, R., Naiman, S., Nahum, L., Levin, E., Kronfeld‐Schor, N., & Cohen, H. Y. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2009.00544.x · Cited by 311 · see citing works
Circadian Clocks and Metabolism
Marcheva, B., Ramsey, K. M., Peek, C. B., Affinati, A., Maury, E., & Bass, J. (2013) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-25950-0_6 · Cited by 282 · see citing works
Mitochondrial sirtuins: regulators of protein acylation and metabolism
He, W., Newman, J. C., Wang, M. Z., Ho, L., & Verdin, E. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.07.004 · Cited by 262 · see citing works
Calorie restriction alters mitochondrial protein acetylation
Schwer, B., Eckersdorff, M., Li, Y., Silva, J. C., Fermin, D., Kurtev, M. V., Giallourakis, C., Comb, M. J., Alt, F. W., & Lombard, D. B. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00503.x · Cited by 259 · see citing works
“S1) (Haigis et al., 2006; Nakagawa et al., 2009).”
Self-citationSirtuin catalysis and regulation
Feldman, J. L., Dittenhafer-Reed, K. E., & Denu, J. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.378877 · Cited by 248 · see citing works
Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes
Cantó, C., Sauve, A. A., & Bai, P. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.01.004 · Cited by 246 · see citing works
Sirtuin regulation in aging and injury
Poulose, N., & Raju, R. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.08.017 · Cited by 236 · see citing works
Huang, J.-Y., Hirschey, M. D., Shimazu, T., Ho, L., & Verdin, E. (2010) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.12.021 · Cited by 231 · see citing works
Protective effects and mechanisms of sirtuins in the nervous system
Zhang, F., Wang, S., Gan, L., Vosler, P. S., Gao, Y., Zigmond, M. J., & Chen, J. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.09.001 · Cited by 211 · see citing works
The Role of Sirtuins in Cellular Homeostasis
Kupis, W., Pałyga, J., Tomal, E., & Niewiadomska, E. (2016) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-016-0492-6 · Cited by 200 · see citing works
Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective
Valerio, A., D'Antona, G., & Nisoli, E. (2011) · Aging · doi:10.18632/aging.100322 · Cited by 196 · see citing works
NAD <sup>+</sup> metabolism: A therapeutic target for age-related metabolic disease
Mouchiroud, L., Houtkooper, R. H., & Auwerx, J. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.789479 · Cited by 193 · see citing works
“than deacetylate (Haigis et al., 2006), and SIRT5 was shown to act as a demalonylase and desuccinylase (Du et al.”
BackgroundInfluentialSIRT3 regulates mitochondrial protein acetylation and intermediary metabolism
Hirschey, M. D., Shimazu, T., Huang, J. Y., Schwer, B., & Verdin, E. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010850 · Cited by 180 · see citing works
NAD+ biosynthesis, aging, and disease
Johnson, S., & Imai, S. (2018) · F1000Research · doi:10.12688/f1000research.12120.1 · Cited by 178 · see citing works
RETRACTED: Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex
Zhang, Q., Wang, S.-Y., Fleuriel, C., Leprince, D., Rocheleau, J. V., Piston, D. W., & Goodman, R. H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610590104 · Cited by 171 · see citing works
RetractedNAD<sup>+</sup>metabolism and oxidative stress: the golden nucleotide on a crown of thorns
Massudi, H., Grant, R., Guillemin, G. J., & Braidy, N. (2012) · Redox Report · doi:10.1179/1351000212y.0000000001 · Cited by 158 · see citing works
Histone deacetylases (HDACs) and brain function
Volmar, C.-H., & Wahlestedt, C. (2015) · Neuroepigenetics · doi:10.1016/j.nepig.2014.10.002 · Cited by 151 · see citing works
Mitochondrial signals drive insulin secretion in the pancreatic β-cell
Wiederkehr, A., & Wollheim, C. B. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.07.016 · Cited by 133 · see citing works
Ogura, M., Nakamura, Y., Tanaka, D., Zhuang, X., Fujita, Y., Obara, A., Hamasaki, A., Hosokawa, M., & Inagaki, N. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.01.081 · Cited by 121 · see citing works
SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma
Jeong, S. M., Lee, A., Lee, J., & Haigis, M. C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.525949 · Cited by 121 · see citing works
Self-citationMatsushita, N., Yonashiro, R., Ogata, Y., Sugiura, A., Nagashima, S., Fukuda, T., Inatome, R., & Yanagi, S. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01475.x · Cited by 106 · see citing works
NAD <sup>+</sup> Biosynthesis and Signaling in Plants
Gakière, B., Hao, J., de Bont, L., Pétriacq, P., Nunes-Nesi, A., & Fernie, A. R. (2018) · Critical Reviews in Plant Sciences · doi:10.1080/07352689.2018.1505591 · Cited by 108 · see citing works
Tauriainen, E., Luostarinen, M., Martonen, E., Finckenberg, P., Kovalainen, M., Huotari, A., Herzig, K.-H., Lecklin, A., & Mervaala, E. (2011) · Journal of Nutrition and Metabolism · doi:10.1155/2011/525094 · Cited by 81 · see citing works
Bao, J., & Sack, M. N. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0402-y · Cited by 67 · see citing works
Ethanol intoxication increases hepatic N-lysyl protein acetylation
Picklo, M. J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.09.039 · Cited by 60 · see citing works
Lee, J. C., Shin, J.-H., Park, B.-W., Kim, G. S., Kim, J. C., Kang, K.-S., & Cha, C. I. (2012) · Brain Research · doi:10.1016/j.brainres.2011.11.019 · Cited by 32 · see citing works
Maldonado, M., Chen, J., Duan, H., Huang, T., Jiang, G., & Zhong, Y. (2021) · Translational Medicine of Aging · doi:10.1016/j.tma.2021.02.001 · Cited by 11 · see citing works
- Authors
- Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W., & Guarente, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Johns Hopkins University (US)
- Regeneron (United States) (US)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Guarente, Leonard
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 126
- Issue
- 5
- Pages
- 941-954
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2056673958
- Cited by
- 1,162
- References
- 56
- Citations by year
- 2026: 29 · 2025: 48 · 2024: 52 · 2023: 45 · 2022: 49 · 2021: 70 · 2020: 60 · 2019: 53 · 2018: 77 · 2017: 62 · 2016: 79 · 2015: 62 · 2014: 65 · 2013: 83 · 2012: 68
- FWCI
- 21.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2511 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- SIRT4, glutamate dehydrogenase, caloric restriction, pancreatic beta cells, insulin secretion, ADP-ribosylation, mitochondrial metabolism, insulinoma cells, phosphodiesterase, glutamine metabolism
- MeSH terms
- Adenosine Diphosphate Ribose, Amino Acids, Animals, Glucose, Glutamate Dehydrogenase, Glutamine, Humans, Insulin, Islets of Langerhans, Mitochondria, NAD, Protein Processing, Post-Translational, Transfection, Down-Regulation, Mice, Knockout, Caloric Restriction, RNA, Small Interfering, Sirtuins, Cell Line, Tumor, Insulin-Secreting Cells, Mice, Sirtuin 1
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