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Sirtuin 4 Is a Lipoamidase Regulating Pyruvate Dehydrogenase Complex Activity
Open accessAbstract
Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.
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In the citing paper
“One study has shown that SIRT4 can regulate the levels of both lipoyl- and biotinyl-lysine modifications in pyruvate dehydrogenase and likely other proteins ((Mathias et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Mathias et al. 2014
In the citing paper
“Lipoylation occurs at two sites in the E2 N-terminal region (K132 and K259 in the human sequence), and is enzymatically reversed by SIRT4 ((Mathias et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Mathias et al. 2014
In the citing paper
“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 Mathias et al. 2014
In the citing paper
“For example, SIRT4 has been shown to cleave e -N -lipoyllysine (Klip) (Mathias et al., 2014) and e -N -(3-methylglutaconyl)lysine (Kmgc) (Anderson et al., 2017), SIRT5 regulates e -N -malonyllysine (Kmal) (Du et al., 2011; Peng et al., 2011; Hirschey and Zhao, 2015; Nishida et al., 2015), e -N -succinyllysine (Ksuc) (Du et al., 2011; Park et al., 2013; Rardin et al., 2013; Hirschey and Zhao, 2015)”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Mathias et al., 2014
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Citations
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
ProteomeXchange provides globally coordinated proteomics data submission and dissemination
Vizcaíno, J. A., Deutsch, E. W., Wang, R., Csordás, A., Reisinger, F., Ríos, D., Dianes, J. A., Sun, Z., Farrah, T., Bandeira, N., et al. (2014) · Nature Biotechnology · doi:10.1038/nbt.2839 · Cited by 2,735
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
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
Proteomic Mapping of Mitochondria in Living Cells via Spatially Restricted Enzymatic Tagging
Martell, J. D., Ting, A. Y., Rhee, H., Zou, P., Udeshi, N. D., Mootha, V. K., & Carr, S. A. (2012) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 1,330
Mammalian 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
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., et al. (2006) · Cell · doi:10.1016/j.cell.2006.06.057 · Cited by 1,162
Lysine glutarylation is a protein posttranslational modification regulated by SIRT5
Tan, M., Peng, C., Anderson, K. A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.014 · Cited by 844 · cited 1×
“More recently, SIRT5 was reported to regulate lysine glutarylation levels, thereby modulating the activity of carbamoyl phosphase synthase 1, a critical enzyme in the urea cycle (Tan et al., 2014).”
BackgroundFrye, R. A. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0897 · Cited by 809
SAINT: probabilistic scoring of affinity purification–mass spectrometry data
Choi, H., Larsen, B., Lin, Z.-Y., Breitkreutz, A., Mellacheruvu, D., Fermin, D., Qin, Z. S., Tyers, M., Gingras, A.-C., & Nesvizhskii, A. I. (2011) · Nature Methods · doi:10.1038/nmeth.1541 · Cited by 800
Cited by
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Cai, L., Ge, Z., Xu, Y., Sun, P., & Huang, G. (2022) · Research Square · doi:10.21203/rs.3.rs-1417679/v2
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Garten, A., & Lavery, G. G. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90256-4.00019-9
Xu, B., Cai, L., Xiao, H., Cai, G., Sun, P., & Huang, G. (2023) · Research Square · doi:10.21203/rs.3.rs-1695035/v2
Hampel, N., Georgy, J., Mehrabipour, M., Lang, A., Scheller, J., Ahmadian, M. R., Floss, D. M., & Piekorz, R. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.16.540489
Xu, B., Cai, X., Xiao, H., & Huang, G. (2023) · Research Square · doi:10.21203/rs.3.rs-3136901/v1
Mehrabipour, M., Dvorský, R., Nakhaei‐Rad, S., Lang, A., Verhülsdonk, P., Ahmadian, M. R., & Piekorz, R. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.23.568463
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Gül, N. (2023) · Akademisyen Kitabevi eBooks · doi:10.37609/akya.2621
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Yang, G., Xiang, J., Yang, X., Liu, X., Li, Y.-C., Li, L., Kang, L., Liang, Z., & Yang, S. (2024) · eLife · doi:10.7554/elife.98524.2
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Lehmkuhl, I., Amin, K., Gabriel, L., Hampel, N., Iram, A., Hesse, J., Wiek, C., Nguyen, J. T. V., Hanenberg, H., Scheller, J., et al. (2025) · FEBS Open Bio · doi:10.1002/2211-5463.70164
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Silveira, S. C. (2018) · theses.fr (ABES) · doi:10.70675/d8951764z7ae2z4d5eza2e1z0b24bea9f901
Liang, X., Yang, X., Wang, S., Zhuo, F., Hou, X., Tu, P., (4829), Y. L., Zeng, K., & Zhang, Q. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.06.016
Zhang, J., Dou, Z. X., Fan, Y.-Y., Sun, D.-G., Fan, X.-J., Yu, Z., & Yang, G. (2026) · Glycoconjugate Journal · doi:10.1007/s10719-026-10223-3
Cho, K. J., Seo, J. H., Kwon, H., Lee, S.-J., Hah, Y., & Park, J. J. (2026) · Cancers · doi:10.3390/cancers18132093
Krekora, J., Dróżdż, J., Pawłowska, E., & Błasiak, J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135780
Sigler-Galván, S., Domínguez-Negrete, A., González‐Dávalos, L., González‐Gallardo, A., Cárabez, A., Luna, M., Carranza-Salas, M., Lozano‐Flores, C., Varela‐Echavarría, A., Shimada, A. S., et al. (2026) · Journal of Applied Animal Research · doi:10.1080/09712119.2026.2695161
Comparative Structure-Based Analysis of Predicted BZD9L1 Binding Modes Across Human Sirtuins
Tan, Y. J., Lee, Y. T., Oon, C. E., & Mancera, R. L. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156840
A framework for understanding post-translational modifications of metabolic origin
Zhou, Y., Zhang, L., Udayanga, D. M. N., Sharifi, N., & Wang, Z. A. (2026) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2026.08.006
Investigation of the classical histone deacetylases and sirtuins using peptide technologies
Rogers, J. M., & Olsen, C. A. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.08.009
Zhang, Y., Liang, Y., Wang, J., Cao, L., Zhang, J., Fu, K., Han, X., Chen, X., Li, G., & Jin, Y. (2026) · Theriogenology · doi:10.1016/j.theriogenology.2026.118191
Yao, L., Zhong, F., Qin, B., Zeng, H., Qiu, Y., Yao, F., Xu, Y., Zhang, J., Lin, J., Deng, K., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117968
BindingDB (2025) · UC San Diego · doi:10.7270/q29w0m52
BindingDB (2023) · UC San Diego · doi:10.7270/q2125xq3
BindingDB Entry 50000621: Potent and Selective Inhibitors of Human Sirtuin 5.
BindingDB (2019) · UC San Diego · doi:10.7270/q2ww7m4j
What are the potentials of the different sirtuin proteins as therapeutic targets?
Fabbrizi, E., Hailu, G. S., Mancini, A., Fiorentino, F., Rotili, D., & Mai, A. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2755133
Metadata
- Authors
- Mathias, R. A., Greco, T. M., Oberstein, A., Budayeva, H. G., Chakrabarti, R., Rowland, E. A., Kang, Y., Shenk, T., & Cristea, I. M.
- Affiliations
- La Trobe University (AU)
- Princeton University (US)
- Corresponding author
- Cristea, Ileana M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1615-1625
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4344121
- OpenAlex
- W2134920945
- Cited by
- 430
- References
- 51
- Citations by year
- 2026: 20 · 2025: 30 · 2024: 29 · 2023: 34 · 2022: 48 · 2021: 46 · 2020: 41 · 2019: 38 · 2018: 43 · 2017: 35 · 2016: 40 · 2015: 25
- FWCI
- 16.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (DP1DA026192)
- National Cancer Institute (CA 82396, R01CA082396)
- National Institute of Allergy and Infectious Diseases (AI78063, R33AI102187, R21AI102187, R01AI078063)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD073044)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SIRT4, pyruvate dehydrogenase complex, mitochondrial sirtuins, acetyl-CoA biosynthesis, hepatic metabolism
- MeSH terms
- Amidohydrolases, Animals, Glutamine, Humans, Thioctic Acid, Liver, Mitochondria, Pyruvate Dehydrogenase Complex, Mitochondrial Proteins, Sirtuins, Mice, Rats, Gene Knockdown Techniques
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