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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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“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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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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