Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
Open accessAbstract
Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.
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SIRT3 is the major mitochondrial protein deacetylase.
“Early experiments using western blotting analysis and antisera specific for acetyl-lysine showed globally increased mitochondrial protein acetylation in mice lacking SIRT3 ((Lombard et al. 2007)), indicating that SIRT3 was the major mitochondrial protein deacetylase.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Lombard et al. 2007
SIRT5 is thought to localize primarily to mitochondria.
“SIRT5 is thought to localize primarily to mitochondria (Lombard et al., 2007; Michishita et al., 2005; Nakagawa et al., 2009; Schlicker et al., 2008).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Lombard et al., 2007
SIRT5 has a major role in controlling lysine succinylation, similar to SIRT3's principal role in mitochondrial lysine acetylation.
“Our data are consistent with a major role for SIRT5 in regulating Ksucc levels, which is analogous to the principal role of SIRT3 in regulating mitochondrial Lys acetylation (Hebert et al., 2013; Lombard et al., 2007; Smith et al., 2011).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Lombard et al., 2007
SIRT5 deficiency does not impact bulk mitochondrial protein acetylation.
“Less is known regarding the functions of SIRT4 and SIRT5, which, unlike SIRT3, do not impact bulk mitochondrial protein acetylation (Lombard et al., 2007).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Lombard et al., 2007
The SIRT3 deacetylase enzyme has emerged as a key regulator of mitochondrial activity.
“The SIRT3 deacetylase enzyme has also emerged as a key regulator of mitochondrial activity (Lombard et al, 2007).”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Lombard et al, 2007
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BackgroundInfluentialSIRT3 regulates mitochondrial protein acetylation and intermediary metabolism
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Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3
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Sirtuins at the Service of Healthy Longevity
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Chapter 8 Acetylation of Mitochondrial Proteins
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- Authors
- Lombard, D. B., Alt, F. W., Cheng, H.-L., Bunkenborg, J., Streeper, R. S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., Yang, Y., Chen, Y., Hirschey, M. D., Bronson, R. T., Haigis, M., Guarente, L. P., Farese, R. V., Weissman, S., Verdin, E., & Schwer, B.
- Affiliations
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- University of Southern Denmark (DK)
- University of California, San Francisco (US)
- Howard Hughes Medical Institute, The Children's Hospital, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115
- Regeneron (United States) (US)
- Yale University (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Alt, Frederick W.
- Verdin, Eric
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-12-01
- Volume
- 27
- Issue
- 24
- Pages
- 8807-8814
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2169418
- OpenAlex
- W2117473844
- Cited by
- 1,216
- References
- 38
- Citations by year
- 2026: 30 · 2025: 38 · 2024: 40 · 2023: 62 · 2022: 69 · 2021: 86 · 2020: 73 · 2019: 77 · 2018: 83 · 2017: 75 · 2016: 85 · 2015: 77 · 2014: 76 · 2013: 94 · 2012: 71
- FWCI
- 16.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Center for Research Resources (1C06RR18928, C06-RR-018928)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- SIRT3, sirtuins, mitochondrial deacetylase, SIRT4, SIRT5, SIRT3 knockout mice, adaptive thermogenesis, energy metabolism, mitochondrial protein acetylation
- MeSH terms
- Acetylation, Animals, Adipose Tissue, Brown, Feeding Behavior, Food Deprivation, Glutamate Dehydrogenase, Histone Deacetylases, Lysine, Mammals, Mitochondria, Liver, Solubility, Sequence Homology, Amino Acid, Gene Targeting, Thermogenesis, Mitochondrial Proteins, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Mice, Sirtuin 2, Sirtuin 3
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