Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress
Open accessAbstract
Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.
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MnSOD carries glutarylation, succinylation, and acetylation at functionally required lysine residues near its active site, with K122 bearing all three modifications.
“MnSOD also carries glutarylation, succinylation, and acetylation at functionally required lysine residues near its active site, K122 in particular bears all three modifications ((Tao et al. 2010)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tao et al. 2010
SIRT3 deacetylates manganese superoxide dismutase and isocitrate dehydrogenase 2.
“The mitochondrial SIRT3 deacetylates two of these enzymes: manganese superoxide dismutase (MnSOD) (Tao et al. 2010) and isocitrate dehydrogenase 2 (IDH2)(Someya et al. 2010).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tao et al. 2010
Two enzymes involved in ROS detoxification, MnSOD and IDH2, are direct targets of SirT3.
“Recently, two enzymes that have a role in the detoxification of ROS were demonstrated to be direct targets of SirT3 (Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Tao et al., 2010
SIRT3 can directly bind and deacetylate SOD2, leading to increased SOD2 activity and subsequently exerting significant effects on mitochondrial reactive oxygen species homeostasis and NLRP3 inflammasome activation.
“More importantly, SIRT3 can directly bind and deacetylate SOD2, leading to increased SOD2 activity and subsequently exerting significant effects on mtROS homeostasis and NLRP3 inflammasome activation.18, 19, 20”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [20]
SOD2 activity is tightly regulated via acetylation at its lysine residues.
“SOD2 activity is known to be tightly regulated via acetylation at its lysine residues.20”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [20]
SOD2 is mainly regulated by deacetylation of specific conserved lysines in a reaction catalyzed by SIRT3.
“because SOD2 is mainly regulated by the deacetylation of specific conserved lysines in a reaction catalyzed by the mitochondrial sirtuin SIRT3,20”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [20]
SIRT3 deacetylates mitochondrial proteins including SOD2, which limits accumulation of mtROS.
“SIRT3 deacetylates a number of mitochondrial proteins including SOD2, which is responsible for limiting the accumulation of mtROS.20”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [20]
MnSOD activity and stability are highly regulated by post-translational modifications, including protein acetylation in mitochondria.
“MnSOD activity and stability are highly regulated by post-translational modifications, including protein acetylation in the mitochondria (Takahashi et al., 2011; Tao et al., 2010).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Tao et al., 2010
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Self-citation
- Authors
- Tao, R., Coleman, M. C., Pennington, J. D., Ozden, O., Park, S.-H., Jiang, H., Kim, H.-S., Flynn, C. R., Hill, S., Hayes McDonald, W., Olivier, A. K., Spitz, D. R., & Gius, D.
- Affiliations
- National Institutes of Health (US)
- University of Iowa (US)
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Gius, David
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 40
- Issue
- 6
- Pages
- 893-904
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3266626
- OpenAlex
- W2039374791
- Cited by
- 899
- References
- 24
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 36 · 2023: 44 · 2022: 48 · 2021: 72 · 2020: 64 · 2019: 66 · 2018: 62 · 2017: 80 · 2016: 71 · 2015: 61 · 2014: 64 · 2013: 68 · 2012: 58
- FWCI
- 21.31
- 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, 959 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
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (F30AG030839)
- National Cancer Institute (P50 CA98131, R01CA133114, R01CA152601, P50CA098131, T32CA078586, P30CA086862)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- SIRT3, manganese superoxide dismutase, protein acetylation, deacetylation, mitochondrial superoxide, ionizing radiation, radiation-induced genomic instability, oncogenic Ras, mammary tumors, liver, hepatocyte injury, mitochondrial deacetylase, tumor microenvironment
- MeSH terms
- Acetylation, Animals, Arginine, Cell Line, Lysine, Superoxide Dismutase, Mutagenesis, Site-Directed, Conserved Sequence, Oxidative Stress, Evolution, Molecular, Mice, Sirtuin 3
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