SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress
Open accessAbstract
The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.
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Cells from SIRT3 knockout mice were highly susceptible to oncogenic transformation, but this susceptibility depended on elevated ROS characteristic of sirt3−/− cells.
“Our finding that loss of SIRT3 loss drives senescence appears to contradict a report in which cells from SIRT3 knockout mice were highly susceptible to oncogenic transformation; however, this susceptibility depended on the elevated ROS characteristic of sirt3−/− cells (Kim et al., 2010).”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Kim et al., 2010
The Results sections on transformation and SOD report that SIRT3−/− mouse embryonic fibroblasts were transformed by a single oncogene and that MnSOD prevented their immortalization by Myc or Ras alone. The claim overgeneralizes the ROS dependence: MnSOD did not prevent immortalization when the cells expressed both Myc and Ras. The paper also reports normal superoxide levels in unstressed knockout cells, rather than uniformly elevated levels. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSIRT3 has been reported as pro-apoptotic, and SIRT3 loss is associated with a tumor-permissive environment via inhibition of ROS production.
“SIRT3 has been reported as pro-apoptotic ((Allison and Milner 2007)) and SIRT3 loss is associated with a tumor-permissive environment via the inhibition of ROS production ((Kim et al. 2010);(Bell et al. 2011);(Finley et al. 2011)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Kim et al. 2010
SirT3 deficiency alone is sufficient for transformation of primary MEFs with Myc and/or RAS to form tumors in xenograft models.
“Specifically, SirT3 deficiency alone is sufficient for the transformation of primary MEFs with Myc and/or RAS to from tumors in xenograft models.”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Kim et al., 2010
SirT3−/− Myc/Ras MEFs exhibit increased glycolysis, decreased oxidative phosphorylation, and increased ROS.
“Kim and colleagues also demonstrated that SirT3−/− Myc/Ras MEFs exhibit increased glycolysis, decreased oxidative phosphorylation and increased ROS.”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Kim et al., 2010
SirT3 is a mitochondrial localized tumor suppressor.
“Recently SirT3 was described to act as a mitochondrial localized tumor suppressor (Kim et al., 2010).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Kim et al., 2010
SirT3 has been demonstrated to act as a tumor suppressor by negatively regulating MnSOD/ROS-mediated genomic instability.
“Previously, SirT3 has been demonstrated to act as a tumor suppressor by negatively regulating MnSOD/ROS-mediated genomic instability (Kim et al., 2010).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Kim et al., 2010
SIRT3 is critical for maintaining mitochondria and metabolism and controls ROS production during HSC aging.
“Another member of the sirtuin family, SIRT3, is critical to the maintenance of mitochondria and metabolism and controls ROS production during HSC aging29.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [29]
Sirtuin-regulated mitochondrial activity acts directly on stem cells and also indirectly alters ROS and nutrient sensing, further changing stem cell phenotypes.
“Likewise, mitochondrial function, largely regulated by sirtuins, not only affects stem cell functions directly but also causes secondary effects on ROS and nutrient-sensing activities, which further modulate stem cell phenotypes29,30,108,113,184.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [29]
SIRT3 and SIRT6 are encoded by genes with tumor-suppressor activity.
“the genes encoding SIRT3 and SIRT6 are tumor suppressors”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Kim et al., 2010
Mitochondrial ROS directly contribute to cellular transformation induced by either Ras or Myc overexpression.
“Recent work demonstrates that mitochondrial ROS directly contribute to cellular transformation induced by either Ras or Myc overexpression.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
Sirt3−/− murine fibroblasts display increased levels of mitochondrial ROS accumulation compared to wild-type cells when either Myc or Ras oncogenes are expressed.
“Moreover, Sirt3−/− murine fibroblasts display increased levels of mitochondrial ROS accumulation (compared to wild-type cells) when either Myc or Ras oncogenes are expressed.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
SIRT3 acts as a tumor suppressor through its regulation of FOXO activity and ROS maintenance.
“The NAD-dependent deacetylase sirtuin 3 (SIRT3) acts as a tumor suppressor through its regulation of FOXO activity and ROS maintenance 72.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
The ROS accumulation in Sirt3−/− fibroblasts is associated with decreased flux through mitochondrial complexes I and III and reduced cellular levels of SOD2.
“This ROS accumulation is associated with decreased flux through mitochondrial complexes I and III (possibly allowing for increased escape of electrons to O2), and reduced cellular levels of SOD2 72.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
Expression of SOD2 inhibited oncogene-mediated transformation of Sirt3−/− cells.
“Expression of SOD2 inhibited this oncogene-mediated transformation of Sirt3−/− cells, suggesting that mitochondrial ROS play an important role in the Sirt3−/− phenotype.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
Sod2−/− fibroblasts are capable of transformation with single oncogenes.
“These finding are consistent with observations in Sod2−/− fibroblasts, which like their Sirt3−/− counterparts, are capable of transformation with single oncogenes 72.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
Sirt3−/− cells become transformed after expression of either Myc or Ras, whereas wild-type cells require expression of both oncogenes.
“Sirt3−/− cells become transformed after expression of either Myc or Ras, whereas wild-type cells require expression of both oncogenes.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
SIRT3 deacetylates FOXO3a, promoting its nuclear localization and transcriptional activation.
“SIRT3 deacetylates FOXO3a, promoting its nuclear localization and transcriptional activation 40, 72.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [72]
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Self-citation
- Authors
- Kim, H.-S., Patel, K., Muldoon-Jacobs, K., Bisht, K. S., Aykin-Burns, N., Pennington, J. D., van der Meer, R., Nguyen, P., Savage, J., Owens, K. M., Vassilopoulos, A., Ozden, O., Park, S.-H., Singh, K. K., Abdulkadir, S. A., Spitz, D. R., Deng, C.-X., & Gius, D.
- Affiliations
- National Institutes of Health (US)
- Roswell Park Comprehensive Cancer Center (US)
- Vanderbilt University Medical Center (US)
- University of Iowa (US)
- Corresponding author
- Deng, Chu-Xia
- Gius, David
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 17
- Issue
- 1
- Pages
- 41-52
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3711519
- OpenAlex
- W2145755327
- Cited by
- 785
- References
- 35
- Citations by year
- 2026: 11 · 2025: 30 · 2024: 35 · 2023: 20 · 2022: 44 · 2021: 49 · 2020: 44 · 2019: 47 · 2018: 48 · 2017: 56 · 2016: 71 · 2015: 53 · 2014: 61 · 2013: 74 · 2012: 67
- FWCI
- 27.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (116430, R01 121904)
- National Institute on Aging (F30AG030839)
- National Cancer Institute (CA094858, CA123484, R01CA116430, R01CA094858, R01CA133114, R01CA100045, R01CA123484, R01CA121904, T32CA078586, P30CA086862)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- SIRT3, sirtuins, tumor suppressor, mitochondria, mitochondrial integrity, mitochondrial metabolism, superoxide, genomic instability, oncogenic transformation, c-Myc, Ras, superoxide dismutase, mammary tumors, breast cancer, cellular stress
- MeSH terms
- Aging, Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Female, Fibroblasts, Humans, Immunohistochemistry, Mitochondria, Stress, Physiological, Superoxides, Genes, Tumor Suppressor, Mice, Knockout, Oxidative Stress, Mice, Sirtuin 3
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