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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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In the citing paper
“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
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Citations
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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