Bmi1 regulates mitochondrial function and the DNA damage response pathway
Open accessAbstract
Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1-/- phenotype. Here we demonstrate that cells derived from Bmi1-/- mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1-/- mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
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- Findingown data
Bmi1-deficient cells have increased intracellular reactive oxygen species.
“Assessment of unfractionated bone marrow, purified LSK cells and bone marrow cells expressing SLAM family receptors previously shown to allow for enrichment of long-term HSC cells (LT-HSCs)11 demonstrated that the absence of Bmi1–/– resulted in increased levels of ROS (Fig. 1a and Supplementary Fig. 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005) source
Not checked in the free run.
- Findingown data
Cells from Bmi1-deficient mice have impaired mitochondrial function.
“Here we demonstrate that cells derived from Bmi1–/– mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway.”
- Also stated in: § Bmi1 regulates ROS levels · plain
“Intact Bmi1–/– thymocytes had both reduced basal mitochondrial oxygen consumption and reduced mitochondrial oxidative capacity (Fig. 1d).”
Quote in the paperSubstantial claim - Also stated in: § Bmi1 regulates ROS levels · plain
- Findingown data
Bmi1 absence increases expression of gene products involved in mitochondrial function and ROS homeostasis.
“We demonstrate that the absence of Bmi1 leads to increased expression of a collection of gene products involved in mitochondrial function and ROS homeostasis.”
Quote in the paperSubstantial claim - Findingown data
Bmi1-deficient cells engage the DNA damage response pathway.
“In addition, consistent with ongoing DNA damage, we observed increased nuclear foci of 53BP1 (also known as Trp53bp1), another known hallmark of DNA damage and DDR activation17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Adams, M. M. & Carpenter, P. B. Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div 1, 19 (2006) source
Not checked in the free run.
- Interpretationnone given
In Bmi1-deficient mice, ROS act independently of the Ink4a/Arf pathway.
“Our observations further indicate that, in Bmi1–/– mice, ROS act independently of the Ink4a/Arf pathway.”
Quote in the paperSubstantial claim
- Interpretationreasoning
Additional Bmi1-regulated pathways exist beyond Ink4a/Arf repression.
“These results therefore indicate that, besides repression of the Ink4a/Arf locus, additional Bmi1-regulated pathways undoubtedly exist.”
Quote in the paperSubstantial claim - Interpretationown data
Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis.
“These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.”
Quote in the paperSubstantial claim - Interpretationown data
Antioxidant treatment or Chk2 deletion substantially improves some but not all aspects of Bmi1-deficient mice.
“Treatment with an antioxidant or interruption of the DDR by Chk2 deletion substantially improves some, but not all, aspects of the Bmi1–/– mice.”
Quote in the paperSubstantial claim - Interpretationreasoning
Polycomb proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
“These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.”
Quote in the paperSubstantial claim - Interpretationown data
Chk2 deletion does not rescue the self-renewal defect in Bmi1-deficient mice.
“We therefore conclude that, whereas Bmi1–/–Chk2–/– mice have an increased number of LSK cells and an apparent improvement in progenitor cell function, deletion of Chk2 does not rescue the self-renewal defect seen in Bmi1–/– mice.”
Quote in the paperSubstantial claim
- May combine two claims. 5
- The quote only partly states this claim. 2
May combine two claims.
Findingown dataBmi1-deficient thymocytes have reduced basal mitochondrial oxygen consumption, reduced oxidative capacity, and reduced ATP levels.
“Intact Bmi1–/– thymocytes had both reduced basal mitochondrial oxygen consumption and reduced mitochondrial oxidative capacity (Fig. 1d).”
- Also stated in: § Bmi1 regulates ROS levels · plain
“Basal ATP levels were also significantly reduced in Bmi1–/– thymocytes (Fig. 1e) as well as in other tissues (Supplementary Fig. 2).”
Quote in the paperSubstantial claim- Also stated in: § Bmi1 regulates ROS levels · plain
May combine two claims.
Findingown dataChk2 deletion increases LSK cell number and improves progenitor cell function but does not restore long-term repopulation.
“As noted in Fig. 4e, the number of LSK cells in mice lacking both Bmi1 and Chk2 was significantly higher than that seen in Bmi1–/– animals.”
- Also stated in: § Chk2 deletion rescues Bmi1–/– mice · plain
“We also observed essentially no contribution to long-term repopulation from the Bmi1–/–Chk2–/– bone marrow (Fig. 4g and Supplementary Fig. 12).”
Quote in the paperSubstantial claim- Rests on an assumption: The LSK bone marrow cell population contains abundant progenitor cells and rarer long-term repopulating cells.
- Also stated in: § Chk2 deletion rescues Bmi1–/– mice · plain
May combine two claims. The quote only partly states this claim.
Findingown dataChk2 deletion improves many Bmi1-deficient phenotypes, including thymus and spleen size, thymocyte maturation, apoptosis, body weight, ataxia, cerebellar development, fertility, and lifespan.
“As previously noted with antioxidant treatment, the overall size of the thymus, as well as the spleen, was significantly larger in the Bmi1–/–Chk2–/– mice than in Bmi1–/–-only mice (Supplementary Fig. 7).”
- Also stated in: § Chk2 deletion rescues Bmi1–/– mice · plain
“Deletion of one copy of Chk2 provided a survival advantage, whereas deletion of both copies of Chk2 was even more effective and extended the median survival of the Bmi1–/–Chk2–/– mice to approximately 6 months.”
Quote in the paperSubstantial claim- Also stated in: § Chk2 deletion rescues Bmi1–/– mice · plain
May combine two claims. The quote only partly states this claim.
Findingown dataNAC treatment reduces ROS and improves thymus size, thymocyte number, CD4+CD8+ frequency, and failure-to-thrive in Bmi1-deficient mice.
“After one week of treatment, ROS levels in Bmi1–/– thymocytes had been reduced to near wild-type levels (Fig. 2a).”
- Also stated in: § Antioxidants can rescue Bmi1–/– mice · hedged
“Finally, NAC administration had effects beyond altering thymocyte function, because this intervention also appeared to partially correct the failure-to-thrive phenotype seen in Bmi1–/– animals”
Quote in the paperSubstantial claim- Also stated in: § Antioxidants can rescue Bmi1–/– mice · hedged
May combine two claims.
Interpretationown dataSustained ROS in Bmi1-deficient mice are sufficient to damage DNA directly and engage the DDR pathway.
“These results indicate that the sustained levels of ROS seen in Bmi1–/– mice are sufficient to damage DNA directly and to engage the DDR pathway.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Interruption of electron transport chain flow in Bmi1-deficient mitochondria is a major source of ROS generation.
“The interruption of flow down the electron transport chain (ETC) evident in Bmi1–/– mitochondria is believed to be a major source for ROS generation.”
The paper relies on this without support.
The LSK bone marrow cell population contains abundant progenitor cells and rarer long-term repopulating cells.
“This cell population is generally believed to contain abundant progenitor cells, as well as rarer, long-term repopulating cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Impaired mitochondrial function is linked to defective HSC maintenance.
“prompted by studies linking impaired mitochondrial function to defective HSC maintenance27-29”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [29]
Compromised mitochondrial function is linked to depressed thymopoiesis.
“in view of a study linking compromised mitochondrial function and depressed thymopoiesis (94).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [94]
Deletion of the polycomb gene Bmi1 leads to mitochondrial dysfunction and increased ROS production in thymocytes.
“Deletion of the polycomb gene Bmi1 leads to mitochondrial dysfunction and increased ROS production in thymocytes 43.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [43]
The thymocyte maturation defect characteristic of Bmi1−/− mice is largely rescued by treatment with antioxidants.
“The thymocyte maturation defect characteristic of Bmi1−/− mice is largely rescued by treatment with antioxidants.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [43]
The citation lists haven’t been fetched yet
References 39 · Cited by 474
- Authors
- Liu, J., Cao, L., Chen, J., Song, S., Lee, I. H., Quijano, C., Liu, H., Keyvanfar, K., Chen, H., Cao, L.-Y., Ahn, B.-H., Kumar, N. G., Rovira, I. I., Xu, X.-L., van Lohuizen, M., Motoyama, N., Deng, C.-X., & Finkel, T.
- Affiliations
- National Institutes of Health (US)
- National Center for Geriatrics and Gerontology (JP)
- Corresponding author
- Cao, Liu
- Cao, Long-Yue
- Finkel, Toren
- ORCID
- Venue
- Nature
- Published
- 2009-04-29
- Volume
- 459
- Issue
- 7245
- Pages
- 387-392
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4721521
- OpenAlex
- W2153463588
- Semantic Scholar
- 8f177942cd47788e8c1133693d2d6af57a89ca88
- Cited by
- 474
- References
- 39
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 28 · 2021: 28 · 2020: 23 · 2019: 18 · 2018: 21 · 2017: 33 · 2016: 33 · 2015: 33 · 2014: 27 · 2013: 41 · 2012: 47
- FWCI
- 19.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute on Aging (R00AG032356)
- National Heart, Lung, and Blood Institute (Z01HL005012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- BMI1, mitochondrial function, DNA damage response, reactive oxygen species, redox homeostasis, Chk2, INK4a/ARF locus, CDKN2A, N-acetylcysteine, stem cell self-renewal, T cell development, lifespan, cellular metabolism, hematopoietic stem cells, neural stem cells
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, DNA Damage, Female, Male, Mitochondria, Nuclear Proteins, Oxidation-Reduction, Proto-Oncogene Proteins, Repressor Proteins, Stem Cells, Thymus Gland, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Polycomb Repressive Complex 1, Checkpoint Kinase 2
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