CoChat
Sign Up
Cited by 1,319Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsMitochondrial Function and Pathology

Telomere dysfunction induces metabolic and mitochondrial compromise

Open access
Sahin, Ergün, Colla, Simona, Liesa, Marc, Moslehi, Javid, Müller, Florian L., Guo, Mira, Cooper, Marcus, Kotton, Darrell +22 more·2011·Nature
DOI 10.1038/nature09787PMC PMC3741661
Open this paper in CoChat — free account

Abstract

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

AI snapshot

Written from the paper’s full text.

TL;DR

Telomere dysfunction in mice represses PGC-1α and PGC-1β through p53, impairing mitochondrial function and metabolism. This telomere–p53–PGC pathway links telomere attrition to cardiomyopathy, defective gluconeogenesis, and stem cell decline.

Key findings

  • Transcriptomic profiling of haematopoietic stem cells, heart, and liver from G4 Tert−/− mice showed broad repression of the PGC-1α/β network, including oxidative phosphorylation, oxidative defence, gluconeogenesis, fatty acid/cholesterol synthesis, and β-oxidation genes; RT–qPCR and western blot confirmed lower PGC-1α/β and targets such as NRF-1, ERRα, PPARα, and TFAM.
  • Mitochondrial consequences included reduced mitochondrial DNA content and density, lower complex I and IV activity, decreased state III respiration, reduced uncoupled respiration in G4 liver and heart (31% and 25%, respectively), lower ATP synthesis/content, and increased ROS/H2O2 production.
  • G4 mice developed dilated cardiomyopathy by 15 months, showed a 30% drop in plasma glucose after 12 h fasting, and had impaired HSC reconstitution; adenoviral Tert partially restored PGC targets and raised glucose by 30% in vivo and 80% in cultured G4 hepatocytes, while adenoviral PGC-1α increased state III and IV respiration in G4 liver mitochondria by 3.1-fold and 3.2-fold.
  • p53 deficiency restored PGC expression and mitochondrial DNA copy number; p53–ER activation repressed PGCs and reduced mitochondrial mass by 10–15%; p53 bound PGC-1α/β promoters and repressed reporters fivefold; p53 loss improved fractional shortening by 30% in a doxorubicin cardiomyopathy protocol.

Methods

  • Used Tert−/− mice across WT, G1, and G4 generations, Terc−/− G2 mice, and p53−/− backgrounds; profiled HSCs, liver, and heart by microarray with SAM or fold-change analysis and Ingenuity pathway analysis, followed by RT–qPCR and western blot.
  • Assessed mitochondrial and metabolic phenotypes via qPCR-based mtDNA quantification, HPLC ATP measurement, Seahorse XF24 and Clark electrode respiration, ROS and carbonylated protein assays, fasting glucose, hepatocyte gluconeogenesis, echocardiography, and competitive transplantation.
  • Mechanistic tests included adenoviral Tert or PGC-1α delivery, p53–ER MEF activation, PGC promoter luciferase reporters, anti-p53 chromatin immunoprecipitation, and doxorubicin-induced cardiomyopathy.

Limitations

  • No dedicated limitations section is present; the authors state that the relative contributions of DNA damage checkpoints versus metabolic/mitochondrial dysfunction require further study, and that p53-mediated PGC repression is context-dependent.
  • Evidence comes from mouse genetic models and cell systems, with no human data; germline p53 deletion and adenoviral overexpression may introduce pleiotropic or context-specific effects.
  • The ROS scavenger N-acetylcysteine did not rescue defective HSC repopulation, indicating increased ROS is not central to HSC failure, although its role in other phenotypes is not fully resolved.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature09787

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 21 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Total ATP content is decreased in G4 hearts and livers.

    “This impaired mitochondrial ATP synthesis is associated with decreased total ATP content in G4 hearts and livers (Fig. 2d).”
    Quote in the paperSubstantial claim
  • Findingown data

    The effect of Ad-PGC-1α on gluconeogenesis is markedly more pronounced in G4 mice than in WT mice or hepatocytes.

    “This Ad-PGC-1α impact was markedly more pronounced in G4 mice than in WT mice or hepatocytes.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Ad-Tert increases glucose output by 80% relative to Ad-GFP controls in cultured G4 hepatocytes.

    “cultured G4 hepatocytes which show an 80% increase in glucose output relative to Ad-GFP controls”
    Quote in the paperSubstantial claim
  • Findingown data

    Respiration uncoupled from ATP synthesis by DNP is reduced in G4 liver and heart mitochondria by 31% and 25%, respectively.

    “respiration uncoupled from ATP synthesis (induced by 2,4-dinitrophenol, DNP) was also reduced in G4 liver and heart mitochondria (31% and 25%, respectively)”
    Quote in the paperSubstantial claim
  • Findingown data

    Complex I and complex IV activity is markedly reduced in G1 and G4 heart and liver when measured in whole tissue lysates or isolated mitochondria.

    “Functionally, telomere dysfunction correlated with a marked decline in complex I and IV activity when assayed with either whole tissue lysates or isolated mitochondria from G1 and G4 heart and liver tissues”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingown data

    G4 mice cannot maintain plasma glucose during fasting, with a marked 30% drop at 12 h, but maintain normal plasma glucose when fed.

    “G4 mice also exhibited an inability to maintain plasma glucose levels under fasting conditions, experiencing a marked 30% drop at 12 h of fasting, yet maintained normal plasma glucose levels under fed conditions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the Tert−/− mouse model, progressive telomere shortening is accompanied by increasing atrophy and functional decline in proliferative organs and by equally severe impairment in relatively quiescent organs such as liver and heart, which do not show substantial apoptosis.

    “In this model, progressive telomere shortening is associated with increasing atrophy and functional decline across proliferative organs (intestinal, haematopoietic) and equally profound impairment in relatively quiescent organs (liver and heart) that do not exhibit significant levels of apoptosis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    G2 Terc−/− liver and heart show reductions in PGC and its targets, mitochondrial DNA content, complex I and IV activity, and ATP levels.

    “as well as reductions in PGC and targets, mitochondrial DNA content, complex I and IV activity, and ATP levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    G4 Tert−/− mice show reduced body weight and a marked decrease in fat mass while lean mass is preserved, with no apparent differences in spontaneous activity or food intake.

    “Body composition analysis showed body weight reduction and striking decrease in fat mass with preserved lean mass, yet no differences in spontaneous activity or food intake were apparent”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ad-PGC-1α rescues gluconeogenesis in vivo and in vitro in G4 hepatocytes.

    “this PGC-mitochondrial link is supported by Ad-PGC-1α-induced rescue of gluconeogenesis in vivo and in vitro in G4 hepatocytes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    G4 Tert−/− mice develop age-progressive dilated cardiomyopathy with left ventricular wall thinning, increased left ventricular diameter, and reduced fractional shortening by 15 months of age.

    “G4 Tert−/− mice exhibited these classical signs of impaired PGC function, including an age-progressive dilated cardiomyopathy with left ventricular wall thinning, increased left ventricular diameter, and reduced fractional shortening by 15 months of age”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mitochondrial DNA content and mitochondrial density are reduced in G1 and G4 heart and liver.

    “We documented reduced mitochondrial DNA content (Fig. 2a) and reduced mitochondrial density in G1 and G4 heart and liver”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    G4 mice show increased ROS levels by FACS in HSCs and increased carbonylated proteins in liver homogenates.

    “which aligned with increased ROS levels by FACS in HSCs and increased carbonylated proteins in liver homogenates”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    WT MEFs or heart tissue from mice treated with doxorubicin show increased p53 levels after 24 h, coincident p53 binding to the PGC-1α promoter, and repression of PGC-1α levels.

    “WT MEF or heart tissues of mice treated with the DNA damage agent doxorubicin showed increased p53 levels after 24 h and coincident binding of p53 to PGC-1α promoter and repression of PGC-1α levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anti-p53 chromatin immunoprecipitation in G2 Terc−/− p53+/+ MEFs, but not p53−/− MEFs, shows physical binding of p53 to PGC-1α fragments containing binding elements at −564 and −954, but not −2317, and to PGC1β fragments containing binding elements at −1616 and −1030.

    “anti-p53 chromatin-immunoprecipitation assays in G2 Terc−/− p53+/+, but not G2 Terc−/− p53−/−, MEFs demonstrated physical binding between p53 and (1) PGC-1α fragments containing p53 binding elements at −564 and −954, but not −2317, and (2) PGC1β fragments containing p53 binding elements at −1616 and −1030”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After 48 h of OHT treatment, G2 Terc−/− p53−/− p53-ER MEFs show a 10-15% decrease in mitochondrial mass, whereas OHT-treated controls show no significant change.

    “after 48 h of OHT treatment, G2 Terc−/− p53−/− p53–ER MEFs showed a 10–15% decrease in mitochondrial mass compared with no significant change in the OHT-treated G2 Terc−/− p53−/− controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increasing p53 dosage in p53−/− or G2 p53−/− MEFs represses PGC-1α and PGC-1β levels and increases occupancy of p53 binding elements in their promoters.

    “Increasing dosage of p53 in either p53−/− or G2 p53−/− MEFs showed repressed PGC-1α and PGC-1β levels and increasing occupancy of p53 binding elements in PGC-1α and PGC-1β promoters”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Telomere-dysfunction-induced repression of the PGC network is associated with mitochondrial dysfunction, as shown by compromised OXPHOS and respiration, decreased ATP generation capacity, and increased oxidative stress.

    “Taken together, these collective data establish that telomere-dysfunction-induced repression of the PGC network is associated with mitochondrial dysfunction as evidenced by compromised OXPHOS and respiration, decreased ATP generation capacity, and increased oxidative stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Multiple levels of evidence establish that telomere dysfunction-induced p53 represses PGC-1α and PGC-1β, linking telomeres to mitochondrial biology, oxidative defence, and metabolism.

    “In summary, multiple levels of evidence establish telomere dysfunction-induced p53 represses PGC-1α and PGC-1β, thereby linking telomeres to mitochondrial biology, oxidative defence, and metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Telomere dysfunction activates p53, which binds and represses the PGC-1α and PGC-1β promoters, creating a direct link between telomere and mitochondrial biology.

    “We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Without telomerase, continued cell division leads to telomere shortening, loss of capping function, and p53 activation.

    “In the absence of telomerase, continued cell division results in telomere shortening, loss of ‘capping’ function, and p53 activation12-15.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [12] Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990) source

      Not checked in the free run.

    • cites [13] Lee, H.-W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998) source

      Not checked in the free run.

    • cites [14] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997) source

      Not checked in the free run.

    • cites [15] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

    “We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Telomere dysfunction-induced repression of the PGC network, with consequent mitochondriopathy and metabolic changes, together with telomere-induced apoptotic and proliferative checkpoints, contributes to functional multi-system decline in telomere dysfunction.

    “We propose that telomere dysfunction-induced repression of the PGC network and consequent mitochondriopathy and metabolic changes, along with telomere-induced apoptotic and proliferative checkpoints, contributes to functional multi-system decline in the setting of telomere dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    p53 deficiency attenuates degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes.

    “p53 deficiency markedly attenuates the degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes15-18.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [15] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999) source

      Not checked in the free run.

    • cites [16] Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003) source

      Not checked in the free run.

    • cites [17] Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004) source

      Not checked in the free run.

    • cites [18] Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PGC-1α and PGC-1β regulate mitochondrial biogenesis and metabolic processes such as gluconeogenesis, fatty acid metabolism, and β-oxidation, processes linked to insulin resistance and diabetes in ageing.

    “The relevance of PGCs to age-related pathologies may stem from their regulation of mitochondrial biogenesis and control of metabolic processes (gluconeogenesis, fatty acid metabolism and β-oxidation), processes that relate to increased insulin resistance and diabetes in the aged9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005) source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Impaired mitochondrial function is linked to defective HSC maintenance.

    “prompted by studies linking impaired mitochondrial function to defective HSC maintenance27-29”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Pannicke, U. et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genet. 41, 101–105 (2008) source

      Not checked in the free run.

    • cites [28] Sankaran, V. G., Orkin, S. H. & Walkley, C. R. Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes Dev. 22, 463–475 (2008) source

      Not checked in the free run.

    • cites [29] Liu, J. et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009) source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Telomere dysfunction activates p53-mediated growth arrest, senescence, and apoptosis, driving progressive atrophy and functional decline in high-turnover tissues.

    “Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Repression of PGC-1α or PGC-1β decreases mitochondrial biogenesis and function, causes cardiomyopathy, and impairs de novo glucose production.

    “Previous work has established that repression of either or both co-activators (PGC-1α or PGC-1β) decreases mitochondrial biogenesis and function, elicits cardiomyopathy and impairs de novo glucose production23-25.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Arany, Z. et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α. Proc. Natl Acad. Sci. USA 103, 10086–10091 (2006) source

      Not checked in the free run.

    • cites [24] Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001) source

      Not checked in the free run.

    • cites [25] Lai, L. et al. Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart. Genes Dev. 22, 1948–1961 (2008) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mitochondrial quantification by qPCR used two different primer sets, one for genomic loci and one for mitochondrial loci.

    “qPCR-based mitochondrial quantification was performed with two different primer sets for genomic and mitochondrial loci.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Chromatin immunoprecipitation used a p53-specific antibody and a control IgG.

    “For chromatin immunoprecipitation, we followed the EZ-Chip protocol (Promega) using p53 specific antibody and control IgG.”
    Quote in the paperNot a substantial claim
25 of 25

  • The paper relies on this without support.

    N-acetylcysteine given from birth effectively scavenges reactive oxygen species in the haematopoietic stem cell compartments of G1 and G4 mice.

    “G1 or G4 mice treated from birth with N-acetylcysteine, a ROS scavenger, did not rescue defective HSC repopulation in competitive transplantations”

  • The paper relies on this without support.

    The G2 Terc−/− mice used have a degree of telomere dysfunction comparable to that of G4 Tert−/− mice.

    “G2 Terc−/− liver and hearts (exhibiting comparable telomere dysfunction as G4 Tert−/− mice)”

  • The paper relies on this without support.

    The transcriptomic network analyses used in this study were unbiased.

    “These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta”

  • The paper relies on this without support.

    The p53 binding elements identified in the PGC-1α and PGC-1β promoters are the functional sites through which p53 represses these genes.

    “anti-p53 chromatin-immunoprecipitation assays in G2 Terc−/− p53+/+, but not G2 Terc−/− p53−/−, MEFs demonstrated physical binding between p53 and (1) PGC-1α fragments containing p53 binding elements at −564 and −954, but not −2317, and (2) PGC1β fragments containing p53 binding elements at −1616 and −1030”
4 of 4

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?

  • TERC−/− mice present altered mitochondrial functions, including increased production of reactive oxygen species from the electron transfer chain.

    “TERC−/− mice present altered mitochondrial functions, including increased production of reactive oxygen species (ROS) from the electron transfer chain (ETC) (Passos et al., 2010; Sahin et al., 2011).”

    From P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan (2016) · cites this paper as Sahin et al., 2011

    The section “Telomere dysfunction decreases mitochondrial mass and energy production” reports impaired mitochondrial function in G2 Terc−/− liver and heart. It reports increased complex I- and II-dependent H2O2 production in G4 mitochondria, which the paper identifies as a Tert−/− model; it does not establish that increase specifically in Terc−/− mice. Page numbers were not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Other mutations in ROS metabolism, such as SOD2 haploinsufficiency, do not cooperate with telomere dysfunction, and N-acetylcysteine treatment does not rescue progeric phenotypes of late-generation TERT-deficient mice.

    “However, other mutations in genes involved in ROS metabolism, such as SOD2 haploinsufficiency, do not cooperate with telomere dysfunction (Guachalla et al., 2009), and the treatment with N‐acetylcysteine does not rescue progeric phenotypes of late‐generation TERT‐deficient mice (Sahin et al., 2011).”

    From P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan (2016) · cites this paper as Sahin et al., 2011

    The section “Telomere dysfunction decreases mitochondrial mass and energy production” (page unavailable) reports that N-acetylcysteine treatment from birth did not rescue defective HSC repopulation in G4 Tert-deficient mice. That supports the cited claim for one phenotype, but the paper does not report a treatment test showing that it failed to rescue progeric phenotypes generally. The SOD2 clause is attributed to a different citation and is not judged here. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In mouse models of accelerated telomere shortening, critically short telomeres repress PGC1-α- and β-mediated mitochondrial biogenesis.

    “In mouse models of accelerated telomere shortening, critically short telomeres have been shown to repress PGC1‐α‐ and β‐mediated mitochondrial biogenesis (Sahin et al, 2011; Chang et al, 2016).”

    From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Sahin et al, 2011

  • Signaling downstream of short telomeres activates p53, which binds and represses PGC-1α and PGC-1β promoters, leading to mitochondrial dysfunction.

    “signaling downstream of short telomeres activates p53, which binds and represses PGC-1α and PGC-1β promoters leading to mitochondrial dysfunction (Sahin et al., 2011).”

    From Telomeres and cell senescence—size matters not (2017) · cites this paper as Sahin et al., 2011

  • Telomere dysfunction has been associated with changes in mitochondrial metabolism.

    “It is interesting that telomere dysfunction has been associated with changes in mitochondrial metabolism (93)”

    From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [93]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Müller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., Foerster, F., Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M., Martin, E. S., Heffernan, T. P., Protopopov, A., Ivanova, E., Mahoney, J. E., Kost-Alimova, M., Perry, S. R., Bronson, R., Liao, R., Mulligan, R., Shirihai, O. S., Chin, L., & DePinho, R. A.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Harvard University (US)
  • Boston University (US)
  • Brigham and Women's Hospital (US)
  • University of Massachusetts Chan Medical School (US)
  • The University of Melbourne (AU)
Corresponding author
DePinho, Ronald A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-02-09
Volume
470
Issue
7334
Pages
359-365
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09787
PMC
PMC3741661
OpenAlex
W2124098526
Semantic Scholar
14115a60df726b2a29c3a0b4d83e9f284c2371bb
Cited by
1,319
References
49
Citations by year
2026: 50 · 2025: 58 · 2024: 73 · 2023: 87 · 2022: 83 · 2021: 100 · 2020: 78 · 2019: 84 · 2018: 81 · 2017: 88 · 2016: 91 · 2015: 93 · 2014: 83 · 2013: 94 · 2012: 111
FWCI
76.58
Type
journal article
Language
en
Update notices
erratum (2011-06-22)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Funders
  • National Cancer Institute (R01CA084628)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK035914, R01DK089185, U24DK59635, P30DK046200, U24DK059635, R01DK063356, R01DK056690, P30DK079638)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
telomere dysfunction, p53, PGC-1α, PGC-1β, telomerase reverse transcriptase, telomerase RNA, mitochondrial biogenesis, mitochondrial dysfunction, gluconeogenesis, cardiomyopathy, reactive oxygen species, cellular senescence, hematopoietic stem cells, liver, heart, aging, transcriptional repression
MeSH terms
Adenosine Triphosphate, Aging, Animals, DNA, Mitochondrial, Doxorubicin, Gluconeogenesis, Hematopoietic Stem Cells, Liver, Mitochondria, Cardiomyopathies, Myocardium, RNA, Transcription Factors, Tumor Suppressor Protein p53, Telomere, Reactive Oxygen Species, Telomerase, Cell Proliferation, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review