• A Corrigendum to this article was published on 22 June 2011

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Understanding the odd science of aging. Cell 120, 437–447 (2005)

  2. 2.

    A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005)

  3. 3.

    , & Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005)

  4. 4.

    Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132, 171–176 (2008)

  5. 5.

    , & Mitochondrial dysfunction and age. Curr. Opin. Clin. Nutr. Metab. Care 10, 688–692 (2007)

  6. 6.

    et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004)

  7. 7.

    & The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Ageing Res. Rev. 8, 173–188 (2009)

  8. 8.

    , & PGC-1α and myokines in the aging muscle—a mini-review. Gerontology 57, 37–43 (2011)

  9. 9.

    , & Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005)

  10. 10.

    & Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010)

  11. 11.

    & Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002)

  12. 12.

    et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990)

  13. 13.

    et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998)

  14. 14.

    et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997)

  15. 15.

    et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999)

  16. 16.

    et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003)

  17. 17.

    et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004)

  18. 18.

    et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002)

  19. 19.

    et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461, 230–235 (2009)

  20. 20.

    et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005)

  21. 21.

    , , & Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 66, 4766–4773 (2006)

  22. 22.

    , & Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice. Proc. Natl Acad. Sci. USA 101, 6080–6085 (2004)

  23. 23.

    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)

  24. 24.

    et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001)

  25. 25.

    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)

  26. 26.

    et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003)

  27. 27.

    et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genet. 41, 101–105 (2008)

  28. 28.

    , & Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes Dev. 22, 463–475 (2008)

  29. 29.

    et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009)

  30. 30.

    et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 47, 29–41 (2005)

  31. 31.

    et al. Attenuation of doxorubicin-induced cardiomyopathy by endothelin-converting enzyme-1 ablation through prevention of mitochondrial biogenesis impairment. Hypertension 55, 738–746 (2010)

  32. 32.

    et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006)

  33. 33.

    et al. Rise in insulin resistance is associated with escalated telomere attrition. Circulation 111, 2171–2177 (2005)

  34. 34.

    & Telomere length in atherosclerosis and diabetes. Atherosclerosis 209, 35–38 (2010)

  35. 35.

    et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999)

  36. 36.

    et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007)

  37. 37.

    , , & Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell 1, 40–46 (2002)

  38. 38.

    & Mitochondria, telomeres and cell senescence. Exp. Gerontol. 40, 466–472 (2005)

  39. 39.

    , , & Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell 137, 1247–1258 (2009)

  40. 40.

    et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006)

  41. 41.

    et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005)

  42. 42.

    et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005)

  43. 43.

    et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA 100, 10794–10799 (2003)

  44. 44.

    et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 63, 5021–5027 (2003)

  45. 45.

    et al. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood 111, 3236–3244 (2008)

Download references

Acknowledgements

We thank C. Bianchi, J. Moriarty, K. Marmon and E. Thompson for excellent mouse husbandry and care. We are grateful to B. Spiegelman, P. Puigserver, J. E. Dominy and J. L. Estall for providing Ad-PGC-1α and Ad-GFP virus and helpful comments on the manuscript. We thank G. I. Evan for the p53–ER construct. We appreciate input, critical comments and helpful discussions from many DePinho/Chin lab members, in particular A.-J. Chen, C. Khoo, R. Carrasco, A. Kimmelman, S. Quayle, D. Liu and R. Wiedemeyer. We acknowledge the services of the Mouse Metabolism Cores at Yale (NIH/NIDDK U24 DK-59635) and at Baylor College of Medicine (BCM) and the BCM Diabetes & Endocrinology Research Center (DERC) grant (P30 DK079638). E.S. was supported by the Deutsche Forschungsgemeinschaft and this work and R.A.D. are supported by R01 and U01 grants from the NIH National Cancer Institute and the Robert A. and Renee E. Belfer Foundation. R.A.D. was supported by an Ellison Foundation for Medical Research Senior Scholar and an American Cancer Society Research Professor award. M.L. is a recipient of a postdoctoral fellowship from Fundación Ramón Areces.

Author information

Author notes

    • Simona Colla
    •  & Marc Liesa

    These authors contributed equally to this work.

Affiliations

  1. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Ergün Sahin
    • , Simona Colla
    • , Florian L. Müller
    • , Richard S. Maser
    • , Giovanni Tonon
    • , Friedrich Foerster
    • , Robert Xiong
    • , Y. Alan Wang
    • , Sachet A. Shukla
    • , Mariela Jaskelioff
    • , Eric S. Martin
    • , Timothy P. Heffernan
    • , Alexei Protopopov
    • , Elena Ivanova
    • , John E. Mahoney
    • , Maria Kost-Alimova
    • , Samuel R. Perry
    • , Lynda Chin
    •  & Ronald A. DePinho
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Ergün Sahin
    • , Simona Colla
    • , Javid Moslehi
    • , Florian L. Müller
    • , Richard S. Maser
    • , Giovanni Tonon
    • , Friedrich Foerster
    • , Mariela Jaskelioff
    • , Eric S. Martin
    • , Lynda Chin
    •  & Ronald A. DePinho
  3. Department of Medicine, Boston University School of Medicine, Massachusetts 02118, USA

    • Marc Liesa
    • , Darrell Kotton
    •  & Orian S. Shirihai
  4. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Javid Moslehi
    • , Ronglih Liao
    •  & Ronald A. DePinho
  5. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA

    • Mira Guo
  6. Division of Cardiovascular Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA

    • Marcus Cooper
  7. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Attila J. Fabian
    • , Richard Mulligan
    •  & Ronald A. DePinho
  8. St Vincent’s Institute and Department of Medicine, St Vincent’s Hospital, University of Melbourne, Victoria 3065, Australia

    • Carl Walkey
  9. Rodent Histopathology Laboratory, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Roderick Bronson

Authors

  1. Search for Ergün Sahin in:

  2. Search for Simona Colla in:

  3. Search for Marc Liesa in:

  4. Search for Javid Moslehi in:

  5. Search for Florian L. Müller in:

  6. Search for Mira Guo in:

  7. Search for Marcus Cooper in:

  8. Search for Darrell Kotton in:

  9. Search for Attila J. Fabian in:

  10. Search for Carl Walkey in:

  11. Search for Richard S. Maser in:

  12. Search for Giovanni Tonon in:

  13. Search for Friedrich Foerster in:

  14. Search for Robert Xiong in:

  15. Search for Y. Alan Wang in:

  16. Search for Sachet A. Shukla in:

  17. Search for Mariela Jaskelioff in:

  18. Search for Eric S. Martin in:

  19. Search for Timothy P. Heffernan in:

  20. Search for Alexei Protopopov in:

  21. Search for Elena Ivanova in:

  22. Search for John E. Mahoney in:

  23. Search for Maria Kost-Alimova in:

  24. Search for Samuel R. Perry in:

  25. Search for Roderick Bronson in:

  26. Search for Ronglih Liao in:

  27. Search for Richard Mulligan in:

  28. Search for Orian S. Shirihai in:

  29. Search for Lynda Chin in:

  30. Search for Ronald A. DePinho in:

Contributions

E.S. performed all experiments and contributed to echocardiographies (J.M., R.L.), mitochondrial respiration studies (M.L., O.S.S., F.L.M., M.C.). S.C. was involved in microarray analysis and most of other experiments. G.T., R.X. and S.A.S. contributed to microarray analysis. D.K., A.J.F., C.W., M.J. and R.M. advised and helped with transplantation experiments. A.P., E.I., J.E.M., M.K.-A., S.R.P. helped with immunohistochemistry and peptide-nuclei-acid-probes-based fluorescence in-situ hybridization (PNA-FISH) studies, R.S.M. and F.F. provided MEFs and helped with MEF studies. R.B. assessed histological slides. E.S.M., T.P.H. and M.G. helped with ChIP experiments. M.G. helped with qPCR experiments. L.C. supervised bioinformatic analysis. L.C. and Y.A.W. helped with writing and contributed intellectually. E.S. and R.A.D. conceived the ideas, designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ronald A. DePinho.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Figures 1-11 with legends, Supplementary Materials and Methods, additional references and Supplementary Tables 1-6.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature09787

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.