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


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.

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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.


  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


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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.

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