Telomere dysfunction induces metabolic and mitochondrial compromise

Ergün Sahin, Simona Colla, Marc Liesa, Javid Moslehi, Florian L. Müller, Mira Guo, Marcus Cooper, Darrell Kotton, Attila J. Fabian, Carl Walkey, 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, Roderick Bronson, Ronglih Liao, Richard Mulligan, Orian S. Shirihai, Lynda Chin and Ronald A. DePinho ()
Additional contact information
Ergün Sahin: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Simona Colla: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Marc Liesa: Boston University School of Medicine
Javid Moslehi: Dana-Farber Cancer Institute, Harvard Medical School
Florian L. Müller: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Mira Guo: School of Engineering and Applied Sciences, Harvard University
Marcus Cooper: University of Massachusetts
Darrell Kotton: Boston University School of Medicine
Attila J. Fabian: Harvard Medical School
Carl Walkey: St Vincent’s Hospital, University of Melbourne
Richard S. Maser: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Giovanni Tonon: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Friedrich Foerster: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Robert Xiong: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Y. Alan Wang: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Sachet A. Shukla: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Mariela Jaskelioff: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Eric S. Martin: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Timothy P. Heffernan: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Alexei Protopopov: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Elena Ivanova: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
John E. Mahoney: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Maria Kost-Alimova: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Samuel R. Perry: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Roderick Bronson: Rodent Histopathology Laboratory, Harvard Medical School
Ronglih Liao: Brigham and Women's Hospital, Harvard Medical School
Richard Mulligan: Harvard Medical School
Orian S. Shirihai: Boston University School of Medicine
Lynda Chin: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Ronald A. DePinho: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute

Nature, 2011, vol. 470, issue 7334, 359-365

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09787

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