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 ProtopopovElena Ivanova, John E. Mahoney, Maria Kost-Alimova, Samuel R. Perry, Roderick Bronson, Ronglih Liao, Richard Mulligan, Orian S. Shirihai, Lynda Chin, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)359-365
Number of pages7
JournalNature
Volume470
Issue number7334
DOIs
Publication statusPublished - Feb 17 2011

ASJC Scopus subject areas

  • General

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