@article{6ef1bdfcdfc141cc9e9f7817db0a2b3f,
title = "Telomere dysfunction induces metabolic and mitochondrial compromise",
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.",
author = "Erg{\"u}n Sahin and Simona Colla and Marc Liesa and Javid Moslehi and M{\"u}ller, {Florian L.} and Mira Guo and Marcus Cooper and Darrell Kotton and Fabian, {Attila J.} and Carl Walkey and Maser, {Richard S.} and Giovanni Tonon and Friedrich Foerster and Robert Xiong and Wang, {Y. Alan} and Shukla, {Sachet A.} and Mariela Jaskelioff and Martin, {Eric S.} and Heffernan, {Timothy P.} and Alexei Protopopov and Elena Ivanova and Mahoney, {John E.} and Maria Kost-Alimova and Perry, {Samuel R.} and Roderick Bronson and Ronglih Liao and Richard Mulligan and Shirihai, {Orian S.} and Lynda Chin and DePinho, {Ronald A.}",
note = "Funding Information: 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-1a 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 Fundaci{\'o}n Ram{\'o}n Areces.",
year = "2011",
month = feb,
day = "17",
doi = "10.1038/nature09787",
language = "English",
volume = "470",
pages = "359--365",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7334",
}