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Telomere dysfunction induces metabolic and mitochondrial compromise

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.

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Figure 1: PGC-regulated genes and networks are repressed in telomere dysfunctional tissues
Figure 2: Telomere dysfunction is associated with reduced mitochondrial DNA content in HSC, liver and heart and impaired mitochondrial function
Figure 3: Telomere dysfunction induces cardiomyopathy, defective gluconeogenesis and reduced HSC reconstitution capacity.
Figure 4: p53 deficiency partially rescues the transcriptional regulation of PGC-1α/β and mitochondrial DNA copy number.
Figure 5: p53 deficiency rescues gluconeogenesis and doxorubicin-induced cardiomyopathy.

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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.

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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.

Corresponding author

Correspondence to Ronald A. DePinho.

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The authors declare no competing financial interests.

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Sahin, E., Colla, S., Liesa, M. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). https://doi.org/10.1038/nature09787

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