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Telomere dysfunction induces metabolic and mitochondrial compromise. Nature

Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 02/2011; 470(7334):359-65. DOI: 10.1038/nature09787
Source: PubMed

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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    • "If telomeres become critically short, normal cells commonly enter a senescent state, marked by overproduction and release of pro-inflammatory cytokines (Blackburn, 2010). Telomeres are not solely biomarkers of disease, as experiments in rodents implicate telomere shortening and lower telomerase activity as causes of mitochondrial damage, increased oxidative stress, and damage to tissues (Jaskelioff et al., 2011; Perez-Rivero et al., 2006; Sahin et al., 2011). "
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