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Nature ; 470(7334): 359-65, 2011 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-21307849

RESUMEN

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-1ß, 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-1ß 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.


Asunto(s)
Mitocondrias/metabolismo , Mitocondrias/patología , Telómero/metabolismo , Telómero/patología , Adenosina Trifosfato/biosíntesis , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Proliferación Celular , ADN Mitocondrial/análisis , Doxorrubicina/toxicidad , Gluconeogénesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Hígado/citología , Hígado/metabolismo , Ratones , Miocardio/citología , Miocardio/metabolismo , ARN/genética , Especies Reactivas de Oxígeno/metabolismo , Telomerasa/deficiencia , Telomerasa/genética , Telómero/enzimología , Telómero/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
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