Telomere dysfunction induces metabolic and mitochondrial compromise

By Ergun Sahin, S. Colla, M. Liesa, J. Moslehi, Florian L. Müller, Mira T Guo, M. Cooper, Darrell N. Kotton, A. Fabian, C. Walkey and 20 more. Nature, 2011

1,328 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/14115a60df726b2a29c3a0b4d83e9f284c2371bb

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Citations in the corpus

Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, positive): “Although little is known about the role of the PGC-1s in melanoma, they have recently been implicated in metabolic shifts in breast cancer cells and colon cancers (Eichner et al., 2010; Bhalla et al., 2011; Sahin et al., 2011; Wang and Moraes, 2011; Girnun, 2012; Klimcakova et al., 2012).”
Causes, consequences, and reversal of immune system aging. (2013, neutral): “It is interesting that telomere dysfunction has been associated with changes in mitochondrial metabolism (93), in view of a study linking compromised mitochondrial function and depressed thymopoiesis (94).”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “Genetic disorders with impairedmitochondrial function are characterized by a rapid onset of symptoms commonly seen in the elderly, such as type II diabetes, muscle loss, and neurodegeneration (Finsterer, 2004; Sahin et al., 2011; Wallace, 2010).”
The Mitochondrial Basis of Aging (2016, background): “PGC-1a, in turn, regulates the activity of several transcription factors involved in creating new mitochondria, including nuclear respiratory factors NRF1 and NRF2 and mitochondrial transcription factor A (TFAM) (Austin and St-Pierre, 2012).”
Metabolic Control of Longevity. (2016, background): “Telomere attrition also promotes p53 activation, hence causing the repression of Pgc1a and Pgc1b, the consequent suppression of the transcription factors nuclear respiratory factor 1 (Nrf1), estrogen-related receptor alpha (Esrra), and Ppara, and hence the inhibition of mitochondrial biogenesis and ”
PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress (2013, neutral): “Since p53 has been shown to negatively regulate PGC1a levels (Sahin et al., 2011; Sen et al., 2011), we searched if there was an association between p53 mutation status and PGC1a expression, but no correlation was found in 60 cell lines with expression andmutation status data.”
Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. (2013, background): “Various studies of HSCs defective in ATP generation indicate that LT-HSCs exhibit mitochondrial defects (Liu et al., 2009; Nakada et al., 2010; Gurumurthy et al., 2010; Gan et al., 2010; Sahin et al., 2011).”
Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “…regulators of mitochondrial physiology and metabolism (Gan et al., 2010), DePinho and his group demonstrated in an elegant study that telomere dysfunction is associated with impairedmitochondrial biogenesis and function, decreased gluconeogenesis, and increased ROS production (Sahin et al., 2011).”
Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury (2011, background): “Reactive oxygen and nitrogen species can attack DNA resulting in several alterations, including DNA breaks, base damage, destruction of sugars, crosslinks and telomere dysfunction [35; 36; 37].”