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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Available from: Giovanni Tonon, Aug 27, 2015
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    • "This has recently been elegantly shown for locus coeruleus (LC) neurons, also displaying a high vulnerability to degeneration in PD (Sanchez-Padilla et al., 2014). It is very likely that a similar mechanism is also present in SN DA neurons, thereby contributing to compromised mitochondrial and bioenergetic function (Kelly, 2011; Sahin et al., 2011; Exner et al., 2012), rendering them more vulnerable to PD-trigger factors and degeneration. "
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    ABSTRACT: Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L-type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.037 · 3.33 Impact Factor
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    • "This is further supported by clearly distinct mouse phenotypes associated with either telomerase deficiency or RAP1 deficiency. Telomerase-deficient mice show a dramatic reduction in lifespan, lower body weight, and decreased fat mass (Herrera et al., 1999; Lee et al., 1998; Sahin et al., 2011). In contrast, Rap1 knockout mice show an obese phenotype and no differences in survival curves as compared to wild-type controls. "
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    ABSTRACT: RAP1 is part of shelterin, the protective complex at telomeres. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the nontelomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knockout mouse. These mice show early onset of obesity, which is more severe in females than in males. Rap1-deficient mice show accumulation of abdominal fat, hepatic steatosis, and high-fasting plasma levels of insulin, glucose, cholesterol, and alanine aminotransferase. Gene expression analyses of liver and visceral white fat from Rap1-deficient mice before the onset of obesity show deregulation of metabolic programs, including fatty acid, glucose metabolism, and PPARα signaling. We identify Pparα and Pgc1α as key factors affected by Rap1 deletion in the liver. We show that RAP1 binds to Pparα and Pgc1α loci and modulates their transcription. These findings reveal a role for a telomere-binding protein in the regulation of metabolism.
    Cell Reports 06/2013; 3(6). DOI:10.1016/j.celrep.2013.05.030 · 8.36 Impact Factor
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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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