title: Telomere dysfunction induces metabolic and mitochondrial compromise.
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.
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ergün
authors.initials: E
authors.lastname: Sahin
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.forename: Florian L
authors.initials: FL
authors.lastname: Müller
authors.forename: Mira
authors.initials: M
authors.lastname: Guo
authors.forename: Marcus
authors.initials: M
authors.lastname: Cooper
authors.forename: Darrell
authors.initials: D
authors.lastname: Kotton
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Fabian
authors.forename: Carl
authors.initials: C
authors.lastname: Walkey
authors.forename: Richard S
authors.initials: RS
authors.lastname: Maser
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Friedrich
authors.initials: F
authors.lastname: Foerster
authors.forename: Robert
authors.initials: R
authors.lastname: Xiong
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.forename: Mariela
authors.initials: M
authors.lastname: Jaskelioff
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.forename: Elena
authors.initials: E
authors.lastname: Ivanova
authors.forename: John E
authors.initials: JE
authors.lastname: Mahoney
authors.forename: Maria
authors.initials: M
authors.lastname: Kost-Alimova
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Perry
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Richard
authors.initials: R
authors.lastname: Mulligan
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000032:analysis; D004317:Doxorubicin / Q000633:toxicity; D005943:Gluconeogenesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D012313:RNA / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency / Q000235:genetics; D016615:Telomere / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C422952:telomerase RNA; D012313:RNA; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D019098:Telomerase; C509187:Tert protein, mouse