Telomere dysfunction induces metabolic and mitochondrial compromise

被引：1040

作者：

Sahin, Erguen ^{[1
,2
]}

Colla, Simona ^{[1
,2
]}

Liesa, Marc ^{[3
]}

Moslehi, Javid ^{[2
,4
]}

Mueller, Florian L. ^{[1
,2
]}

Guo, Mira ^{[5
]}

Cooper, Marcus ^{[6
]}

Kotton, Darrell ^{[3
]}

Fabian, Attila J. ^{[7
]}

Walkey, Carl ^{[8
,9
]}

Maser, Richard S. ^{[1
,2
]}

Tonon, Giovanni ^{[1
,2
]}

Foerster, Friedrich ^{[1
,2
]}

Xiong, Robert ^{[1
]}

Wang, Y. Alan ^{[1
]}

Shukla, Sachet A. ^{[1
]}

Jaskelioff, Mariela ^{[1
,2
]}

Martin, Eric S. ^{[1
,2
]}

Heffernan, Timothy P. ^{[1
]}

Protopopov, Alexei ^{[1
]}

Ivanova, Elena ^{[1
]}

Mahoney, John E. ^{[1
]}

Kost-Alimova, Maria ^{[1
]}

Perry, Samuel R. ^{[1
]}

Bronson, Roderick ^{[10
]}

Liao, Ronglih ^{[4
]}

Mulligan, Richard ^{[7
]}

Shirihai, Orian S. ^{[3
]}

Chin, Lynda ^{[1
,2
]}

DePinho, Ronald A. ^{[1
,2
,4
,7
]}

机构：

[1] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[5] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA

[6] Univ Massachusetts, Div Cardiovasc Med, Worcester, MA 01605 USA

[7] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[8] Univ Melbourne, St Vincents Hosp, St Vincents Inst, Victoria 3065, Australia

[9] Univ Melbourne, St Vincents Hosp, Dept Med, Victoria 3065, Australia

[10] Harvard Univ, Sch Med, Rodent Histopathol Lab, Boston, MA 02115 USA

来源：

NATURE | 2011年 / 470卷 / 7334期

关键词：

HEART-FAILURE; STEM-CELLS; DAMAGE; LEADS; PGC-1-ALPHA; MICE; COACTIVATORS; HOMEOSTASIS; BIOGENESIS; CARCINOMA;

D O I：

10.1038/nature09787

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1 alpha and PGC-1 beta, 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-1a 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-1 alpha and PGC-1 beta 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.

引用

页码：359 / 365

页数：7

共 45 条

[1] Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α [J].