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Telomere dysfunction induces metabolic and mitochondrial compromise

机译：端粒功能障碍引起代谢和线粒体损害

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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-la and PGC-1β, also known as Ppargcla and Ppargclb, 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-la and PGC-lβ 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.
机译：端粒功能异常激活p53介导的细胞生长停滞，衰老和凋亡，从而驱动高周转组织的进行性萎缩和功能下降。端粒功能障碍在许多组织中的广泛不利影响，包括更多的静止系统，促使进行转录组网络分析，以鉴定在造血干细胞，心脏和肝脏中起作用的常见机制。这些无偏研究揭示了过氧化物酶体增殖物激活受体γ，共激活因子1α和β（分别为PGC-1a和PGC-1β，也分别称为Ppargcla和Ppargclb）的强烈抑制，以及小鼠端粒网络中端粒酶逆转录酶无效（ Tert）或端粒酶RNA成分（Terc）基因。与PGC作为线粒体生理和代谢的主要调节剂一致，端粒功能异常与线粒体生物发生和功能受损，糖异生减少，心肌病和活性氧增加有关。在端粒功能障碍的情况下，增强的Tert或PGC-1a表达或p53的种系缺失（也称为Trp53）可基本上恢复PGC网络表达，线粒体呼吸，心脏功能和糖异生。我们证明端粒功能障碍激活p53，其继而结合并抑制PGC-1a和PGC-1β启动子，从而在端粒和线粒体生物学之间建立直接联系。我们建议，端粒p53-PGC轴有助于器官和代谢衰竭，并减少端粒功能障碍情况下的机体适应性。

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  • 来源
    《Nature》 |2011年第7334期|p.359-365|共7页
  • 作者

    Erguen Sahin; Simona Colla; Marc Liesa; Javid Moslehi; Florian L. Mueller; Mira Guo; Marcus Cooper; Darrell Kotton; Attila J. Fabian; Carl Walkey; Richard S. Maser; Giovanni Tonon; Friedrich Foerster; Robert Xiong; Y. Alan Wang; Sachet A. Shukla; Mariela Jaskelioff; Eric S. Martin; Timothy P. Heffernan; Alexei Protopopov; Elena Ivanova; John E. Mahoney; Maria Kost-Alimova; Samuel R. Perry; Roderick Bronson; Ronglih Liao; Richard Mulligan; Orian S. Shirihai; Lynda Chin; Ronald A. DePinho;

  • 作者单位

    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnDepartment of Medicine, Boston University School of Medicine, Massachusetts 02118, USA;

    rnDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnSchool of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA;

    rnDivision of Cardiovascular Medicine, University of Massachusetts, Worcester, Massachusetts 01605, USA;

    rnDepartment of Medicine, Boston University School of Medicine, Massachusetts 02118, USA;

    rnDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnSt Vincent's Institute and Department of Medicine, St Vincent's Hospital, University of Melbourne, Victoria 3065, Australia.;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnRodent Histopathology Laboratory, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnDepartment of Medicine, Boston University School of Medicine, Massachusetts 02118, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;

    rnBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

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