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The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR

机译：代谢产物α-酮戊二酸通过抑制ATP合酶和TOR延长寿命

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摘要

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that a-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex Ⅴ of the mito-chondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
机译：代谢和衰老有着密切的联系。与随意喂养相比，饮食限制在不断进化的生物体中持续延长寿命并延缓与年龄有关的疾病。营养物限制的相似条件以及营养物或能量代谢的遗传或药理扰动也具有长寿益处。最近，已鉴定出几种调节衰老的代谢物。然而，其背后的分子机制在很大程度上尚不清楚。在这里，我们显示α-酮戊二酸（α-KG），一种三羧酸循环中间体，延长了成年秀丽隐杆线虫的寿命。使用称为药物亲和力响应靶标稳定性（DARTS）的小分子靶标鉴定策略，将ATP合酶亚基β鉴定为α-KG的新型结合蛋白。 ATP合酶，也称为线粒体电子传输链的复合物Ⅴ，是主要的细胞能量生成机制，在整个进化过程中高度保守。尽管线粒体功能的完全丧失是有害的，但已显示电子传输链的部分抑制可延长秀丽隐杆线虫的寿命。我们表明，α-KG抑制ATP合酶，类似于ATP合酶敲低，α-KG的抑制作用导致秀丽隐杆线虫和哺乳动物细胞中ATP含量降低，耗氧量降低和自噬增加。我们提供的证据表明，α-KG的寿命增加需要ATP合酶亚基β，并且依赖于下游雷帕霉素（TOR）的靶标。饥饿时内源性α-KG水平升高，α-KG不会延长饮食限制动物的寿命，这表明α-KG是通过饮食限制介导寿命的关键代谢产物。我们的分析揭示了常见代谢物，通用细胞能量生成器和饮食限制生物体寿命之间的新分子联系，从而为预防和治疗衰老及与年龄有关的疾病提出了新的策略。

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  • 来源
    《Nature》 |2014年第7505期|397-401|共5页
  • 作者

    Randall M. Chin; Xudong Fu; Melody Y. Pai; Laurent Vergnes; Heejun Hwang; Gang Deng; Simon Diep; Brett Lomenick; Vijaykumar S. Meli; Gabriela C. Monsalve; Eileen Hu; Stephen A. Whelan; Jennifer X. Wang; Gwanghyun Jung; Gregory M. Soils; Farbod Fazlollahi; Chitrada Kaweeteerawat; Austin Quach; Mahta Nili; Abby S. Krall; Hilary A. Godwin; Helena R. Chang; Kym F. Faull; Feng Guo; Meisheng Jiang; Sunia A. Trauger; Alan Saghatelian; Daniel Braas; Heather R. Christofk; Catherine F. Clarke; Michael A. Teitell; Michael Petrascheck; Karen Reue; Michael E. Jung; Alison R. Frand; Jing Huang; 35;

  • 作者单位

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA;

    Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;

    Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA;

    Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

    Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA;

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA,UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA,UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA,Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA,Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA,Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA,Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA;

    Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA,Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA;

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