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

Academic Article
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Overview

related to degree

  • Solis, Gregory, Ph.D. in Chemical Biology, Scripps Research 2012 - 2018

authors

  • Chin, R. M.
  • Fu, X.
  • Pai, M. Y.
  • Vergnes, L.
  • Hwang, H.
  • Deng, G.
  • Diep, S.
  • Lomenick, B.
  • Meli, V. S.
  • Monsalve, G. C.
  • Hu, E.
  • Whelan, S. A.
  • Wang, J. X.
  • Jung, G.
  • Solis, Gregory
  • Fazlollahi, F.
  • Kaweeteerawat, C.
  • Quach, A.
  • Nili, M.
  • Krall, A. S.
  • Godwin, H. A.
  • Chang, H. R.
  • Faull, K. F.
  • Guo, F.
  • Jiang, M.
  • Trauger, S. A.
  • Saghatelian, Alan
  • Braas, D.
  • Christofk, H. R.
  • Clarke, C. F.
  • Teitell, M. A.
  • Petrascheck, Michael
  • Reue, K.
  • Jung, M. E.
  • Frand, A. R.
  • Huang, J.

publication date

  • June 2014

journal

  • Nature  Journal

abstract

  • 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 α-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 mitochondrial 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.

subject areas

  • Animals
  • Caenorhabditis elegans
  • Cell Line
  • Enzyme Activation
  • Enzyme Inhibitors
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Ketoglutaric Acids
  • Longevity
  • Mice
  • Mitochondrial Proton-Translocating ATPases
  • Protein Binding
  • TOR Serine-Threonine Kinases
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Identity

PubMed Central ID

  • PMC4263271

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature13264

PubMed ID

  • 24828042
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Additional Document Info

start page

  • 397

end page

  • 401

volume

  • 510

issue

  • 7505

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