Mitochondrial metabolites extend lifespan

Robert J. Mishur, Maruf Khan, Erin Munkácsy, Lokendra Sharma, Alex Bokov, Haley Beam, Oxana Radetskaya, Megan Borror, Rebecca Lane, Yidong Bai, Shane L. Rea

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long-lived respiratory mutants generate elevated amounts of α-ketoacids. These compounds are structurally related to α-ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild-type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia-inducible factor-1 (HIF-1). We also find that an α-ketoglutarate mimetic, 2,4-pyridinedicarboxylic acid (2,4-PDA), is alone sufficient to increase the lifespan of wild-type worms and this effect is blocked by removal of HIF-1. HIF-1 is constitutively active in isp-1(qm150) Mit mutants, and accordingly, 2,4-PDA does not further increase their lifespan. Incubation of mouse 3T3-L1 fibroblasts with life-prolonging α-ketoacids also results in HIF-1α stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.

Original languageEnglish (US)
Pages (from-to)336-348
Number of pages13
JournalAging cell
Issue number2
StatePublished - Apr 1 2016


  • Aging
  • Caenorhabditis elegans
  • EGL-9/PHD
  • Glutaric acidemia
  • Hypoxia-inducible factor isp-1
  • Hypoxia-inducible factor-1
  • Jumonji domain-containing
  • Metabolism
  • Mit mutants
  • Mitochondria
  • α-ketoglutarate-dependent hydroxylases

ASJC Scopus subject areas

  • Aging
  • Cell Biology


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