A metabolic signature for long life in the Caenorhabditis elegans Mit mutants

Jeffrey A. Butler, Robert J. Mishur, Shylesh Bhaskaran, Shane L. Rea

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants. We show that accumulation of these compounds is dependent on concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild-type animals was reduced using RNA interference we observed an unprecedented effect on lifespan - as RNAi dosage was increased lifespan was significantly shortened, but, at higher doses, it was significantly lengthened, suggesting that DLD plays a unique role in modulating length of life. Our findings provide novel insight into the origin of the Mit phenotype.

Original languageEnglish (US)
Pages (from-to)130-138
Number of pages9
JournalAging cell
Volume12
Issue number1
DOIs
StatePublished - Feb 2013

Keywords

  • Branched-chain α-keto acids
  • clk-1
  • isp-1
  • mev-1
  • nuo-6
  • tpk-1
  • ucr-2.3

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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    Butler, J. A., Mishur, R. J., Bhaskaran, S., & Rea, S. L. (2013). A metabolic signature for long life in the Caenorhabditis elegans Mit mutants. Aging cell, 12(1), 130-138. https://doi.org/10.1111/acel.12029