RRC ID 46277
Author Butler JA, Mishur RJ, Bhaskaran S, Rea SL.
Title A metabolic signature for long life in the Caenorhabditis elegans Mit mutants.
Journal Aging Cell
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.
Volume 12(1)
Pages 130-8
Published 2013-2-1
DOI 10.1111/acel.12029
PMID 23173729
PMC PMC3552119
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Dihydrolipoamide Dehydrogenase / genetics Dihydrolipoamide Dehydrogenase / metabolism Longevity / genetics Longevity / physiology* Mutation*
IF 7.238
Times Cited 40
C.elegans tm2258 tm2285