Open AccessA metabolic signature for long life in the C aenorhabditis elegans M it mutants
Author(s) -
Butler Jeffrey A.,
Mishur Robert J.,
Bhaskaran Shylesh,
Rea Shane L.
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12029
Subject(s) - caenorhabditis elegans , mutant , biology , rna interference , phenotype , mitochondrion , protein subunit , gene , microbiology and biotechnology , genetics , wild type , biochemistry , rna
Summary Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong C aenorhabditis 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 M it 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 A lzheimer's disease. When the expression of DLD in wild‐type animals was reduced using RNA interference we observed an unprecedented effect on lifespan – as RNA i 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 M it phenotype.