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CEST‐2.2 overexpression alters lipid metabolism and extends longevity of mitochondrial mutants
Author(s) -
Piazzesi Antonia,
Wang Yiru,
Jackson Joshua,
Wischhof Lena,
ZeislerDiehl Viktoria,
Scifo Enzo,
Oganezova Ina,
Hoffmann Thorben,
Gómez Martín Pablo,
Bertan Fabio,
Wrobel Chester J J,
Schroeder Frank C,
Ehninger Dan,
Händler Kristian,
Schultze Joachim L,
Schreiber Lukas,
EchtenDeckert Gerhild,
Nicotera Pierluigi,
Bano Daniele
Publication year - 2022
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202152606
Subject(s) - caenorhabditis elegans , biology , mitochondrion , mutant , bioenergetics , phenotype , microbiology and biotechnology , lipidome , lipid metabolism , longevity , transcriptome , genetics , gene , gene expression , biochemistry
Mitochondrial dysfunction can either extend or decrease Caenorhabditis elegans lifespan, depending on whether transcriptionally regulated responses can elicit durable stress adaptation to otherwise detrimental lesions. Here, we test the hypothesis that enhanced metabolic flexibility is sufficient to circumvent bioenergetic abnormalities associated with the phenotypic threshold effect, thereby transforming short‐lived mitochondrial mutants into long‐lived ones. We find that CEST‐2.2, a carboxylesterase mainly localizes in the intestine, may stimulate the survival of mitochondrial deficient animals. We report that genetic manipulation of cest‐2.2 expression has a minor lifespan impact on wild‐type nematodes, whereas its overexpression markedly extends the lifespan of complex I‐deficient gas‐1(fc21) mutants. We profile the transcriptome and lipidome of cest‐2.2 overexpressing animals and show that CEST‐2.2 stimulates lipid metabolism and fatty acid beta‐oxidation, thereby enhancing mitochondrial respiratory capacity through complex II and LET‐721/ETFDH, despite the inherited genetic lesion of complex I. Together, our findings unveil a metabolic pathway that, through the tissue‐specific mobilization of lipid deposits, may influence the longevity of mitochondrial mutant C. elegans .