TY  - JOUR
AU  - Piazzesi, Antonia
AU  - Wang, Yiru
AU  - Jackson, Joshua
AU  - Wischhof, Lena
AU  - Zeisler-Diehl, Viktoria
AU  - Scifo, Enzo
AU  - Oganezova, Ina
AU  - Hoffmann, Nils Thorben
AU  - Gomez, Pablo
AU  - Bertan, Fabio
AU  - Wrobel, Chester J J
AU  - Schroeder, Frank C
AU  - Ehninger, Dan
AU  - Händler, Kristian
AU  - Schultze, Joachim L
AU  - Schreiber, Lukas
AU  - Echten-Deckert, Gerhild
AU  - Nicotera, Pierluigi
AU  - Bano, Daniele
TI  - CEST‐2.2 overexpression alters lipid metabolism and extends longevity of mitochondrial mutants
JO  - EMBO reports
VL  - 23
IS  - 5
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00524
SP  - e52606
PY  - 2022
AB  - 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.
KW  - Animals
KW  - Caenorhabditis elegans: metabolism
KW  - Caenorhabditis elegans Proteins: genetics
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Lipid Metabolism: genetics
KW  - Longevity: genetics
KW  - Mitochondria: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9066074
C6  - pmid:35297148
DO  - DOI:10.15252/embr.202152606
UR  - https://pub.dzne.de/record/163786
ER  -