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Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction
Author(s) -
Gioran Anna,
Piazzesi Antonia,
Bertan Fabio,
Schroer Jonas,
Wischhof Lena,
Nicotera Pierluigi,
Bano Daniele
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899558
Subject(s) - biology , metabolite , metabolomics , mitochondrion , xanthine , omics , computational biology , bioinformatics , genetics , biochemistry , enzyme
Aberrant mitochondrial function contributes to the pathogenesis of various metabolic and chronic disorders. Inhibition of insulin/ IGF ‐1 signaling ( IIS ) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Using an unbiased multi‐omics approach, we report here that IIS inhibition reduces protein synthesis and favors catabolism in mitochondrial deficient Caenorhabditis elegans . We unveil that the lifespan extension does not occur through the restoration of mitochondrial respiration, but as a consequence of an ATP ‐saving metabolic rewiring that is associated with an evolutionarily conserved phosphoproteome landscape. Furthermore, we identify xanthine accumulation as a prominent downstream metabolic output of IIS inhibition. We provide evidence that supplementation of FDA ‐approved xanthine derivatives is sufficient to promote fitness and survival of nematodes carrying mitochondrial lesions. Together, our data describe previously unknown molecular components of a metabolic network that can extend the lifespan of short‐lived mitochondrial mutant animals.