TY  - JOUR
AU  - Gioran, Anna
AU  - Piazzesi, Antonia
AU  - Bertan, Fabio
AU  - Schroer, Jonas
AU  - Wischhof, Lena
AU  - Nicotera, Pierluigi
AU  - Bano, Daniele
TI  - Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.
JO  - The EMBO journal
VL  - 38
IS  - 6
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-06905
SP  - e99558
PY  - 2019
AB  - 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.
KW  - Adenosine Triphosphate: metabolism
KW  - Animals
KW  - Caenorhabditis elegans: drug effects
KW  - Caenorhabditis elegans: growth & development
KW  - Caenorhabditis elegans: metabolism
KW  - Caenorhabditis elegans Proteins: genetics
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Insulin: chemistry
KW  - Insulin-Like Growth Factor I: antagonists & inhibitors
KW  - Longevity
KW  - Metabolome
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mitochondria: pathology
KW  - Mitochondrial Diseases: metabolism
KW  - Mitochondrial Diseases: pathology
KW  - Mitochondrial Diseases: prevention & control
KW  - Proteome
KW  - Transcriptome
KW  - Xanthine: administration & dosage
KW  - Xanthine: metabolism
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
KW  - Insulin (NLM Chemicals)
KW  - Proteome (NLM Chemicals)
KW  - Xanthine (NLM Chemicals)
KW  - Insulin-Like Growth Factor I (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30796049
C2  - pmc:PMC6418696
DO  - DOI:10.15252/embj.201899558
UR  - https://pub.dzne.de/record/140583
ER  -