Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction

The EMBO Journal
Anna GioranDaniele Bano

Abstract

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.

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Methods Mentioned

BETA
fluorescence recovery after photobleaching
proteomic profiling
NMR
Assay
transgenic
RNA
electrophoresis

Software Mentioned

BLASTP
Ingenuity Pathway Analysis , IPA
Molecule Activity Predictor ( MAP )
GraphPad Prism
COPAS
Lifespan
R
Path Designer
STRING
Fiji

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