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

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.

Uric acid induces stress resistance and extends the life span through activating the stress response factor DAF-16/FOXO and SKN-1/NRF2

“…Consistent with previous studies, in the present study, we found that exogenously supplemented intermediates of purine metabolism, e.g., uric acid in food, significantly prolonged the life span of the nematodes. In support of our findings, other researchers have also found that supplementing the food of C. elegans with other purine metabolic intermediates, including allantoin [46] and xanthine [47], significantly extended the life span of worms. These results reveal that purine metabolic intermediates play an important role in the regulation of aging and that endogenous purine metabolites may be developed into potential strategies for the prevention and treatment of aging and age-related diseases.…”

Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators

“…Previous studies have identified that older subjects have higher glutamine compared to younger subjects (Kaiser et al, 2005), confirming our observation. The classifier also identified that elevated xanthine was associated with increased LTL, confirming a multi-omics study that showed xanthine as a pro-survival metabolite with aberrant mitochondrial function (Gioran et al, 2019). Similarly, our model also suggested that elevated beta-sitosterol is increased with longer LTL.…”

OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential

“…AMPK activation, glycolysis upregulation, and mitochondrial biogenesis have been documented in mouse and C . elegans OXPHOS disease models (Gioran et al, 2019; Haynes et al, 2007; Kuhl et al , 2017; Nargund et al, 2015; Viscomi et al, 2011; Wredenberg et al, 2002). Importantly, pharmacological activation of AMPK by AICAR partially corrects COX deficiency (Viscomi et al, 2011).…”