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

Area of Science:

• Mitochondrial biology
• Metabolic disorders
• Aging research

Background:

• Mitochondrial dysfunction is implicated in metabolic and chronic diseases.
• Insulin/IGF-1 signaling (IIS) inhibition shows therapeutic potential for mitochondrial disorders, but mechanisms are unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which IIS inhibition benefits mitochondrial disease models.
• To identify metabolic adaptations and therapeutic targets associated with IIS inhibition in mitochondrial mutants.

Main Methods:

• Utilized an unbiased multi-omics approach in *Caenorhabditis elegans* with mitochondrial deficiency.
• Analyzed protein synthesis, catabolism, phosphoproteome, and metabolic outputs.
• Assessed the impact of xanthine derivative supplementation on nematode fitness and survival.

Main Results:

• IIS inhibition reduced protein synthesis and promoted catabolism, leading to lifespan extension independent of mitochondrial respiration restoration.
• Identified an ATP-saving metabolic rewiring linked to a conserved phosphoproteome.
• Discovered xanthine accumulation as a key metabolic output of IIS inhibition.
• Supplementation with FDA-approved xanthine derivatives improved fitness and survival in mitochondrial mutant nematodes.

Conclusions:

• IIS inhibition extends lifespan in mitochondrial mutants through metabolic rewiring, not direct mitochondrial respiration improvement.
• Xanthine accumulation is a crucial downstream mediator of IIS inhibition's benefits.
• Xanthine derivatives represent a potential therapeutic strategy for mitochondrial diseases.