A new study has identified a mechanism by which imbalanced nucleotide metabolism can drive inflammation through mitochondrial DNA (mtDNA) instability. The findings add to growing evidence that disruptions in cellular nucleotide pools influence immune signaling and age-associated pathology.
Researchers investigated how nucleotide deficiency contributes to inflammation by examining mtDNA integrity under conditions of metabolic imbalance. They found that when ribonucleotides are mistakenly incorporated into mtDNA, the altered DNA becomes more prone to instability and release into the cytosol. Once in the cytosol, mtDNA activates the cGAS-STING signaling pathway, a well-known mediator of innate immune responses.
The study used multiple experimental models. In mice lacking the mitochondrial exonuclease MGME1, age-related renal inflammation was associated with elevated ribonucleotide incorporation into mtDNA. Similar patterns were observed in various tissues of aged mice and in cells deficient in the mitochondrial protease YME1L. These findings suggest that defective mitochondrial quality control contributes to accumulation of ribonucleotides in mtDNA across different biological contexts.
The authors also examined cellular senescence, a state characterized by permanent cell-cycle arrest and secretion of inflammatory mediators. Reduced deoxyribonucleotide synthesis in senescent cells increased the ribonucleotide content of mtDNA. This, in turn, promoted mtDNA leakage, cGAS-STING activation, and the senescence-associated secretory phenotype (SASP). Notably, supplementation with deoxyribonucleosides suppressed this inflammatory cascade, pointing to a possible metabolic strategy for modulating SASP-related processes.
The results highlight the vulnerability of mtDNA to nucleotide imbalance and its central role in linking metabolic dysregulation with inflammation. For pathology and laboratory medicine, these findings underscore the importance of mitochondrial integrity as both a marker and a driver of disease processes associated with aging and chronic inflammation.
While the study was performed primarily in mouse models and cultured cells, it provides a mechanistic framework for understanding how ribonucleotide incorporation contributes to mtDNA instability and inflammatory signaling. Future research may clarify whether similar processes are active in human tissues and whether interventions targeting nucleotide metabolism could have clinical relevance.
Newsletters
Receive the latest pathologist news, personalities, education, and career development – weekly to your inbox.
