Ribonucleotide incorporation into mitochondrial DNA drives inflammation.

ABSTRACT: Metabolic dysregulation can lead to inflammatory responses^1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling³. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME1⁴, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads

SUBMITTER: Bahat A 

PROVIDER: S-EPMC12629987 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature