Ribonucleotide misincorporation into mtDNA triggers inflammation and senescence

By Agewell Brief Editorial Desk · Published November 1, 2025 at 8:00 a.m. EDT

Original reporting: Ribonucleotide incorporation into mitochondrial DNA drives inflammation.

Nucleotide imbalance drives age-related inflammation by destabilizing mitochondrial DNA, activating cGAS-STING and SASP.

Three things to remember

Nucleotide imbalance increases ribonucleotide misincorporation into mtDNA.
This triggers mtDNA release, cGAS-STING activation, and SASP.
Adding deoxyribonucleosides suppresses the inflammatory response.

Source

This signal is based on Ribonucleotide incorporation into mitochondrial DNA drives inflammation. from PubMed. Read the original report for full context.

Health note: Mouse and cell models; human relevance not yet established.

Pioneer Lineage · Historical Precursors

Scientific Precursors & Foundational Discoveries

1974 Tomas Lindahl

Lindahl discovered that ribonucleotides are frequently incorporated into DNA during replication and that they are normally removed by DNA repair mechanisms. He showed that RNA residues in DNA are intrinsically unstable and that their presence can lead to strand breaks and mutagenesis. This finding directly anticipates the modern observation that ribonucleotide misincorporation into mtDNA is a key trigger for inflammation and senescence, highlighting the importance of ribonucleotide excision repair in maintaining genomic stability.

1970s David A. Clayton

Clayton characterized the unique structure and replication of mitochondrial DNA, including the displacement loop (D-loop) and the presence of RNA primers. He demonstrated that mitochondrial DNA replication involves RNA-DNA hybrid intermediates and that ribonucleotides are transiently incorporated. This work laid the foundation for understanding how imbalances in nucleotide pools can lead to aberrant ribonucleotide incorporation into mtDNA, which is now shown to drive cGAS-STING-mediated inflammation and SASP.

Three things to remember

Source

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