Ribonucleotide incorporation into mitochondrial DNA drives inflammation
Metabolic dysregulation can lead to inflammatory responses<sup>1,2</sup>. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling<sup>3</sup>. 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 MGME1<sup>4</sup>, 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 to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
Authors
- Sadig Niftullayev
- Anders R. Clausen (ORCID: https://orcid.org/0000-0002-5069-0930)
- Thomas Langer (ORCID: https://orcid.org/0000-0003-1250-1462)
- Patrick Giavalisco (ORCID: https://orcid.org/0000-0002-4636-1827)
- Louise Jenninger
- Hendrik Nolte (ORCID: https://orcid.org/0000-0003-1560-5099)
- Athanasios Katsalifis (ORCID: https://orcid.org/0000-0003-3494-7617)
- Manuel Rogg (ORCID: https://orcid.org/0000-0002-6658-9159)
- Nils‐Göran Larsson (ORCID: https://orcid.org/0000-0001-5100-996X)
- Dusanka Milenkovic (ORCID: https://orcid.org/0000-0003-0151-8760)
- Erik Larsson (ORCID: https://orcid.org/0000-0003-1400-0119)
- Julien Prudent (ORCID: https://orcid.org/0000-0003-3821-6088)
- Micheal E. Barnett
- Thomas MacVicar (ORCID: https://orcid.org/0000-0001-9846-6359)
- Paul A. Kirschner (ORCID: https://orcid.org/0000-0002-8743-0462)
- Amir Bahat
- Christoph Schell (ORCID: https://orcid.org/0000-0001-5344-624X)
- Maria Falkenberg (ORCID: https://orcid.org/0000-0001-8713-173X)
- Isabella Muylaert
- Eileen Cors
- Vincent Paupe
- Marc Schwill (ORCID: https://orcid.org/0009-0006-6264-5375)
Institutions
- University of Freiburg (DE)
- University of Cologne (DE)
- University of Cambridge (GB)
- University Medical Center Freiburg (DE)
- Karolinska Institutet (SE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Max Planck Institute for Biology of Ageing (DE)
- MRC Mitochondrial Biology Unit (GB)
- University of Gothenburg (SE)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1038/s41586-025-09541-7
- Citations
- 12
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 9.57
Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Knut och Alice Wallenbergs Stiftelse
- Max-Planck-Gesellschaft
- Medical Research Council