biostudies-literatureUnknown628(8009)Kang YMitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response^1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)⁵. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms⁵, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranNature844-853https://www.ebi.ac.uk/biostudies/studies/S-EPMC11041766biostudies-literatureAncestral allele of DNA polymerase gamma modifies antiviral tolerance.PMC11041766Verma RWartiovaara KHepojoki JMito TManninen TKant RUusimaa JNyman TASuomalainen AKang YOthman AZamboni NPaetau AMaldonado RSVapalahti OKareinen LSingh SKipar ATerzioglu MfalseAncestral allele of DNA polymerase gamma modifies antiviral tolerance.Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response^1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)⁵. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms⁵, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stran2024-01-01T00:00:00Z2024 Apr2026-06-01T21:48:16.115Z2025-04-06T03:16:42.319ZS-EPMC110417663857068510.1038/s41586-024-07260-z