Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

• 成果类型: Article
• 署名作者: Kang, Yilin; Hepojoki, Jussi; Maldonado, Rocio Sartori; Mito, Takayuki; Terzioglu, Muegen; Manninen, Tuula; Kant, Ravi; Singh, Sachin; Othman, Alaa; Verma, Rohit; Uusimaa, Johanna; Wartiovaara, Kirmo; Kareinen, Lauri; Zamboni, Nicola; Nyman, Tuula Anneli; Paetau, Anders; Kipar, Anja; Vapalahti, Olli; Suomalainen, Anu
• 署名单位: University of Helsinki; University of Helsinki; University of Zurich; University of Helsinki; Fahrenheit Universities; Medical University Gdansk; University of Oslo; University of Oslo; National Hospital Norway; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Oulu; University of Oulu; University of Helsinki; Helsinki University Central Hospital; Finnish Food Authority; University of Helsinki; University of Helsinki
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5598
• DOI: 10.1038/s41586-024-07260-z
• 发表日期: 2024-04-25
• 关键词: cryo-em; citrate synthase; phylogenetic analysis; sierpinski triangles; algorithms; symmetry; muscle; forms

摘要

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 symptoms 5 , 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-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals 6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism. The POLG1 mutation p.W748S, which is associated with mitochondrial recessive ataxia syndrome, dampens innate immune responses by compromising mtDNA replisome stability, and this explains why a viral infection can trigger the development of the disease and contribute to its variable clinical manifestation.