Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

Yilin Kang, Jussi Hepojoki, Rocio Sartori Maldonado, Takayuki Mito, Mügen Terzioglu, Tuula Manninen, Ravi Kant, Sachin Singh, Alaa Othman, Rohit Verma, Johanna Uusimaa, Kirmo Wartiovaara, Lauri Kareinen, Nicola Zamboni, Tuula Anneli Nyman, Anders Paetau, Anja Kipar, Olli Vapalahti and Anu Suomalainen ()
Additional contact information
Yilin Kang: University of Helsinki
Jussi Hepojoki: University of Helsinki
Rocio Sartori Maldonado: University of Helsinki
Takayuki Mito: University of Helsinki
Mügen Terzioglu: University of Helsinki
Tuula Manninen: University of Helsinki
Ravi Kant: University of Helsinki
Sachin Singh: University of Oslo and Rikshospitalet Oslo
Alaa Othman: ETH Zürich
Rohit Verma: University of Helsinki
Johanna Uusimaa: University of Oulu
Kirmo Wartiovaara: University of Helsinki
Lauri Kareinen: University of Helsinki
Nicola Zamboni: ETH Zürich
Tuula Anneli Nyman: University of Oslo and Rikshospitalet Oslo
Anders Paetau: University of Helsinki
Anja Kipar: University of Zürich
Olli Vapalahti: University of Helsinki
Anu Suomalainen: University of Helsinki

Nature, 2024, vol. 628, issue 8009, 844-853

Abstract: Abstract 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) response1–4. 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-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 individuals6 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.

Date: 2024
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DOI: 10.1038/s41586-024-07260-z

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