Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity
DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in POLG, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POLγ variants. Our data reveal that these mutations significantly impair POLγ activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POLγ, particularly in the POLγB subunit, which may explain the higher activity of mouse POLγ and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of POLG mutations.
Authors
- Aleksandra Trifunović (ORCID: https://orcid.org/0000-0002-5472-3517)
- Sara Volta
- Claes M. Gustafsson (ORCID: https://orcid.org/0000-0003-3531-8468)
- Louise Jenninger
- Sirelin Sillamaa (ORCID: https://orcid.org/0000-0001-8077-9963)
- Michal A. Minczuk (ORCID: https://orcid.org/0000-0001-8242-1420)
- Massimo Zeviani (ORCID: https://orcid.org/0000-0002-9067-5508)
- Urška Rovšnik (ORCID: https://orcid.org/0000-0001-5889-6899)
- Bertil Macao (ORCID: https://orcid.org/0000-0001-6511-6125)
- Anu Suomalainen (ORCID: https://orcid.org/0000-0003-4833-5195)
- Raffaele Cerutti (ORCID: https://orcid.org/0009-0000-6939-8684)
- Sebastian Valenzuela (ORCID: https://orcid.org/0000-0001-5153-8431)
- Alessandro Zuppardo (ORCID: https://orcid.org/0000-0001-9601-3567)
- Maria Falkenberg (ORCID: https://orcid.org/0000-0001-8713-173X)
- Carlo Fiore Viscomi (ORCID: https://orcid.org/0000-0001-6050-0566)
- Pedro Silva-Pinheiro (ORCID: https://orcid.org/0000-0002-0872-5749)
- Xuefeng Zhu (ORCID: https://orcid.org/0000-0002-4759-4446)
- Samantha Corrà (ORCID: https://orcid.org/0000-0003-1985-6194)
- Karin Johansson
- Emily Hoberg
- Hannah J Davis
Institutions
- Zhejiang A & F University (CN)
- University of Helsinki (FI)
- North China University of Science and Technology (CN)
- University of Padua (IT)
- University of Cambridge (GB)
- IRCCS Materno Infantile Burlo Garofolo (IT)
- Helsinki University Hospital (FI)
- Mary Lyon Centre at MRC Harwell (GB)
- Veneto Institute of Molecular Medicine (IT)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- MRC Mitochondrial Biology Unit (GB)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1038/s41467-025-60059-y
- Citations
- 3
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Swedish Cancer Foundation
- Champ Foundation
- Kempe Foundation
- European Commission
- Università degli Studi di Padova
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Umeå Universitet
- Göteborgs Universitet
- Kempestiftelserna
- Stockholms Universitet
- Science for Life Laboratory
- Medical Research Council