Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity

Samantha Corrà, Alessandro Zuppardo, Sebastian Valenzuela, Louise Jenninger, Raffaele Cerutti, Sirelin Sillamaa, Emily Hoberg, Katarina A. S. Johansson, Urska Rovsnik, Sara Volta, Pedro Silva-Pinheiro, Hannah Davis, Aleksandra Trifunovic, Michal Minczuk, Claes M. Gustafsson, Anu Suomalainen, Massimo Zeviani, Bertil Macao, Xuefeng Zhu (), Maria Falkenberg () and Carlo Viscomi ()
Additional contact information
Samantha Corrà: Via Orus
Alessandro Zuppardo: Via Orus
Sebastian Valenzuela: Medicinaregatan 9A
Louise Jenninger: Medicinaregatan 9A
Raffaele Cerutti: Via Orus
Sirelin Sillamaa: Medicinaregatan 9A
Emily Hoberg: Medicinaregatan 9A
Katarina A. S. Johansson: Medicinaregatan 9A
Urska Rovsnik: Medicinaregatan 9A
Sara Volta: Via Orus
Pedro Silva-Pinheiro: Hills Road
Hannah Davis: Becquerel Ave
Aleksandra Trifunovic: CECAD Research Center
Michal Minczuk: Hills Road
Claes M. Gustafsson: Medicinaregatan 9A
Anu Suomalainen: University of Helsinki
Massimo Zeviani: Via Belzoni 160
Bertil Macao: Medicinaregatan 9A
Xuefeng Zhu: Medicinaregatan 9A
Maria Falkenberg: Medicinaregatan 9A
Carlo Viscomi: Via Orus

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60059-y

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