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

Author

Listed:
  • Samantha Corrà

    (Via Orus)

  • Alessandro Zuppardo

    (Via Orus
    Via Ugo Bassi)

  • Sebastian Valenzuela

    (Medicinaregatan 9A)

  • Louise Jenninger

    (Medicinaregatan 9A)

  • Raffaele Cerutti

    (Via Orus
    Via Ugo Bassi)

  • Sirelin Sillamaa

    (Medicinaregatan 9A)

  • Emily Hoberg

    (Medicinaregatan 9A)

  • Katarina A. S. Johansson

    (Medicinaregatan 9A)

  • Urska Rovsnik

    (Medicinaregatan 9A)

  • Sara Volta

    (Via Orus
    Via Ugo Bassi)

  • Pedro Silva-Pinheiro

    (Hills Road)

  • Hannah Davis

    (Becquerel Ave)

  • Aleksandra Trifunovic

    (CECAD Research Center)

  • Michal Minczuk

    (Hills Road
    University of Cambridge)

  • Claes M. Gustafsson

    (Medicinaregatan 9A)

  • Anu Suomalainen

    (University of Helsinki
    University of Helsinki)

  • Massimo Zeviani

    (Via Belzoni 160
    Via Istria 61)

  • Bertil Macao

    (Medicinaregatan 9A)

  • Xuefeng Zhu

    (Medicinaregatan 9A
    North China University of Science and Technology
    Zhejiang A&F University)

  • Maria Falkenberg

    (Medicinaregatan 9A)

  • Carlo Viscomi

    (Via Orus
    Via Ugo Bassi)

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.

Suggested Citation

  • Samantha Corrà & Alessandro Zuppardo & Sebastian Valenzuela & Louise Jenninger & Raffaele Cerutti & Sirelin Sillamaa & Emily Hoberg & Katarina A. S. Johansson & Urska Rovsnik & Sara Volta & Pedro Silv, 2025. "Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60059-y
    DOI: 10.1038/s41467-025-60059-y
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