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<p>DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in <i>POLG</i>, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common <i>POLG</i> 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 <i>POLG</i> mutations, providing crucial insights into the pathogenesis of <i>POLG</i>-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of <i>POLG</i> mutations.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月23日

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  • 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,
  • Carlo Viscomi

摘要

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.