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In Vivo And In Vitro Mechanistic Characterization Of A Clinically Relevant PolγA Mutation

Pedro Silva-Pinheiro, Carlos Pardo-Hernández, Aurelio Reyes, Lisa Tilokani, Anup Mishra, Raffaele Cerutti, Shuaifeng Li, Dieu Hien Ho, Sebastian Valenzuela, Anil Sukru Dogan, Peter Bradley, Patricio Fernandez-Silva, Aleksandra Trifunovic, Julien Prudent, Michal Minczuk, Laurence Bindoff, Bertil Macao, Massimo Zeviani, Maria Falkenberg, Carlo Viscomi

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AbstractMutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generated a POLGA449T/A449T mouse model, which reproduces the most common human recessive mutation of POLG, encoding the A467T change, and dissected the mechanisms underlying pathogenicity. We show that the A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ in vivo and in vitro. Interestingly, the A467T mutation also strongly impairs interactions with POLγB, the homodimeric accessory subunit of holo-POLγ. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA, which in turn exacerbates the molecular phenotypes of PolgA449T/A449T mice. Importantly, we validated this mechanism for other mutations affecting the interaction between the two POLγ subunits. We suggest that LONP1 dependent degradation of POLγA can be exploited as a target for the development of future therapies.