Small molecules restore mutant mitochondrial DNA polymerase activity

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S. Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V. Gruszczyk, Seoeun Lee, Katarina A. S. Johansson, Javier Miralles Fusté, Yonghong Shi, S. Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M. Griffin, Carlos Pardo-Hernández, Thomas A. Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E. Jones, Xie Xie, Simon Giroux (), Claes M. Gustafsson () and Maria Falkenberg ()
Additional contact information
Sebastian Valenzuela: University of Gothenburg
Xuefeng Zhu: University of Gothenburg
Bertil Macao: University of Gothenburg
Mattias Stamgren: Pretzel Therapeutics
Carol Geukens: Pretzel Therapeutics
Paul S. Charifson: Pretzel Therapeutics
Gunther Kern: Pretzel Therapeutics
Emily Hoberg: University of Gothenburg
Louise Jenninger: University of Gothenburg
Anja V. Gruszczyk: Pretzel Therapeutics
Seoeun Lee: University of Gothenburg
Katarina A. S. Johansson: University of Gothenburg
Javier Miralles Fusté: Pretzel Therapeutics
Yonghong Shi: Pretzel Therapeutics
S. Jordan Kerns: Pretzel Therapeutics
Laleh Arabanian: Pretzel Therapeutics
Gabriel Martinez Botella: Pretzel Therapeutics
Sofie Ekström: Pretzel Therapeutics
Jeremy Green: Pretzel Therapeutics
Andrew M. Griffin: Pretzel Therapeutics
Carlos Pardo-Hernández: Pretzel Therapeutics
Thomas A. Keating: Pretzel Therapeutics
Barbara Küppers-Munther: Pretzel Therapeutics
Nils-Göran Larsson: Karolinska Institutet
Cindy Phan: Pretzel Therapeutics
Viktor Posse: Pretzel Therapeutics
Juli E. Jones: Pretzel Therapeutics
Xie Xie: Pretzel Therapeutics
Simon Giroux: Pretzel Therapeutics
Claes M. Gustafsson: University of Gothenburg
Maria Falkenberg: University of Gothenburg

Nature, 2025, vol. 642, issue 8067, 501-507

Abstract: Abstract Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

Date: 2025
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DOI: 10.1038/s41586-025-08856-9

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