Small molecules restore mutant mitochondrial DNA polymerase activity

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits<sup>1</sup>. 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 exists<sup>2</sup>. 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.

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Journal
Nature
Published
2025-04-09
DOI
https://doi.org/10.1038/s41586-025-08856-9
Citations
10
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
8.06
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article

Small molecules restore mutant mitochondrial DNA polymerase activity

Anja V. Gruszczyk, Xie Xie, Andrew M. Griffin, Claes M. Gustafsson et al.
10 citations
Nature
Mitochondrial Function and Pathology
8.06
article

Small molecules restore mutant mitochondrial DNA polymerase activity

Anja V. Gruszczyk, Xie Xie, Andrew M. Griffin, Claes M. Gustafsson, Simon Ekström, Louise Jenninger, Thomas A. Keating, Cindy Phan, Viktor Posse, Barbara Küppers-Munther, Javier Miralles Fusté, Nils‐Göran Larsson, Laleh S. Arabanian, Paul S. Charifson, S. Jordan Kerns, Bertil Macao, Sebastian Valenzuela, Jeremy Green, Simon Giroux, Seoeun Lee, Yonghong Shi, Maria Falkenberg, Gabriel Martinez Botella, Xuefeng Zhu, Juli E. Jones, Karin Johansson, Carlos Pardo-Hernández, Günther Kern, Emily Hoberg, Mattias Stamgren, Carol Geukens
article en
10 citations

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 subunits<sup>1</sup>. 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 exists<sup>2</sup>. 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.

NatureVol. 642(8067)
Karolinska Institutet (SE), Profu (Sweden) (SE), APT Therapeutics (United States) (US), University of Gothenburg (SE)
Good health and well-being
Openalex Percentile: Top 2%
Mitochondrial Function and Pathology
8.06
DOIOpen Access PDFOpenAlex
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