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Valenzuela S, Zhu X, Macao B, Stamgren M, Geukens C, Charifson PS, Kern G, Hoberg E, Jenninger L, Gruszczyk AV, Lee S, Johansson KAS, Miralles Fusté J, Shi Y, Kerns SJ, Arabanian L, Martinez Botella G, Ekström S, Green J, Griffin AM, Pardo-Hernández C, Keating TA, Küppers-Munther B, Larsson NG, Phan C, Posse V, Jones JE, Xie X, Giroux S, Gustafsson CM, Falkenberg M
Nature 642 (8067) 501-507 [2025-06-00; online 2025-04-09]
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.
Integrated Microscopy Technologies Gothenburg [Service]
PubMed 40205042
DOI 10.1038/s41586-025-08856-9
Crossref 10.1038/s41586-025-08856-9
pmc: PMC12158775
pii: 10.1038/s41586-025-08856-9