Small molecules restore mutant mitochondrial DNA polymerase activity

• 成果类型: Article
• 署名作者: Valenzuela, Sebastian; Zhu, Xuefeng; Macao, Bertil; Stamgren, Mattias; Geukens, Carol; Charifson, Paul S.; Kern, Gunther; Hoberg, Emily; Jenninger, Louise; Gruszczyk, Anja V.; Lee, Seoeun; Johansson, Katarina A. S.; Fuste, Javier Miralles; Shi, Yonghong; Kerns, S. Jordan; Arabanian, Laleh; Botella, Gabriel Martinez; Ekstroem, Sofie; Green, Jeremy; Griffin, Andrew M.; Pardo-Hernandez, Carlos; Keating, Thomas A.; Kuppers-Munther, Barbara; Larsson, Nils-Goran; Phan, Cindy; Posse, Viktor; Jones, Juli E.; Xie, Xie; Giroux, Simon; Gustafsson, Claes M.; Falkenberg, Maria
• 署名单位: University of Gothenburg; Karolinska Institutet
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2846
• DOI: 10.1038/s41586-025-08856-9
• 发表日期: 2025-06-12
• 关键词: d-loop; mutations; gamma; reconstitution; replication; exonuclease; holoenzyme; twinkle

摘要

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase gamma (POL gamma), a heterotrimeric complex consisting of a catalytic POL gamma A subunit and two accessory POL gamma B 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 POL gamma. PZL-A binds to an allosteric site at the interface between the catalytic POL gamma A subunit and the proximal POL gamma B subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POL gamma 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.