Small molecules restore mutant mitochondrial DNA polymerase activity
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.
Article Details
Authors (31)
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
Maria Falkenberg