Small molecules restore mutant mitochondrial DNA polymerase activity
Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S. Charifson, Günther Kern, Emily Hoberg, Louise Jenninger, Anja V. Gruszczyk, Seoeun Lee, Karin Johansson, Javier Miralles Fusté, Yonghong Shi, S. Jordan Kerns, Laleh S. 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
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 subunits 1 . 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 2 . 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.