A new study published in the June 12, 2025 issue of Nature reports that the small molecule PZL-A can directly restore the function of DNA polymerase gamma (POLγ), impaired by POLG mutations causing severe mitochondrial disorders. This work has also been selected for Nature Highlights.
POLG mutations disrupt mitochondrial DNA (mtDNA) replication, leading to a range of progressive and often fatal diseases. PZL-A binds to an allosteric site of POLγ unaffected by most mutations, restoring wild-type-like enzymatic activity even in mutant forms. In patient-derived fibroblasts, PZL-A significantly improved mtDNA replication and oxidative phosphorylation (OXPHOS) activity.
These findings open a promising path toward the first disease-modifying treatment for POLG-related mitochondrial diseases, which currently lack effective therapies.
Source: Nature (June 12, 2025), Article Link
【My Thoughts】
Unlike gene-editing approaches, the strategy of pharmacologically restoring mutant enzyme function represents a highly elegant therapeutic concept. This could offer new hope for patients with mitochondrial diseases. I look forward to seeing how this approach progresses toward clinical applications.
