Development of organocatalytic switches of OGG1 that protect mitochondria under oxidative stress

Mitochondrial dysfunction is a major component of neurodegeneration. The mitochondrial genome is prone to oxidative damage, and repair proteins are important to maintain mitochondrial DNA integrity. OGG1 initiates base excision repair of oxidative DNA lesions in both nuclear and mitochondrial genomes. While inhibitors of OGG1 have been extensively explored, pharmacological activation of OGG1 through catalytic reprogramming remains underdeveloped. Herein, we report the discovery of mitochondrial enriched organocatalytic switches of OGG1. Biochemical analysis, mutational profiling, and X-ray crystallography confirmed active-site binding and preferential stimulation of β-elimination over glycosylase turnover, effectively reprogramming OGG1. We demonstrate that ORCAs protect mitochondrial function and morphology under oxidative stress, specifically affecting mitochondrial membrane potential and fragment number while attenuating metabolic stress. Mechanistically, ORCAs improved NAD levels in mouse dissociated cortical neurons and provided neuroprotection in a retina axotomy model. Together, the findings position OGG1-ORCAs as potential novel therapies for the treatment of age-related diseases and neurodegeneration.