RNA-seq of patient-derived glutamatergic neurons carrying Leigh Syndrome causing compound heterozygous mutations in the SURF1 gene treated with Omaveloxolone.

Leigh Syndrome (LS) is a rare, progressive mitochondrial encephalopathy that manifests in infancy or early childhood and is characterized by neurodevelopmental regression, brainstem and basal ganglia lesions, and premature mortality. At the molecular level, LS is driven by mutations that impair oxidative phosphorylation (OXPHOS), disrupting energy production in metabolically active tissues such as the brain, heart, and muscle. Among these, mutations in SURF1—a nuclear gene essential for cytochrome c oxidase (COX, Complex IV) assembly—are among the most common causes of nuclear-encoded LS. Omaveloxolone, an FDA-approved Nrf2 activator for Friedreich’s Ataxia, has recently gained attention for its neuroprotective properties across a range of preclinical models. Treatment of patient neurons with omaveloxolone promoted neurite outgrowth, and activated PINK1/PRKN-mediated mitophagy. Functionally, omaveloxolone reduced neuronal hyperexcitability and apoptosis, and normalized aberrant synaptic pathway activity via deactivation of the SNARE complex.