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

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.