MITOCHONDRIAL REDOX IMBALANCE AND CoQ10 DEFICIENCY IN RETT SYNDROME: INSIGHTS FROM PATIENT-DERIVED FIBROBLASTS.

Abstract

Rett syndrome (RTT), a neurodevelopmental disorder primarily affecting females, is characterized by mutations in the MECP2 gene, leading to systemic oxidative stress and mitochondrial dysfunction. This study investigates the role of Coenzyme Q₁₀ (CoQ₁₀), particularly its reduced form ubiquinol, in modulating oxidative stress and mitochondrial function in primary dermal fibroblasts derived from RTT patients with distinct MeCP2 mutations. Baseline assessments revealed significant CoQ₁₀ deficiencies and elevated reactive oxygen species (ROS) levels, notably in fibroblasts with the T158M mutation. Ubiquinol supplementation effectively restored CoQ₁₀ levels and improved redox balance in these cells. Additionally, treatment influenced mitochondrial dynamics, as evidenced by alterations in the expression of fission and fusion proteins and modulated the activity of paraoxonase 2 (PON2), an enzyme involved in cellular antioxidant defense. In conclusion, our data suggest that CoQ₁₀ supplementation could mitigate oxidative damage and preserve mitochondrial integrity, but we are far from being able to claim that it can represents an effective therapeutic strategy to complement current pharmacological treatments in RTT patients. Further research is warranted to explore the potential of CoQ₁₀ as an adjunctive treatment, particularly during the early stages of RTT.