Lipid peroxidation-induced cell death in Rett syndrome

Rett Syndrome (RTT) is a rare neurodevelopmental disorder, primarily affecting girls (1:10,000 live births), largely caused by mutations in the X-linked gene MECP2, an epigenetic regulator encoding for the methyl-CpG binding protein 2 (MeCP2). Recent evidence links ferroptosis, an iron-dependent cell death characterized by lipid peroxide accumulation, to neurodegenerative and neurodevelopmental disorders like autism. Several RTT hallmarks, including redox imbalance, excess labile iron, increased lipid peroxidation, and impaired antioxidant enzyme activity, align with ferroptosis characteristics. Therefore, we investigated ferroptosis's role in RTT using human primary fibroblasts from healthy and RTT subjects, treating them with ferroptosis inducers: erastin and RSL3. Our findings show RTT cells are highly susceptible to ferroptosis, marked by elevated lipid peroxidation and mitochondrial reactive oxygen species (mtROS) production, crucial for ferroptotic cell death. We also observed altered iron metabolism and dysregulated ferritinophagy. RTT fibroblasts exhibited an imbalanced antioxidant defense, particularly after ferroptotic stimuli, and ferroptosis inducers worsened redox imbalance compared to controls. Importantly, a ferroptosis inhibitor (Ferrostatin-1) and a SOD mimetic (mito-TEMPO) prevented these effects and normalized the altered basal conditions of RTT cells. In conclusion, our results reveal a general dysregulation in RTT cells contributing to increased ferroptosis sensitivity. This suggests a significant role for ferroptosis in RTT pathophysiology and progression, potentially opening new therapeutic avenues for this condition.