MeCP2 at the crossroads of hypoxia, oxidative stress, and gene regulation in Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females, caused by mutations in the X-linked gene <i>MECP2</i>. This gene encodes methyl CpG binding protein 2 (MeCP2), a multifunctional epigenetic regulator critical for neuronal gene regulation. In addition to well-characterized neurological symptoms, such as seizures and motor abnormalities, RTT patients frequently present with irregular breathing patterns that induce intermittent hypoxia, suggesting that MeCP2 contributes to respiratory regulation as well as the brain's cellular and molecular response to hypoxia. Mechanistically, MeCP2 appears to influence hypoxia-induced expression of the neuroprotective peptide brain-derived neurotrophic factor (BDNF), as impaired BDNF regulation in MeCP2-deficient neurons contributes to hypoxia vulnerability. RTT patients also display increased oxidative stress, marked by elevated lipid peroxidation, DNA damage, and reduced antioxidant production. Dysfunctional mitochondria in MeCP2-deficient astrocytes and neurons further propagate oxidative damage and non-cell-autonomous effects of MeCP2 loss. Moreover, recent transcriptomic studies revealed widespread transcriptional dysregulation in RTT, including pathways associated with mitochondrial function and oxidative stress. We review and discuss an expanded role for MeCP2 as a critical integrator of hypoxia sensing, oxidative stress regulation, and transcriptional adaptation in the developing brain, offering new insights into treatments targeting the complex pathophysiology of RTT.