Emerging Mitochondrial Perspectives and Potential Therapeutics in Genetic Developmental and Epileptic Encephalopathy (DEE)

Developmental and Epileptic Encephalopathies (DEEs) comprise a heterogeneous group of severe neurological disorders with early onset refractory epilepsy and profound neurodevelopmental impairments. Despite the availability of more than thirty anti-seizure medications, most individuals with DEE remain refractory, experiencing persistent seizures that impose substantial burdens on patients, caregivers, and health care systems. DEEs are predominantly genetic, largely caused by de novo mutations, although non-genetic factors also contribute. Crucially, developmental deficits in DEE arise from both the underlying etiology and the disruptive effects of epileptic activity on the developing brain, distinguishing DEE from epilepsies without major neurodevelopmental involvement. Seizures during critical developmental windows exert acute and enduring effects on neurogenesis, synaptogenesis, circuit refinement, pruning, and brain maturation, which can greatly disrupt neurodevelopment. Mitochondria emerge as central regulators at the intersection of neurodevelopment and epilepsy. Mitochondrial dysfunction, whether from primary genetic mutations or seizure-induced injury, impairs bioenergetics, calcium homeostasis, redox states, and metabolic signaling, lowers seizure thresholds, and increases neuronal vulnerability. Moreover, mitochondrial metabolism directly interfaces with epigenetic regulation, linking energy state to long-term gene expression, altering developmental programming. This review synthesizes current knowledge on mitochondrial contributions to DEE pathogenesis, clinical diagnosis, and highlights emerging mitochondrial-targeted therapeutic strategies.