Oxidative stress and neuronal alteration: Mitochondrial dysfunction as a key player in intractable epilepsy - a...

Drug-resistant epilepsy (DRE) still poses one of the greatest therapeutic challenges, afflicting about one-third of all patients with epilepsy in the world. Despite spectacular advances in the fields of anti-seizure medications and neurostimulation techniques, treatment outcomes in DRE have reached plateau levels, signifying an urgent need for better mechanistic understanding and therapeutic strategies. New evidence increasingly elucidates mitochondrial dysfunction as a lens through which to understand seizure generation, pharmacoresistance, and disease progression. Mitochondria are regulators of ATP production, calcium buffering, and redox homeostasis; disruption of any such pathway will result in neuronal hyperexcitability, oxidative injury, and cell death. Moreover, mitochondrial DNA mutations and heteroplasmy threshold can correlate with seizure onset, seizure severity, and Response to treatment, thus being potential biomarkers for risk stratification. This narrative review surveys both preclinical and clinical evidence for mitochondrial dysfunction in epilepsy, examining oxidative stress pathways, mitophagy, and mitochondrial permeability transition pore opening as key mechanisms of neuronal vulnerability. We subsequently analyze various preclinical models of mitochondrial dysfunction, pointing out their respective strengths and weaknesses. Emerging therapeutic strategies, encompassing pharmacological agents, gene therapy, diet, and natural compounds, are then reviewed, which aim to resolve issues surrounding mitochondrial health on a molecular basis. By straddling the mechanistic and clinical narratives, this work foregrounds mitochondrial-centered approaches as promises for both the diagnostic and therapeutic arsenal in the management of DRE.