The Intersection of Impaired Ion Channels and Depleted Mitochondria in Epileptic Seizures: A Narrative Review

Carmen Rubio^1,#, Norma Serrano-García^1,#, Ángel Lee², Javier Pérez-Villavicencio^1,3, Omar Villa-Robledo^1,4, Rodrigo Mercado Pimentel⁵, Héctor Romo-Parra^1,6, Moisés Rubio-Osornio^7,*
1 Department of Neurophysiology, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
2 National Institute of Public Health, Cuernavaca, Mexico
3 Department of Electrical Engineering, Basic Sciences and Engineering Division, Iztapalapa Campus, Metropolitan Autonomous University, Mexico City, Mexico
4 Faculty of Medicin and Nutrition, Autonomous University of Baja California, Mexicali, Baja California, Mexico
5 Department of Neurosurgery, Hospital San Javier, Guadalajara, Mexico
6 Psychology Department, Ibero-American University, Santa Fe Campus, Mexico City, Mexico
7 Department of Neurochemistry, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
* Corresponding Author: Moisés Rubio-Osornio. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Transporters and Channels in Brain Physiology: From Molecular Biophysics to Cellular Dynamics)

BIOCELL https://doi.org/10.32604/biocell.2026.081478

Received 03 March 2026; Accepted 16 June 2026; Published online 03 July 2026

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Abstract

Epilepsy is sustained by a self-reinforcing triad of ion channel dysfunction, mitochondrial impairment, and oxidative stress that lowers seizure threshold and drives epileptogenesis. This review examines how genetic channelopathies and redox-dependent post-translational modifications of voltage-gated sodium, calcium, and potassium channels disrupt excitatory–inhibitory balance, and how electron transport chain dysfunction amplifies reactive oxygen species, compromises adenosine triphosphate (ATP)-dependent membrane stability, and activates mechanistic target of rapamycin complex 1. Key convergences include oxidative ion channel modification, ATP-sensitive potassium channel impairment, synaptic lipid peroxidation, and gamma-aminobutyric acid (GABA)-ergic transporter dysfunction. Temporal lobe epilepsy is characterized by focal mitochondrial pathology, whereas genetic generalized epilepsies reflect thalamocortical channelopathies, a distinction with direct therapeutic implications. Precision strategies integrating mitochondria-targeted antioxidants, ion channel modulators, antioxidant supplementation N-acetylcysteine, α-lipoic acid, and mTOR inhibitors (rapamycin, everolimus) provide a mechanistic framework for interrupting the redox–metabolic–electrical feedback loop sustaining seizures and advancing disease modification.

Keywords

Epilepsy; epileptogenesis; ion channelopathies; mitochondrial dysfunction; oxidative stress; mechanistic target of rapamycin complex 1; lipid peroxidation; redox signaling

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The Intersection of Impaired Ion Channels and Depleted Mitochondria in Epileptic Seizures: A Narrative Review

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