Antiseizure Medications Impact Mitochondrial Ion Channels via Novel Bioenergetic and Neural Mechanisms

Antiseizure medications (ASMs) have traditionally been characterized by their modulation of neuronal ion channels and synaptic processes; however, accumulating evidence indicates that numerous ASMs also directly modulate mitochondrial function. Specifically, several ASMs interact with ion channels located in both the inner and outer mitochondrial membranes, including the voltage-dependent anion channel (VDAC), the mitochondrial calcium uniporter (MCU), the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX), the mitochondrial permeability transition pore (mPTP), and mitochondrial ATP-sensitive potassium channels (mitoKATP). Modulation of these channels regulates critical processes in epilepsy, including Ca²⁺ homeostasis, ATP synthesis, redox equilibrium, and susceptibility to neuronal apoptosis. Phenytoin and carbamazepine reduce voltage-dependent anion channel isoform 1 (VDAC1)-associated mitochondrial permeability by modulating the Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 protein (Bcl-2) ratio; ethosuximide limits mitochondrial Ca²⁺ overload through modulation of the MCU complex; valproic acid stabilizes NCLX function and prevents mPTP opening via antioxidant mechanisms; levetiracetam contributes to preserving intracellular Ca²⁺ handling; and mitoKATP activators, including diazoxide and retigabine, promote mitochondrial membrane potential stability and reduce seizure-induced reactive oxygen species (ROS) generation. The mitochondrial effects vary according to epilepsy subtype, contributing to the attenuation of hippocampal apoptosis in temporal lobe epilepsy and thalamocortical network modulation in generalized epilepsies. In this narrative review we examine the experimental and molecular evidence demonstrating how ASMs modulate mitochondrial ion channels and how these interactions contribute to their anticonvulsant mechanisms, thereby broadening the understanding of mitochondria as key functional components in antiseizure pharmacology.