Epilepsy: Mitochondrial connections to the 'Sacred' disease
- PMID: 37582467
- DOI: 10.1016/j.mito.2023.08.002
Epilepsy: Mitochondrial connections to the 'Sacred' disease
Abstract
Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms of epilepsy makes diagnosis challenging. Diagnosis and monitoring of childhood epilepsy add to the need for non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms of epileptogenesis are not fully understood, evidence for mitochondrial involvement is substantial. Seizures affect 35%-60% of patients diagnosed with mitochondrial diseases. Mitochondrial dysfunction is pathophysiological in various epilepsies, including those of non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads to altered neuronal bioenergetics, metabolism and neurological complications, including seizures. Iron-dependent lipid peroxidation initiates ferroptosis, a cell death pathway that aligns with altered mitochondrial bioenergetics, metabolism and morphology found in neurodegenerative diseases (NDDs). Studies in mouse genetic models with seizure phenotypes where the function of an essential selenoprotein (GPX4) is targeted suggest roles for ferroptosis in epilepsy. GPX4 is pivotal in NDDs, where selenium protects interneurons from ferroptosis. Selenium is an essential central nervous system micronutrient and trace element. Low serum concentrations of selenium and other trace elements and minerals, including iron, are noted in diagnosing childhood epilepsy. Selenium supplements alleviate intractable seizures in children with reduced GPX activity. Copper and cuproptosis, like iron and ferroptosis, link to mitochondria and NDDs. Connecting these mechanistic pathways to selenoproteins provides new insights into treating seizures, pointing to using medicines including prodrugs of lipoic acid to treat epilepsy and to potential alternative therapeutic approaches including transcranial magnetic stimulation (transcranial), photobiomodulation and vagus nerve stimulation.
Keywords: Cuproptosis/copper; Epilepsy; Ferroptosis/iron; Mitochondria; Neurodegenerative disease; Reactive oxygen species (ROS); Seizure.
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The following authors make the following disclosures in addition to their academic and nonprofit roles. Walter H. Moos is a co-founder and managing director of Pandect Bioventures. He is also chairman emeritus of ShangPharma Innovation, has been a consultant to Aduro Biotech (Chinook Therapeutics), is an advisor to Azkarra Therapeutics, and serves on the boards of directors of Circle Pharma, Rigel Pharmaceuticals and Valitor. Douglas V. Faller is chief medical officer of Oryzon Genomics, scientific founder and chair of the scientific advisory board of Viracta Therapeutics, co-founder and vice president at Phoenicia Biosciences and serves as a consultant to Briacell Therapeutics. Kosta Steliou is the founder and chief scientific officer of PhenoMatriX. Krishna Kodukula has consulted with and/or served as an executive or on the boards of various biotechnology and pharmaceutical companies from time to time, including PhenoMatriX, and he has been an executive-in-residence at Pandect Bioventures and ShangPharma Innovation. Demetrios G. Vavvas is a co-founder of Drusolv Therapeutics, a member of the scientific and clinical advisory boards of Olix Pharma and Valitor, and a consultant for TwentyTwenty, Sumitomo/Sunovion, and Cambridge Polymer Group.
