Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

• DOI: 10.1371/journal.pone.0214250
• Publication Date: 2019-03-28T13:47:45Z
• Authors: Amanda H. Kahn-Kirby; Akiko Amagata; Celine I. Maeder; Janet J. Mei; Steve Sideris; Yuko Kosaka; Andrew Hinman; Stephanie A. Malone; Joel J. Bruegger; Leslie Wang; Virna Kim; William D. Shrader; Kevin G. Hoff; Joey C. Latham; Euan A. Ashley; Matthew T. Wheeler; Enrico Bertini; Rosalba Carrozzo; Diego Martinelli; Carlo Dionisi-Vici; Kimberly A. Chapman; Gregory M. Enns; William Gahl; Lynne Wolfe; Russell P. Saneto; Simon C. Johnson; Jeffrey K. Trimmer; Matthew B. Klein; Charles R. Holst
• Keywords: GPX4

Background Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation energy. Epilepsy common symptom mitochondrial disease, vast majority cases, refractory to commonly used antiepileptic drugs. Ferroptosis recently-described form iron- lipid-dependent regulated cell death associated with glutathione depletion production lipid peroxides lipoxygenase enzymes. Activation ferroptosis pathway has been implicated growing number disorders, including epilepsy. Given that balancing activities peroxidase-4 (GPX4) 15-lipoxygenase (15-LO), targeting these enzymes may provide rational therapeutic strategy modulate seizure. The clinical-stage vatiquinone (EPI-743, α-tocotrienol quinone) was reported reduce seizure frequency morbidity children disorder pontocerebellar hypoplasia type 6. We sought elucidate molecular mechanism EPI-743 explore potential 15-LO treat additional disease-associated epilepsies. Methods Primary fibroblasts B-lymphocytes derived from patients epilepsy were cultured under standardized conditions. induced treatment irreversible GPX4 inhibitor RSL3 or combination pharmacological excess iron. co-administered endpoints, viability 15-LO-dependent oxidation, measured. Results potently prevented patient cells representing five distinct pediatric syndromes Cytoprotection preceded dose-dependent decrease general oxidation specific product 15-hydroxyeicosatetraenoic acid (15-HETE). Conclusions These findings support continued clinical evaluation as agent for PCH6 other diseases