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Kahn-Kirby, Amanda H; Amagata, Akiko; Maeder, Celine I; Mei, Janet J; Sideris, Steve; Kosaka, Yuko; Hinman, Andrew; Malone, Stephanie A; Bruegger, Joel J; Wang, Leslie; Kim, Virna; Shrader, William D; Hoff, Kevin G; Latham, Joey C; Ashley, Euan A; Wheeler, Matthew T; Bertini, Enrico; Carrozzo, Rosalba; Martinelli, Diego; Dionisi-Vici, Carlo; Chapman, Kimberly A; Enns, Gregory M; Gahl, William; Wolfe, Lynne; Saneto, Russell P; Johnson, Simon C; Trimmer, Jeffrey K; Klein, Matthew B; Holst, Charles R
PloS one, 03/2019, Letnik: 14, Številka: 3Journal Article
Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.
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