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

PLoS One. 2019 Mar 28;14(3):e0214250. doi: 10.1371/journal.pone.0214250. eCollection 2019.


Background: 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.

Methods: 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.

Results: 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).

Conclusions: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 15-Lipoxygenase / metabolism
  • Carbolines / pharmacology*
  • Cell Line
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism
  • Epilepsy / pathology
  • Ferroptosis / drug effects*
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors*
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / pharmacology


  • Carbolines
  • Hydroxyeicosatetraenoic Acids
  • RSL3 compound
  • Ubiquinone
  • alpha-tocotrienol quinone
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Arachidonate 15-Lipoxygenase