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.
Amanda H Kahn-Kirby  1 ,  Akiko Amagata  1 ,  Celine I Maeder  1 ,  Janet J Mei  1 ,  Steve Sideris  1 ,  Yuko Kosaka  1 ,  Andrew Hinman  1 ,  Stephanie A Malone  1 ,  Joel J Bruegger  1 ,  Leslie Wang  1 ,  Virna Kim  1 ,  William D Shrader  1 ,  Kevin G Hoff  1 ,  Joey C Latham  1 ,  Euan A Ashley  2 ,  Matthew T Wheeler  2 ,  Enrico Bertini  3 ,  Rosalba Carrozzo  3 ,  Diego Martinelli  3 ,  Carlo Dionisi-Vici  4 ,  Kimberly A Chapman  5 ,  Gregory M Enns  6 ,  William Gahl  7 ,  Lynne Wolfe  7 ,  Russell P Saneto  8 ,  Simon C Johnson  9  10 ,  Jeffrey K Trimmer  1 ,  Matthew B Klein  1 ,  Charles R Holst  1
Affiliations
  • 1. BioElectron Technology Corporation, Mountain View, California, United States of America.
  • 2. Stanford Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, California, United States of America.
  • 3. Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Research Hospital, Rome, Italy.
  • 4. Clinical Division and Research Unit of Metabolic Diseases, Bambino Gesù Children's Hospital, Rome, Italy.
  • 5. Children's National Rare Disease Institute, Children's National Health System, Washington, D.C., United States of America.
  • 6. Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
  • 7. NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, Maryland, United States of America.
  • 8. Division of Pediatric Neurology, Department of Neurology, Neuroscience Institute, Seattle Children's Hospital, Seattle, Washington, United States of America.
  • 9. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
  • 10. Department of Neurology, University of Washington, Seattle, Washington, United States of America.
PMID: 30921410 DOI: 10.1371/journal.pone.0214250
Abstract

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.

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