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

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-ViciKimberly A Chapman, Gregory M Enns, William Gahl, Lynne Wolfe, Russell P Saneto, Simon C Johnson, Jeffrey K Trimmer, Matthew B Klein, Charles R Holst

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)e0214250
JournalPLoS One
Volume14
Issue number3
DOIs
Publication statusPublished - Mar 28 2019

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Mitochondrial Diseases
epilepsy
Arachidonate 15-Lipoxygenase
lipoxygenase
Epilepsy
phospholipid-hydroperoxide glutathione peroxidase
therapeutics
seizures
Lipids
Glutathione
glutathione
Seizures
lipid peroxidation
Therapeutics
Iron
Tocotrienols
iron
anticonvulsants
Hydroxyeicosatetraenoic Acids
tocotrienols

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Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., ... Holst, C. R. (2019). Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy. PLoS One, 14(3), e0214250. https://doi.org/10.1371/journal.pone.0214250

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

In: PLoS One, Vol. 14, No. 3, 28.03.2019, p. e0214250.

Research output: Contribution to journalArticle

Kahn-Kirby, AH, Amagata, A, Maeder, CI, Mei, JJ, Sideris, S, Kosaka, Y, Hinman, A, Malone, SA, Bruegger, JJ, Wang, L, Kim, V, Shrader, WD, Hoff, KG, Latham, JC, Ashley, EA, Wheeler, MT, Bertini, E, Carrozzo, R, Martinelli, D, Dionisi-Vici, C, Chapman, KA, Enns, GM, Gahl, W, Wolfe, L, Saneto, RP, Johnson, SC, Trimmer, JK, Klein, MB & Holst, CR 2019, 'Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy', PLoS One, vol. 14, no. 3, pp. e0214250. https://doi.org/10.1371/journal.pone.0214250
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. / Targeting ferroptosis : A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy. In: PLoS One. 2019 ; Vol. 14, No. 3. pp. e0214250.
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T1 - Targeting ferroptosis

T2 - A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

AU - Kahn-Kirby, Amanda H

AU - Amagata, Akiko

AU - Maeder, Celine I

AU - Mei, Janet J

AU - Sideris, Steve

AU - Kosaka, Yuko

AU - Hinman, Andrew

AU - Malone, Stephanie A

AU - Bruegger, Joel J

AU - Wang, Leslie

AU - Kim, Virna

AU - Shrader, William D

AU - Hoff, Kevin G

AU - Latham, Joey C

AU - Ashley, Euan A

AU - Wheeler, Matthew T

AU - Bertini, Enrico

AU - Carrozzo, Rosalba

AU - Martinelli, Diego

AU - Dionisi-Vici, Carlo

AU - Chapman, Kimberly A

AU - Enns, Gregory M

AU - Gahl, William

AU - Wolfe, Lynne

AU - Saneto, Russell P

AU - Johnson, Simon C

AU - Trimmer, Jeffrey K

AU - Klein, Matthew B

AU - Holst, Charles R

PY - 2019/3/28

Y1 - 2019/3/28

N2 - 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.

AB - 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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DO - 10.1371/journal.pone.0214250

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JO - PLoS One

JF - PLoS One

SN - 1932-6203

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