Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response

Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Fer roptosis has recently been shown to be involved in FA cellular degeneration; howeve...

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Autores: Sanz Alcázar, Arabela, Portillo-Carrasquer, Marta, Delaspre, Fabien, Pazos Gil, Maria, Tamarit Sumalla, Jordi, Ros Salvador, Joaquim, Cabiscol Català, Elisa
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2024
País:España
Recursos:Universitat de Lleida (UdL)
Repositório:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/466974
Acesso em linha:https://doi.org/10.1016/j.redox.2024.103339
https://hdl.handle.net/10459.1/466974
Access Level:Acceso aberto
Palavra-chave:Friedreich ataxia
Dorsal root ganglia
Ferroptosis
NRF2
LKB1/AMPK pathway
MT-6378
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spelling Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 responseSanz Alcázar, ArabelaPortillo-Carrasquer, MartaDelaspre, FabienPazos Gil, MariaTamarit Sumalla, JordiRos Salvador, JoaquimCabiscol Català, ElisaFriedreich ataxiaDorsal root gangliaFerroptosisNRF2LKB1/AMPK pathwayMT-6378Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Fer roptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and the activation of GSK3β, which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. MT-6378, an AMPK activator, restored NRF2 levels, increased GPX4 levels and reduced lipid peroxidation. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.This work was supported by Ministerio de Economía y Competitividad, MINECO (Spain) [grants PN-P21018 and PDC-N21019] and Generalitat de Catalunya [SGR2009-00196]. Arabela Sanz-Alcázar received first a Ph.D. fellowship from the Generalitat de Catalunya and after, she held predoctoral fellowship “Ajuts al Personal Investigador en Formacio ´ " from IRBLleida/Diputacio ´ de Lleida. Marta PortilloCarrasquer received a PhD fellowship from the Generalitat de Catalunya. Maria Pazos received a PhD fellowship from the Universitat de Lleida. The funding sources have no involvement in study design; collection, analysis and interpretation of data; neither in the writing of the report.Elsevier2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1016/j.redox.2024.103339https://hdl.handle.net/10459.1/466974reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésP21018Reproducció del document publicat a: https://doi.org/10.1016/j.redox.2024.103339Redox Biology, 2024, vol. 76, 103339cc-by-nc-nd (c) The Authors, 2024Attribution-NonCommercial-NoDerivatives 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:repositori.udl.cat:10459.1/4669742026-06-24T12:42:17Z
dc.title.none.fl_str_mv Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
title Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
spellingShingle Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
Sanz Alcázar, Arabela
Friedreich ataxia
Dorsal root ganglia
Ferroptosis
NRF2
LKB1/AMPK pathway
MT-6378
title_short Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
title_full Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
title_fullStr Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
title_full_unstemmed Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
title_sort Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response
dc.creator.none.fl_str_mv Sanz Alcázar, Arabela
Portillo-Carrasquer, Marta
Delaspre, Fabien
Pazos Gil, Maria
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author Sanz Alcázar, Arabela
author_facet Sanz Alcázar, Arabela
Portillo-Carrasquer, Marta
Delaspre, Fabien
Pazos Gil, Maria
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author_role author
author2 Portillo-Carrasquer, Marta
Delaspre, Fabien
Pazos Gil, Maria
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
Cabiscol Català, Elisa
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Friedreich ataxia
Dorsal root ganglia
Ferroptosis
NRF2
LKB1/AMPK pathway
MT-6378
topic Friedreich ataxia
Dorsal root ganglia
Ferroptosis
NRF2
LKB1/AMPK pathway
MT-6378
description Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Fer roptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and the activation of GSK3β, which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. MT-6378, an AMPK activator, restored NRF2 levels, increased GPX4 levels and reduced lipid peroxidation. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1016/j.redox.2024.103339
https://hdl.handle.net/10459.1/466974
url https://doi.org/10.1016/j.redox.2024.103339
https://hdl.handle.net/10459.1/466974
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv P21018
Reproducció del document publicat a: https://doi.org/10.1016/j.redox.2024.103339
Redox Biology, 2024, vol. 76, 103339
dc.rights.none.fl_str_mv cc-by-nc-nd (c) The Authors, 2024
Attribution-NonCommercial-NoDerivatives 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
rights_invalid_str_mv cc-by-nc-nd (c) The Authors, 2024
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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