Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsl root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and...

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Autores: Britti, Elena, Delaspre, Fabien, Sanz Alcázar, Arabela, Medina Carbonero, Marta, Llovera i Tomàs, Marta, Purroy Lledós, Rosa, Mincheva Tasheva, Stefka, Tamarit Sumalla, Jordi, Ros Salvador, Joaquim
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/72921
Acceso en línea:https://doi.org/10.1042/BCJ20200331
http://hdl.handle.net/10459.1/72921
Access Level:acceso abierto
Palabra clave:Calcitriol
Calcium homoeostasis
Frataxin
Mitochondrial dysfunction
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spelling Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich AtaxiaBritti, ElenaDelaspre, FabienSanz Alcázar, ArabelaMedina Carbonero, MartaLlovera i Tomàs, MartaPurroy Lledós, RosaMincheva Tasheva, StefkaTamarit Sumalla, JordiRos Salvador, JoaquimCalcitriolCalcium homoeostasisFrataxinMitochondrial dysfunctionFriedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsl root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.This work has been funded by project SAF2017-83883-R from MINECO (Spain), by Ataxia U.K. and by Associació Catalana d'Atàxies (ACAH).Portland PressBiochemical Society202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionhttps://doi.org/10.1042/BCJ20200331http://hdl.handle.net/10459.1/72921http://hdl.handle.net/10459.1/72921reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83883-RVersió postprint del document publicat a: https://doi.org/10.1042/BCJ20200331Biochemical Journal, 2021, vol. 478, núm. 1(c) Authors, 2021info:eu-repo/semantics/openAccessoai:recercat.cat:10459.1/729212026-05-29T05:05:01Z
dc.title.none.fl_str_mv Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
title Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
spellingShingle Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
Britti, Elena
Calcitriol
Calcium homoeostasis
Frataxin
Mitochondrial dysfunction
title_short Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
title_full Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
title_fullStr Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
title_full_unstemmed Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
title_sort Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia
dc.creator.none.fl_str_mv Britti, Elena
Delaspre, Fabien
Sanz Alcázar, Arabela
Medina Carbonero, Marta
Llovera i Tomàs, Marta
Purroy Lledós, Rosa
Mincheva Tasheva, Stefka
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
author Britti, Elena
author_facet Britti, Elena
Delaspre, Fabien
Sanz Alcázar, Arabela
Medina Carbonero, Marta
Llovera i Tomàs, Marta
Purroy Lledós, Rosa
Mincheva Tasheva, Stefka
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
author_role author
author2 Delaspre, Fabien
Sanz Alcázar, Arabela
Medina Carbonero, Marta
Llovera i Tomàs, Marta
Purroy Lledós, Rosa
Mincheva Tasheva, Stefka
Tamarit Sumalla, Jordi
Ros Salvador, Joaquim
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Calcitriol
Calcium homoeostasis
Frataxin
Mitochondrial dysfunction
topic Calcitriol
Calcium homoeostasis
Frataxin
Mitochondrial dysfunction
description Friedreich Ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsl root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. We provide data that calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both, frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1042/BCJ20200331
http://hdl.handle.net/10459.1/72921
http://hdl.handle.net/10459.1/72921
url https://doi.org/10.1042/BCJ20200331
http://hdl.handle.net/10459.1/72921
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-83883-R
Versió postprint del document publicat a: https://doi.org/10.1042/BCJ20200331
Biochemical Journal, 2021, vol. 478, núm. 1
dc.rights.none.fl_str_mv (c) Authors, 2021
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Authors, 2021
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Portland Press
Biochemical Society
publisher.none.fl_str_mv Portland Press
Biochemical Society
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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