Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A

Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosom...

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Autores: Fernández, B., Fernández, Elena, Gómez-Suaga, P., Gil, Fernando, Molina Villalba, Isabel, Ferrer, Isidro, Patel, S., Churchill, G. C., Hilfiker, Sabine
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/157423
Acceso en línea:http://hdl.handle.net/10261/157423
Access Level:acceso abierto
Palabra clave:Iron
Lysosome
NAADP
Neurodegeneration
RAB7A
TPCN1
TPCN2
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spelling Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7AFernández, B.Fernández, ElenaGómez-Suaga, P.Gil, FernandoMolina Villalba, IsabelFerrer, IsidroPatel, S.Churchill, G. C.Hilfiker, SabineIronLysosomeNAADPNeurodegenerationRAB7ATPCN1TPCN2Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load.This work was supported by funding from FEDER, The Spanish Ministry of Economy and Competitiveness (MINECO; SAF2014-58653-R), the Foundation BBVA and the Michael J. Fox Foundation. B.F. was supported by CEI Biotic Granada (CAEP2-13) and by a Juan de la Cierva Fellowship (JCI-2010-07703).Peer reviewedTaylor & FrancisEuropean CommissionMinisterio de Economía y Competitividad (España)Michael J. Fox Foundation for Parkinson's ResearchConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201720172016info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/157423reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58653-Rhttp://dx.doi.org/10.1080/15548627.2016.1190072Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1574232026-05-22T06:33:51Z
dc.title.none.fl_str_mv Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
title Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
spellingShingle Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
Fernández, B.
Iron
Lysosome
NAADP
Neurodegeneration
RAB7A
TPCN1
TPCN2
title_short Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
title_full Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
title_fullStr Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
title_full_unstemmed Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
title_sort Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A
dc.creator.none.fl_str_mv Fernández, B.
Fernández, Elena
Gómez-Suaga, P.
Gil, Fernando
Molina Villalba, Isabel
Ferrer, Isidro
Patel, S.
Churchill, G. C.
Hilfiker, Sabine
author Fernández, B.
author_facet Fernández, B.
Fernández, Elena
Gómez-Suaga, P.
Gil, Fernando
Molina Villalba, Isabel
Ferrer, Isidro
Patel, S.
Churchill, G. C.
Hilfiker, Sabine
author_role author
author2 Fernández, Elena
Gómez-Suaga, P.
Gil, Fernando
Molina Villalba, Isabel
Ferrer, Isidro
Patel, S.
Churchill, G. C.
Hilfiker, Sabine
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
Ministerio de Economía y Competitividad (España)
Michael J. Fox Foundation for Parkinson's Research
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Iron
Lysosome
NAADP
Neurodegeneration
RAB7A
TPCN1
TPCN2
topic Iron
Lysosome
NAADP
Neurodegeneration
RAB7A
TPCN1
TPCN2
description Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load.
publishDate 2016
dc.date.none.fl_str_mv 2016
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/157423
url http://hdl.handle.net/10261/157423
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58653-R
http://dx.doi.org/10.1080/15548627.2016.1190072
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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