Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease

[Background]: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macropha...

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Autores: Mata, Mario de la, Cotán, David, Oropesa-Ávila, Manuel, Villanueva-Paz, Marina, Lavera, I. de, Álvarez-Córdoba, Mónica, Luzón-Hidalgo, Raquel, Suarez-Rivero, Juan M., Tiscornia, Gustavo, Sánchez-Alcázar, José Antonio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/163476
Acceso en línea:http://hdl.handle.net/10261/163476
Access Level:acceso abierto
Palabra clave:Gaucher disease
Coenzyme Q10
Efferocytosis
Inflammasome
Oxidative stress
Mitochondria
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spelling Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher diseaseMata, Mario de laCotán, DavidOropesa-Ávila, ManuelVillanueva-Paz, MarinaLavera, I. deÁlvarez-Córdoba, MónicaLuzón-Hidalgo, RaquelSuarez-Rivero, Juan M.Tiscornia, GustavoSánchez-Alcázar, José AntonioGaucher diseaseCoenzyme Q10EfferocytosisInflammasomeOxidative stressMitochondria[Background]: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease. In addition, the beneficial effects of coenzyme Q10 (CoQ) supplementation on cellular alterations were evaluated. Chemically-induced Gaucher macrophages were developed by differentiateing THP-1 monocytes to macrophages by treatment with phorbol 12-myristate 13-acetate (PMA) and then inhibiting intracellular GCase with conduritol B-epoxide (CBE), a specific irreversible inhibitor of GCase activity, and supplementing the medium with exogenous GlcCer. This cell model accumulated up to 16-fold more GlcCer compared with control THP-1 cells. [Results]: Chemically-induced Gaucher macrophages showed impaired autophagy flux associated with mitochondrial dysfunction and increased oxidative stress, inflammasome activation and impaired efferocytosis. All abnormalities were partially restored by supplementation with CoQ. [Conclusion]: These data suggest that targeting mitochondria function and oxidative stress by CoQ can ameliorate the pathological phenotype of Gaucher cells. Chemically-induced Gaucher macrophages provide cellular models that can be used to investigate disease pathogenesis and explore new therapeutics for GD.This work was supported by FIS PI13/00129 grant, Instituto de Salud Carlos III, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermos de Neurodegeneración con Acumulación Cerebral de Hierro).Peer ReviewedBioMed CentralAsociación de Enfermos de Patologías Mitocondriales (España)European CommissionJunta de AndalucíaInstituto de Salud Carlos IIIENACH AsociaciónConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2018201820172018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/163476reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1186/s13023-017-0574-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1634762026-05-22T06:33:51Z
dc.title.none.fl_str_mv Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
title Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
spellingShingle Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
Mata, Mario de la
Gaucher disease
Coenzyme Q10
Efferocytosis
Inflammasome
Oxidative stress
Mitochondria
title_short Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
title_full Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
title_fullStr Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
title_full_unstemmed Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
title_sort Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
dc.creator.none.fl_str_mv Mata, Mario de la
Cotán, David
Oropesa-Ávila, Manuel
Villanueva-Paz, Marina
Lavera, I. de
Álvarez-Córdoba, Mónica
Luzón-Hidalgo, Raquel
Suarez-Rivero, Juan M.
Tiscornia, Gustavo
Sánchez-Alcázar, José Antonio
author Mata, Mario de la
author_facet Mata, Mario de la
Cotán, David
Oropesa-Ávila, Manuel
Villanueva-Paz, Marina
Lavera, I. de
Álvarez-Córdoba, Mónica
Luzón-Hidalgo, Raquel
Suarez-Rivero, Juan M.
Tiscornia, Gustavo
Sánchez-Alcázar, José Antonio
author_role author
author2 Cotán, David
Oropesa-Ávila, Manuel
Villanueva-Paz, Marina
Lavera, I. de
Álvarez-Córdoba, Mónica
Luzón-Hidalgo, Raquel
Suarez-Rivero, Juan M.
Tiscornia, Gustavo
Sánchez-Alcázar, José Antonio
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Asociación de Enfermos de Patologías Mitocondriales (España)
European Commission
Junta de Andalucía
Instituto de Salud Carlos III
ENACH Asociación
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Gaucher disease
Coenzyme Q10
Efferocytosis
Inflammasome
Oxidative stress
Mitochondria
topic Gaucher disease
Coenzyme Q10
Efferocytosis
Inflammasome
Oxidative stress
Mitochondria
description [Background]: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease. In addition, the beneficial effects of coenzyme Q10 (CoQ) supplementation on cellular alterations were evaluated. Chemically-induced Gaucher macrophages were developed by differentiateing THP-1 monocytes to macrophages by treatment with phorbol 12-myristate 13-acetate (PMA) and then inhibiting intracellular GCase with conduritol B-epoxide (CBE), a specific irreversible inhibitor of GCase activity, and supplementing the medium with exogenous GlcCer. This cell model accumulated up to 16-fold more GlcCer compared with control THP-1 cells. [Results]: Chemically-induced Gaucher macrophages showed impaired autophagy flux associated with mitochondrial dysfunction and increased oxidative stress, inflammasome activation and impaired efferocytosis. All abnormalities were partially restored by supplementation with CoQ. [Conclusion]: These data suggest that targeting mitochondria function and oxidative stress by CoQ can ameliorate the pathological phenotype of Gaucher cells. Chemically-induced Gaucher macrophages provide cellular models that can be used to investigate disease pathogenesis and explore new therapeutics for GD.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
2018
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/10261/163476
url http://hdl.handle.net/10261/163476
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1186/s13023-017-0574-8
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
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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