Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/9015 |
Resumo: | 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. |
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Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher diseaseGaucher diseaseInflammasomeEfferocytosisOxidative stressMitochondriaCoenzyme Q10Background 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.BioMed CentralSapientiaMata, Mario de laCotán, DavidOropesa-Ávila, ManuelVillanueva-Paz, MarinaLavera, Isabel deÁlvarez-Córdoba, MónicaLuzón-Hidalgo, RaquelSuárez-Rivero, Juan M.Tiscornia, GustavoSánchez-Alcázar, José A.2017-03-07T10:01:15Z2017-02-062017-02-06T17:04:06Z2017-02-06T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/9015engOrphanet Journal of Rare Diseases. 2017 Feb 06;12(1):23http://dx.doi.org/10.1186/s13023-017-0574-8info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:20:21Zoai:sapientia.ualg.pt:10400.1/9015Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:01:01.338916Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
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 Inflammasome Efferocytosis Oxidative stress Mitochondria Coenzyme Q10 |
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 |
author |
Mata, Mario de la |
author_facet |
Mata, Mario de la Cotán, David Oropesa-Ávila, Manuel Villanueva-Paz, Marina Lavera, Isabel de Álvarez-Córdoba, Mónica Luzón-Hidalgo, Raquel Suárez-Rivero, Juan M. Tiscornia, Gustavo Sánchez-Alcázar, José A. |
author_role |
author |
author2 |
Cotán, David Oropesa-Ávila, Manuel Villanueva-Paz, Marina Lavera, Isabel de Álvarez-Córdoba, Mónica Luzón-Hidalgo, Raquel Suárez-Rivero, Juan M. Tiscornia, Gustavo Sánchez-Alcázar, José A. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Mata, Mario de la Cotán, David Oropesa-Ávila, Manuel Villanueva-Paz, Marina Lavera, Isabel de Álvarez-Córdoba, Mónica Luzón-Hidalgo, Raquel Suárez-Rivero, Juan M. Tiscornia, Gustavo Sánchez-Alcázar, José A. |
dc.subject.por.fl_str_mv |
Gaucher disease Inflammasome Efferocytosis Oxidative stress Mitochondria Coenzyme Q10 |
topic |
Gaucher disease Inflammasome Efferocytosis Oxidative stress Mitochondria Coenzyme Q10 |
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 |
2017-03-07T10:01:15Z 2017-02-06 2017-02-06T17:04:06Z 2017-02-06T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/9015 |
url |
http://hdl.handle.net/10400.1/9015 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Orphanet Journal of Rare Diseases. 2017 Feb 06;12(1):23 http://dx.doi.org/10.1186/s13023-017-0574-8 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
BioMed Central |
publisher.none.fl_str_mv |
BioMed Central |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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