Coenzyme Q(10) 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/10400.1/11333 |
Resumo: | Background: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal beta-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 Q(10) (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 Q(10) partially restores pathological alterations in a macrophage model of Gaucher diseaseTriggers mitochondria degradationLysosomal storage disordersParkinsons diseaseMouse modelDysfunctionDeficiencyMitophagyAutophagyMiceAccumulationGaucher diseaseCoenzyme Q10MitochondriaOxidative stressInflammasomeEfferocytosisBackground: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal beta-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 Q(10) (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.FIS [PI13/00129]; Instituto de Salud Carlos III, Spain; Fondo Europeo de Desarrollo Regional (FEDER-Union Europea); Proyecto de Investigacion de Excelencia de la Junta de Andalucia [CTS-5725]; AEPMI (Asociacion de Enfermos de Patologia Mitocondrial); ENACH (Asociacion de Enfermos de Neurodegeneracion con Acumulacion Cerebral de Hierro)Biomed CentralSapientiade la Mata, MarioCotan, DavidOropesa-Avila, ManuelVillanueva-Paz, Marinade lavera, IsabelAlvarez-Cordoba, MonicaLuzón-Hidalgo, RaquelSuarez-Rivero, Juan M.Tiscornia, GustavoSanchez-Alcazar, José A.2018-12-07T14:53:03Z2017-022017-02-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/11333eng1750-1172https://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:RCAAP2023-07-24T10:23:07Zoai:sapientia.ualg.pt:10400.1/11333Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:02:51.271864Repositório 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 Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
title |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
spellingShingle |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease de la Mata, Mario Triggers mitochondria degradation Lysosomal storage disorders Parkinsons disease Mouse model Dysfunction Deficiency Mitophagy Autophagy Mice Accumulation Gaucher disease Coenzyme Q10 Mitochondria Oxidative stress Inflammasome Efferocytosis |
title_short |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
title_full |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
title_fullStr |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
title_full_unstemmed |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
title_sort |
Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease |
author |
de la Mata, Mario |
author_facet |
de la Mata, Mario Cotan, David Oropesa-Avila, Manuel Villanueva-Paz, Marina de lavera, Isabel Alvarez-Cordoba, Monica Luzón-Hidalgo, Raquel Suarez-Rivero, Juan M. Tiscornia, Gustavo Sanchez-Alcazar, José A. |
author_role |
author |
author2 |
Cotan, David Oropesa-Avila, Manuel Villanueva-Paz, Marina de lavera, Isabel Alvarez-Cordoba, Monica Luzón-Hidalgo, Raquel Suarez-Rivero, Juan M. Tiscornia, Gustavo Sanchez-Alcazar, 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 |
de la Mata, Mario Cotan, David Oropesa-Avila, Manuel Villanueva-Paz, Marina de lavera, Isabel Alvarez-Cordoba, Monica Luzón-Hidalgo, Raquel Suarez-Rivero, Juan M. Tiscornia, Gustavo Sanchez-Alcazar, José A. |
dc.subject.por.fl_str_mv |
Triggers mitochondria degradation Lysosomal storage disorders Parkinsons disease Mouse model Dysfunction Deficiency Mitophagy Autophagy Mice Accumulation Gaucher disease Coenzyme Q10 Mitochondria Oxidative stress Inflammasome Efferocytosis |
topic |
Triggers mitochondria degradation Lysosomal storage disorders Parkinsons disease Mouse model Dysfunction Deficiency Mitophagy Autophagy Mice Accumulation Gaucher disease Coenzyme Q10 Mitochondria Oxidative stress Inflammasome Efferocytosis |
description |
Background: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal beta-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 Q(10) (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 |
2017-02 2017-02-01T00:00:00Z 2018-12-07T14:53:03Z |
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/10400.1/11333 |
url |
http://hdl.handle.net/10400.1/11333 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1750-1172 https://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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RCAAP |
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RCAAP |
reponame_str |
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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