2024-03-29T05:49:53Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1634762021-09-22T12:11:56Zcom_10261_128com_10261_1col_10261_381
Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease
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
Asociación de Enfermos de Patologías Mitocondriales (España)
European Commission
Junta de Andalucía
Instituto de Salud Carlos III
ENACH Asociación
Gaucher disease
Coenzyme Q10
Efferocytosis
Inflammasome
Oxidative stress
Mitochondria
[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.
2018-04-11T10:09:18Z
2018-04-11T10:09:18Z
2017
2018-04-11T10:09:18Z
artículo
Orphanet Journal of Rare Diseases 12(1): 23 (2017)
http://hdl.handle.net/10261/163476
10.1186/s13023-017-0574-8
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100011011
28166796
eng
Publisher's version
https://doi.org/10.1186/s13023-017-0574-8
Sí
http://creativecommons.org/licenses/by/4.0/
openAccess
BioMed Central