GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models
| العنوان: | GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models |
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| المؤلفون: | Franck Brouillard, Maryvonne Baudouin-Legros, Sandra Moriceau, Thao Nguyen-Khoa, Mario Ollero, Ludovic Jeanson, Stéphanie Trudel, Janine Fritsch, Corine Matar, Fatima Djouadi, Marc Conti, Mairead Kelly-Aubert, Aleksander Edelman |
| المصدر: | Human Molecular Genetics. 20:2745-2759 |
| بيانات النشر: | Oxford University Press (OUP), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Cystic Fibrosis, Respiratory chain, Cystic Fibrosis Transmembrane Conductance Regulator, Radiation-Protective Agents, Biology, Gene mutation, Mitochondrion, Cystic fibrosis, Cell Line, Mice, chemistry.chemical_compound, Internal medicine, Genetics, medicine, Animals, Mice, Inbred CFTR, Interleukin 8, Molecular Biology, Genetics (clinical), Dicarboxylic Acid Transporters, Membrane Potential, Mitochondrial, Mice, Knockout, chemistry.chemical_classification, Reactive oxygen species, Electron Transport Complex I, Interleukin-8, Membrane Transport Proteins, Recovery of Function, General Medicine, Glutathione, medicine.disease, Molecular biology, Cystic fibrosis transmembrane conductance regulator, Mitochondria, Endocrinology, chemistry, Mutation, biology.protein |
| الوصف: | Cystic fibrosis (CF), a multisystem disease caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations, is associated with an abnormal inflammatory response and compromised redox homeostasis in the airways. Recent evidence suggests that dysfunctional CFTR leads to redox imbalance and to mitochondrial reduced glutathione (mtGSH) depletion in CF models. This study was designed to investigate the consequences of mtGSH depletion on mitochondrial function and inflammatory response. mtGSH depletion was confirmed in colonic epithelium of CFTR-null mice and in CFTR-mutated human epithelial cells. GSH uptake experiments performed on isolated mitochondria suggest that mtGSH depletion is not due to a defective GSH transport capacity by CF mitochondria, despite the decreased expression of two mtGSH carriers, oxoglutarate carrier and dicarboxylate carrier. CM-H(2)DCFDA [5 (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester] fluorescence and aconitase activity showed an increase in reactive oxygen species levels in CFTR-defective cells and a pro-oxidative environment within CF mitochondria. The activities of respiratory chain complexes were further examined. Results showed a selective loss of Complex I (CI) function in CF models associated with an altered mitochondrial membrane potential (Δψ(m)). CI analysis showed normal expression but an overoxidation of its NADH-ubiquinone oxidoreductase Fe-S protein 1 subunit. GSH monoethyl ester (GSH-EE) significantly enhanced mtGSH levels in the IB3-1/C38 model and reversed CI inhibition, suggesting that mtGSH depletion is responsible for the loss of CI activity. Furthermore, GSH-EE attenuated Δψ(m) depolarization and restored normal IL-8 secretion by CFTR-defective cells. These studies provide evidence for a critical role of a mtGSH defect in mitochondrial dysfunction and abnormal IL-8 secretion in CF cells and reveal the therapeutic potential of mitochondria-targeted antioxidants in CF. |
| تدمد: | 1460-2083 0964-6906 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f6b787f1d155bd93b9064a301e3eb69 https://doi.org/10.1093/hmg/ddr173 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0f6b787f1d155bd93b9064a301e3eb69 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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