RGD Reference Report - GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models. - Rat Genome Database

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GSH monoethyl ester rescues mitochondrial defects in cystic fibrosis models.

Authors: Kelly-Aubert, M  Trudel, S  Fritsch, J  Nguyen-Khoa, T  Baudouin-Legros, M  Moriceau, S  Jeanson, L  Djouadi, F  Matar, C  Conti, M  Ollero, M  Brouillard, F  Edelman, A 
Citation: Kelly-Aubert M, etal., Hum Mol Genet. 2011 Jul 15;20(14):2745-59. Epub 2011 Apr 25.
RGD ID: 6484688
Pubmed: PMID:21518732   (View Abstract at PubMed)
DOI: DOI:10.1093/hmg/ddr173   (Journal Full-text)

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 (Deltapsi(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 Deltapsi(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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cystic fibrosis  ISONdufs1 (Mus musculus)6484688; 6484688protein:increased oxidation:colonic epithelium and mitochondrion (mouse)RGD 
cystic fibrosis  IEP 6484688protein:increased oxidation:colonic epithelium and mitochondrion (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ndufs1  (NADH:ubiquinone oxidoreductase core subunit S1)

Genes (Mus musculus)
Ndufs1  (NADH:ubiquinone oxidoreductase core subunit S1)

Genes (Homo sapiens)
NDUFS1  (NADH:ubiquinone oxidoreductase core subunit S1)


Additional Information