Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress.
Br J Pharmacol
; 171(8): 2147-58, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24319993
ABSTRACT
BACKGROUND AND PURPOSE:
The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc-. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction. EXPERIMENTALAPPROACH:
We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line. KEYRESULTS:
Glutamate-resistant mitochondria were less fragmented and displayed seemingly contradictory features mitochondrial calcium and superoxide were increased while high-resolution respirometry suggested a reduction in mitochondrial respiration. This was interpreted as a reverse activity of the ATP synthase under oxidative stress, leading to hydrolysis of ATP to maintain or even elevate the mitochondrial membrane potential, suggesting these cells endure ineffective energy metabolism to protect their membrane potential. Glutamate-resistant cells were also resistant to oligomycin, an inhibitor of the ATP synthase, but sensitive to deoxyglucose, an inhibitor of hexokinases. Exchanging glucose with galactose rendered resistant cells 1000-fold more sensitive to oligomycin. These results, together with a strong increase in cytosolic hexokinase 1 and 2, a reduced lactate production and an increased activity of glucose-6-phosphate dehydrogenase, suggest that glutamate-resistant HT22 cells shuttle most available glucose towards the hexose monophosphate shunt to increase glutathione recovery. CONCLUSIONS AND IMPLICATIONS These results indicate that mitochondrial and metabolic adaptations play an important role in the resistance of cells to oxidative stress.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Estresse Oxidativo
/
Metabolismo Energético
/
Hipocampo
/
Mitocôndrias
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2014
Tipo de documento:
Article