Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis.
J Biol Chem
; 272(34): 21388-95, 1997 Aug 22.
Article
en En
| MEDLINE
| ID: mdl-9261153
ABSTRACT
The key events implicated in ceramide-triggered apoptosis remain unknown. In this study we show that 25 microM C6-ceramide induced significant H2O2 production within 60 min, which increased up to 180 min in human myeloid leukemia U937 cells. Inactive analogue dihydro-C6-ceramide had no effect. Furthermore, no H2O2 production was observed in C6-ceramide-treated U937 rho degrees cells, which are mitochondrial respiration-deficient. We also present evidence that ceramide-induced activation of the transcription factors NF-kappaB and AP-1 is mediated by mitochondrial derived reactive oxygen species. Both H2O2 production, transcription factor activation as well as apoptosis could be inhibited by rotenone and thenoyltrifluoroacetone (specific mitochondrial complexes I and II inhibitors) and antioxidants, N-acetylcysteine and pyrrolidine dithiocarbamate. These effects could be potentiated by antimycin A (specific complex III mitochondrial inhibitor). H2O2 production was also inhibitable by ruthenium red, suggesting a role of mitochondrial calcium homeostasis alterations in ceramide-induced oxidative stress. Finally, C6-ceramide had no influence on mitochondrial membrane potential within the first 6 h. Altogether, our study points to reactive oxygen species, generated at the ubiquinone site of the mitochondrial respiratory chain, as an early major mediator in ceramide-induced apoptosis.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ceramidas
/
Apoptosis
/
Peróxido de Hidrógeno
/
Mitocondrias
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
1997
Tipo del documento:
Article
País de afiliación:
Francia