Journal
CELL DEATH AND DIFFERENTIATION
Volume 9, Issue 9, Pages 1007-1016Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401064
Keywords
apoptosis in undifferentiated cells; redox imbalance; GSH/GSSG ratio and apoptosis; mitochondrial apoptosis signaling; tert-butylhydroperoxide; mitochondrial ROS and permeability transition pore
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Funding
- NIDDK NIH HHS [DK44510, R01 DK044510, R01 DK044510-09] Funding Source: Medline
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Our recent study has demonstrated that cellular redox imbalance can directly initiate apoptosis in a mitotic competent PC-12 cell line without the involvement of reactive oxygen species (ROS). However, whether cell apoptosis induced by ROS is, in fact, mediated by a loss of redox balance caused by the oxidant is unresolved. The linkage between oxidant-mediated apoptosis and the induction of cellular redox was examined in PC-12 cells using the oxidant, tert-butylhydroperoxide (TBH). TBH caused cell apoptosis in 24 h that was preceded by an early increase (30 min) in oxidized glutathione (GSSG). Pretreatment with N-acetyl cysteine prevented TBH-induced GSSG increases and cell apoptosis. Altered Bax/BcL-2 expression and release of mitochondrial cytochrome c occurred post-redox imbalance and was kinetically linked to caspase-3 activation and poly ADP-ribose polymerase cleavage. Moreover, cell apoptosis was attenuated by inhibition of caspase-9, but not caspase-8, and blockade of mitochondrial ROS generation and permeability transition pore attenuated caspase 3 activation and c 11 apoptosis. Collectively, these results show that TBH-induced GSSG elevation is associated with the disruption of mitochondrial integrity, activation of caspase-3 and cell apoptosis. This redox induction of the apoptotic cascade was dissociated from cellular GSH efflux.
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