期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 44, 期 5, 页码 768-778出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2007.09.011
关键词
NCM460 cells; intestinal epithelial cells; apoptosis; redox imbalance; GSH/GSSG ratio; mitochondrial redox; menadione; mitochondrial GSH transporters; free radicals
资金
- NIDDK NIH HHS [DK 44510, R01 DK044510, R01 DK044510-13A1, R01 DK044510-14] Funding Source: Medline
Previously. we showed that cellular glutathione/glutathione disulfide (GSH/GSSG) play an important role in apoptotic signaling, and early studies linked mitochondrial GSH (mtGSH) loss to enhanced cytotoxicity. The current study focuses on the contribution of mitochondrial GSH transport and mitochondrial GSH/GSSG status to apoptosis initiation in a nontransformed colonic epithelial cell line, NCM460, using menadione (MQ), a quinone with redox cycling bioreactivity, as a model of oxidative challenge. Our results implicate the semiquinone radical in MQ-mediated apoptosis, which was associated with marked oxidation of the mitochondrial soluble GSH and protein-bound thiol pools, mitochondria-to-cytosol translocation of cytochrome c, and activation of caspase-9. MQ-induced apoptosis was potentiated by inhibition of mtGSH uptake in accordance with exacerbated mitochondrial GSSG (mtGSSG) and protein-SSG and compromised mitochondrial respiratory activity. Moreover, cell apoptosis was prevented by N-acetyl-L-Cysteine (NAC) pretreatment, which restored cellular redox homeostasis. Importantly, mtGSH transport inhibition effectively blocked NAC-mediated protection in accordance with its failure to attenuate mtGSSG. These results support the importance of mitochondrial GSH transport and the mtGSH status in oxidative cell killing. (c) 2007 Elsevier Inc. All rights reserved.
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