Contribution of mitochondrial GSH transport to matrix GSH status and colonic epithelial cell apoptosis

Magdalena L. Circu, Cynthia Rodriguez, Ronald Maloney, Mary Pat Moyer, Tak Yee Aw

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)768-778
Number of pages11
JournalFree Radical Biology and Medicine
Issue number5
StatePublished - Mar 1 2008
Externally publishedYes


  • Apoptosis
  • Free radicals
  • GSH/GSSG ratio
  • Intestinal epithelial cells
  • Menadione
  • Mitochondrial GSH transporters
  • Mitochondrial redox
  • NCM460 cells
  • Redox imbalance

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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