System xc- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency

Pankaj Kumar Mandal, Alexander Seiler, Tamara Perisic, Pirkko Kölle, Ana Banjac Canak, Heidi Förster, Norbert Weiss, Elisabeth Kremmer, Michael W. Lieberman, Shiro Bannai, Peter Kuhlencordt, Hideyo Sato, Georg W. Bornkamm, Marcus Conrad

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

GSH is the major antioxidant and detoxifier of xenobiotics in mammalian cells. A strong decrease of intracellular GSH has been frequently linked to pathological conditions like ischemia/reperfusion injury and degenerative diseases including diabetes, atherosclerosis, and neurodegeneration. Although GSH is essential for survival, the deleterious effects of GSH deficiency can often be compensated by thiol-containing antioxidants. Using three genetically defined cellular systems, we show here that forced expression of xCT, the substrate-specific subunit of the cystine/glutamate antiporter, in γ-glutamylcysteine synthetase knock-out cells rescues GSH deficiency by increasing cellular cystine uptake, leading to augmented intracellular and surprisingly high extracellular cysteine levels. Moreover, we provide evidence that under GSH deprivation, the cytosolic thioredoxin/thioredoxin reductase system plays an essential role for the cells to deal with the excess amount of intracellular cystine. Our studies provide first evidence that GSH deficiency can be rescued by an intrinsic genetic mechanism to be considered when designing therapeutic rationales targeting specific redox enzymes to combat diseases linked to GSH deprivation.

Original languageEnglish (US)
Pages (from-to)22244-22253
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number29
DOIs
StatePublished - Jul 16 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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