Redox imbalance in cystine/glutamate transporter-deficient mice

Hideyo Sato, Ayako Shiiya, Mayumi Kimata, Kanako Maebara, Michiko Tamba, Yuki Sakakura, Nobuo Makino, Fumihiro Sugiyama, Ken Ichi Yagami, Takashi Moriguchi, Satoru Takahashi, Shiro Bannai

Research output: Contribution to journalArticlepeer-review

242 Citations (Scopus)

Abstract

Cystine/glutamate transporter, designated as system xc -, mediates cystine entry in exchange for intracellular glutamate in mammalian cells. This transporter consists of two protein components, xCT and 4F2 heavy chain, and the former is predicted to mediate the transport activity. This transporter plays a pivotal role for maintaining the intracellular GSH levels and extracellular cystine/cysteine redox balance in cultured cells. To clarify the physiological roles of this transporter in vivo, we generated and characterized mice lacking xCT. The xCT-/- mice were healthy in appearance and fertile. However, cystine concentration in plasma was significantly higher in these mice, compared with that in the littermate xCT+/+ mice, while there was no significant difference in plasma cysteine concentration. Plasma GSH level in xCT-/- mice was lower than that in the xCT+/+ mice. The embryonic fibroblasts derived from xCT-/- mice failed to survive in routine culture medium, and 2-mercaptoethanol was required for survival and growth. When 2-mercaptoethanol was removed from the culture medium, cysteine and GSH in these cells dramatically decreased, and cells started to die within 24 h. N-Acetyl cysteine also rescued xCT-/--derived cells and permitted growth. These results demonstrate that system xc- contributes to maintaining the plasma redox balance in vivo but is dispensable in mammalian development, although it is vitally important to cells in vitro.

Original languageEnglish
Pages (from-to)37423-37429
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
Publication statusPublished - 2005 Nov 11

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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