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System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency.
Mandal, Pankaj Kumar; Seiler, Alexander; Perisic, Tamara; Kölle, Pirkko; Banjac Canak, Ana; Förster, Heidi; Weiss, Norbert; Kremmer, Elisabeth; Lieberman, Michael W; Bannai, Shiro; Kuhlencordt, Peter; Sato, Hideyo; Bornkamm, Georg W; Conrad, Marcus.
Afiliação
  • Mandal PK; Institute of Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, 81377 Munich, Germany.
J Biol Chem ; 285(29): 22244-53, 2010 Jul 16.
Article em En | MEDLINE | ID: mdl-20463017
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 gamma-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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sistema y/ de Transporte de Aminoácidos / Tiorredoxina Redutase 1 / Glutationa Limite: Animals Idioma: En Ano de publicação: 2010 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sistema y/ de Transporte de Aminoácidos / Tiorredoxina Redutase 1 / Glutationa Limite: Animals Idioma: En Ano de publicação: 2010 Tipo de documento: Article