Cited by 269Sulfur Compounds in BiologyRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

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System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione Deficiency

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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·2010·Journal of Biological Chemistry

DOI 10.1074/jbc.m110.121327PMC PMC2903358

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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 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.

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Authors: Mandal, P. K., Seiler, A., Perisic, T., Kölle, P., Banjac Canak, A., Förster, H., Weiss, N., Kremmer, E., Lieberman, M. W., Bannai, S., Kuhlencordt, P., Sato, H., Bornkamm, G. W., & Conrad, M.
Affiliations: Helmholtz Munich (DE)
Ludwig-Maximilians-Universität München (DE)
Houston Methodist (US)
Yamagata University (JP)
Corresponding author: Conrad, Marcus
ORCID: Mandal, Pankaj Kumar
Kremmer, Elisabeth
Lieberman, Michael W.
Sato, Hideyo
Conrad, Marcus
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2010-07
Volume: 285
Issue: 29
Pages: 22244-22253
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m110.121327
PMC: PMC2903358
OpenAlex: W1995185113
Cited by: 269
References: 44
Citations by year: 2026: 11 · 2025: 36 · 2024: 45 · 2023: 31 · 2022: 24 · 2021: 24 · 2020: 16 · 2019: 9 · 2018: 14 · 2017: 12 · 2016: 9 · 2015: 5 · 2014: 6 · 2013: 10 · 2012: 5
FWCI: 4.19
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 3728 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Site cant be reached (submittedVersion)
Funders: Deutsche Forschungsgemeinschaft
Deutsche Krebshilfe
Japan Society for the Promotion of Science
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords: glutathione deficiency, SLC7A11, thioredoxin reductase 1, thioredoxin, gamma-glutamylcysteine synthetase, cystine uptake, redox homeostasis, thiol antioxidants, glutathione synthesis, ischemia-reperfusion injury, oxidative enzymes
MeSH terms: Animals, Cysteine, Extracellular Space, Glutamate-Cysteine Ligase, Glutathione, Cell Death, Coculture Techniques, Buthionine Sulfoximine, Amino Acid Transport System y+, Intracellular Space, Green Fluorescent Proteins, Mice, Thioredoxin Reductase 1, Thioredoxin Reductase 2

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System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione Deficiency

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