The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
System xc− and Thioredoxin Reductase 1 Cooperatively Rescue Glutathione Deficiency
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“NAC also participates to the control of the intracellular redox state by supplying cysteine into the cystine/cysteine redox couple (Mandal et al., 2010).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Mandal et al., 2010
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
Trachootham, D., Alexandre, J., & Huang, P. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2803 · Cited by 5,452
Hayes, J. D., & Pulford, D. J. (1995) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409239509083491 · Cited by 3,464
Nordberg, J., & Arnér, E. S. J. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00724-9 · Cited by 2,720
Glutathione Transferases—Structure and Catalytic Activit
Mannervik, B., Danielson, U. H., & KETTERER, B. (1988) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238809088226 · Cited by 1,759
Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., & Yamamoto, M. P. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.21.16023 · Cited by 1,473
Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.005 · Cited by 1,470
Sato, H., Tamba, M., Ishii, T., & Bannai, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11455 · Cited by 1,111
Fernandes, A. P., & Holmgren, A. (2004) · Antioxidants and Redox Signaling · doi:10.1089/152308604771978354 · Cited by 670
Prinz, W. A., Åslund, F., Holmgren, A., & Beckwith, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.25.15661 · Cited by 662
Cited by
Sorted by citations
Ferroptosis: mechanisms, biology and role in disease
Jiang, X., Stockwell, B. R., & Conrad, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00324-8 · Cited by 7,973
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy
Koppula, P., Zhuang, L., & Gan, B. (2020) · Protein & Cell · doi:10.1007/s13238-020-00789-5 · Cited by 2,640
Targeting Ferroptosis to Iron Out Cancer
Hassannia, B., Vandenabeele, P., & Berghe, T. V. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.04.002 · Cited by 2,498
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis
Ingold, I., Berndt, C., Schmitt, S., Doll, S. G., Poschmann, G., Buday, K., Roveri, A., Peng, X., Freitas, F. P., Seibt, T., et al. (2017) · Cell · doi:10.1016/j.cell.2017.11.048 · Cited by 1,712
Metadata
- 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
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 285
- Issue
- 29
- Pages
- 22244-22253
- ISSN
- 0021-9258 (ISSN-L)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
