Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis
Open accessAbstract
Background & aims Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion.Methods We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging.Results In isolated mitochondria and primary hepatocytes, superoxide scavenging by SOD mimetics or purified SOD decreased superoxide and peroxynitrite generation but increased H(2)O(2) following mGSH depletion, despite mitochondrial peroxiredoxin/thioredoxin defense. Selective mGSH depletion sensitized hepatocytes to cell death induced by SOD mimetics, and this was prevented by RIP1 kinase inhibition with necrostatin-1 or GSH repletion with GSH ethyl ester (GSHee). Mice fed the methionine-choline deficient (MCD) diet or MAT1A(-/-) mice exhibited reduced SOD2 activity; in vivo treatment with SOD mimetics increased liver damage, inflammation, and fibrosis, despite a decreased superoxide and 3-nitrotyrosine immunoreactivity, effects that were ameliorated by mGSH replenishment with GSHee, but not NAC. As a proof-of-principle of the detrimental role of superoxide scavenging when mGSH was depleted transgenic mice overexpressing SOD2 exhibited enhanced susceptibility to MCD-mediated SH.Conclusions These findings underscore a critical role for mGSH in the therapeutic potential of superoxide scavenging in SH, and suggest that the combined approach of superoxide scavenging with mGSH replenishment may be important in SH.
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Without proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states results in decreased levels of mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular protection.
“Without proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states result in decreased levels of mitochondrial antioxidants including mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular protection [30].”
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Cites
Oxyl radicals, redox-sensitive signalling cascades and antioxidants
Genestra, M. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2007.04.009 · Cited by 4,930 · see citing works
Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388 · see citing works
Steatohepatitis: A tale of two “hits”?
Day, C. P., & James, O. F. W. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70599-2 · Cited by 4,285 · see citing works
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A., & Yuan, J. (2005) · Nature Chemical Biology · doi:10.1038/nchembio711 · Cited by 3,068 · see citing works
Identification of RIP1 kinase as a specific cellular target of necrostatins
Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I. L., Korkina, O., Teng, X., Abbott, D., Cuny, G. D., Yuan, C., Wagner, G., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.83 · Cited by 2,059 · see citing works
Giorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005) · Cell · doi:10.1016/j.cell.2005.05.011 · Cited by 1,176 · see citing works
Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations
Murphy, M. P., & Smith, R. A. J. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105110 · Cited by 1,173 · see citing works
Self-citationCytokines in Alcoholic and Nonalcoholic Steatohepatitis
Tilg, H., & Diehl, A. M. (2000) · New England Journal of Medicine · doi:10.1056/nejm200011163432007 · Cited by 935 · see citing works
Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis.
Pérez-Carreras, M., Del Hoyo, P., Martín, M. A., Rubio, J. C., Martín, A., Castellano, G., Colina, F., Arenas, J., & Solis-Herruzo, J. A. (2003) · Hepatology · doi:10.1002/hep.1840380426 · Cited by 734 · see citing works
Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis
Marı́, M., Caballero, F. G., Colell, A., Morales, A., Caballería, J., Fernandez, A., Enrich, C., Fernández-Checa, J. C., & García‐Ruiz, C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.07.006 · Cited by 605 · see citing works
Self-citationBell, E. L., Klimova, T. A., Eisenbart, J., Moraes, C. T., Murphy, M. P., Budinger, G. R. S., & Chandel, N. S. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200609074 · Cited by 568 · see citing works
Self-citationSuperoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential
Batinic̈‐Haberle, I., Reboucas, J. S., & Spasojević, I. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2876 · Cited by 531 · see citing works
Animal models of nonalcoholic fatty liver disease
Hebbard, L., & George, J. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.191 · Cited by 495 · see citing works
A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase
Melov, S., Schneider, J. A., Day, B. J., Hinerfeld, D. A., Coskun, P. E., Mirra, S. S., Crapo, J. D., & Wallace, D. C. (1998) · Nature Genetics · doi:10.1038/ng0298-159 · Cited by 487 · see citing works
Lu, S. C., Alvarez, L., Huang, Z.-Z., Chen, L., An, W., Corrales, F. J., Avila, M. A., Kanel, G., & Mato, J. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091016398 · Cited by 449 · see citing works
Self-citationPessayre, D., & Fromenty, B. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.03.004 · Cited by 441 · see citing works
Manganese superoxide dismutase in disease
MacMillan-Crow, L. A., & Cruthirds, D. L. (2001) · Free Radical Research · doi:10.1080/10715760100300281 · Cited by 371 · see citing works
Mitochondrial Adaptations to Obesity-Related Oxidant Stress
Yang, S., Zhu, H., Li, Y., Lin, H., Gabrielson, K., Trush, M. A., & Diehl, A. M. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.1829 · Cited by 366 · see citing works
Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis
Pérez-Carreras, M. (2003) · Hepatology · doi:10.1053/jhep.2003.50398 · Cited by 340 · see citing works
García‐Ruiz, C., Colell, A., Morales, A., Kaplowitz, N., & Fernández-Checa, J. C. (1995) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10539-7 · Cited by 337 · see citing works
Self-citationMethionine Metabolism and Liver Disease
Mato, J. M., Martínez‐Chantar, M. L., & Lu, S. C.-L. (2008) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.28.061807.155438 · Cited by 311 · see citing works
Self-citationBeckman, K. B., & Ames, B. N. (2000) · Elsevier eBooks · doi:10.1016/b978-044482650-3/50027-4 · Cited by 307 · see citing works
Sod mimetics are coming of age
Salvemini, D., Riley, D. P., & Cuzzocrea, S. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd796 · Cited by 260 · see citing works
Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis
Caballero, F., Fernández, A., Matías, N., Martínez-Gili, L., Fucho, R., Elena, M., Caballería, J., Morales, A., Fernández-Checa, J. C., & García‐Ruiz, C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.099333 · Cited by 238 · see citing works
Self-citationSteatohepatitis Induced by Intragastric Overfeeding in Mice *
Deng, Q.-G., She, H., Cheng, J. H., French, S. W., Koop, D. R., Xiong, S., & Tsukamoto, H. (2005) · Hepatology · doi:10.1002/hep.20877 · Cited by 215 · see citing works
Self-citationServiddio, G., Bellanti, F., Tamborra, R., Rollo, T., Capitanio, N., Romano, A. D., Sastre, J., Vendemiale, G., & Altomare, E. (2008) · Gut · doi:10.1136/gut.2007.147496 · Cited by 214 · see citing works
Han, D., Canali, R., Rettori, D., & Kaplowitz, N. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.5.1136 · Cited by 212 · see citing works
Self-citationRedox Control of Liver Function in Health and Disease
Marı́, M., Colell, A., Morales, A., von Montfort, C., García‐Ruiz, C., & Fernández-Checa, J. C. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2634 · Cited by 201 · see citing works
Self-citationNonalcoholic Steatohepatitis in Children
Carter-Kent, C. A., Yerian, L. M., Brunt, E. M., Angulo, P., Kohli, R., Ling, S. C., Xanthakos, S. A., Whitington, P. F., Charatcharoenwitthaya, P., Yap, J. Y. K., et al. (2009) · Hepatology · doi:10.1002/hep.23133 · Cited by 200 · see citing works
Nguyen, T. T. M., Stevens, M. V., Kohr, M. J., Steenbergen, C., Sack, M. N., & Murphy, E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.243469 · Cited by 189 · see citing works
Role of CHOP in Hepatic Apoptosis in the Murine Model of Intragastric Ethanol Feeding
Ji, C., Mehrian‐Shai, R., Chan, C., Hsu, Y., & Kaplowitz, N. (2005) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000174691.03751.11 · Cited by 189 · see citing works
Self-citationFernández, A., Llacuna, L., Fernández-Checa, J. C., & Colell, A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.4909-08.2009 · Cited by 150 · see citing works
Batinic̈‐Haberle, I., Cuzzocrea, S., Reboucas, J. S., Ferrer‐Sueta, G., Mazzon, E., Paola, R. D., Radí, R., Spasojević, I., Benov, L., & Salvemini, D. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.09.042 · Cited by 140 · see citing works
Laurent, A., Nicco, C., Nhieu, J. T. V., Borderie, D., Chéreau, C., Conti, F., Jaffray, P., Soubrane, O., Calmus, Y., Weill, B. J., et al. (2004) · Hepatology · doi:10.1002/hep.20177 · Cited by 120 · see citing works
Demicheli, V., Quijano, C., Álvarez, B., & Radí, R. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.01.034 · Cited by 103 · see citing works
Increase in liver antioxidant enzyme activities in non‐alcoholic fatty liver disease
Perlemuter, G., Spraul, A., Cosson, C., Conti, M., Bigorgne, A., Paradis, V., Corre, M., Prat, L., Kuoch, V., Basdevant, A., et al. (2005) · Liver International · doi:10.1111/j.1478-3231.2005.01126.x · Cited by 98 · see citing works
Marı́, M., Colell, A., Morales, A., Caballero, F., Moles, A., Fernández, A., Terrones, O., Basáñez, G., Antonsson, B. E., García‐Ruiz, C., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.01.073 · Cited by 96 · see citing works
Raineri, I., Carlson, E. J., Gacayan, R., Carra, S., Oberley, T. D., Huang, T.-T., & Epstein, C. J. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00686-4 · Cited by 73 · see citing works
Kondrikov, D., Fonseca, F. V., Elms, S. C., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.063172 · Cited by 47 · see citing works
García-Ruiz, I., Fernández-Moreira, D., Solís-Muñoz, P., Rodríguez-Juan, C., Díaz-Sanjuán, T., Muñoz-Yagüe, T., & Solís-Herruzo, J. A. (2010) · Journal of Proteome Research · doi:10.1021/pr9011427 · Cited by 46 · see citing works
Larosche, I., Choumar, A., Fromenty, B., Lettéron, P., Abbey‐Toby, A., Remmen, H. V., Epstein, C. J., Richardson, A. G., Feldmann, G., Pessayre, D., et al. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.11.004 · Cited by 38 · see citing works
Self-citationLowes, D. A., & Galley, H. F. (2011) · Biochemical Journal · doi:10.1042/bj20102135 · Cited by 37 · see citing works
Defective Antioxidant Defense System in Patients with a Human Leptin Gene Mutation
Özata, M., Üçkaya, G., Aydın, A., et al. (2000) · Hormone and Metabolic Research · doi:10.1055/s-2007-978634 · Cited by 30 · see citing works
Metabolic Effects of Dietary Manganese Supplementation in ob/ob Mice
Welsh, J., Narbaitz, R. M., & Bégin‐Heick, N. (1985) · Journal of Nutrition · doi:10.1093/jn/115.7.919 · Cited by 15 · see citing works
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Gebhardt, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i26.8491 · Cited by 275 · see citing works
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
- Authors
- Montfort, C. V., Matias, N., Fernandez, A., Fucho, R., de la Rosa, L. C., Martinez-Chantar, M. L., Mato, J. M., Machida, K., Tsukamoto, H., Murphy, M. P., Mansouri, A., Kaplowitz, N., Garcia-Ruiz, C., & Fernandez-Checa, J. C.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- CIC bioGUNE (ES)
- University of Southern California (US)
- MRC Mitochondrial Biology Unit (GB)
- Université Paris Diderot (FR)
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 57
- Issue
- 4
- Pages
- 852-859
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC3445734
- OpenAlex
- W2036167505
- Cited by
- 83
- References
- 44
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 3 · 2020: 8 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 3 · 2015: 5 · 2014: 15 · 2013: 6 · 2012: 2
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- Universidad de Navarra
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (P50-AA11999, R01AA018857, P50AA011999)
- National Center for Complementary and Integrative Health (R01AT001576, R01AT-1576)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- steatohepatitis, mitochondrial glutathione, superoxide radical scavenging, manganese superoxide dismutase, hydrogen peroxide, peroxynitrite, superoxide dismutase mimetic, necrostatin-1, RIP1 kinase, methionine-choline-deficient diet, hepatocyte death, liver fibrosis, oxidative stress
- MeSH terms
- Superoxide Dismutase 2, Alanine Transaminase, Animals, Antimycin A, Choline Deficiency, Diet, Disease Models, Animal, Fatty Liver, Glutathione, Hydrogen Peroxide, Male, Metalloporphyrins, Methionine, Methionine Adenosyltransferase, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Liver, Oxidation-Reduction, Pentanoic Acids, Superoxides, Superoxide Dismutase, Thioredoxins, Free Radical Scavengers, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Hepatocytes, Mice, Peroxiredoxin III, Primary Cell Culture
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