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Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels
Open accessAbstract
Uncoupling protein 2 (UCP2) is suggested to be a regulator of reactive oxygen species production in mitochondria. We performed a detailed study of brain injury, including regional and cellular distribution of UCP2 mRNA, as well as measures of oxidative stress markers following permanent middle cerebral artery occlusion in UCP2 knockout (KO) and wild‐type (WT) mice. Three days post ischemia, there was a massive induction of UCP2 mRNA confined to microglia in the peri‐infarct area of WT mice. KO mice were less sensitive to ischemia as assessed by reduced brain infarct size, decreased densities of deoxyuridine triphosphate nick end‐labelling (TUNEL)‐labelled cells in the peri‐infact area and lower levels of lipid peroxidation compared with WT mice. This resistance may be related to the substantial increase of basal manganese superoxide dismutase levels in neurons of KO mice. Importantly, we found a specific decrease of mitochondrial glutathione (GSH) levels in UCP2 expressing microglia of WT, but not in KO mice after ischemia. This specific association between UCP2 and mitochondrial GSH levels regulation was further confirmed using lipopolysaccharide models of peripheral inflammation, and in purified peritoneal macrophages. Moreover, our data imply that UCP2 is not directly involved in the regulation of ROS production but acts by regulating mitochondrial GSH levels in microglia.
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“Consistent with these latter findings, knockout of UCP2 was found to be protective in a model of cerebral ischemic injury (110).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [110]
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BackgroundInfluentialSelf-citationSuperoxide activates mitochondrial uncoupling proteins
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“It now appears that ROS production in mammalian cells is mainly a toxic by-product of the mitochondrial electron transport chain ( Raha and Robinson 2000 ).”
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“ROS have been implicated in the pathogenesis of ischemic brain injury (Chan 1996).”
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“Moreover, UCP2 has been implicated in the control of mitochondrial ROS levels (Negre-Salvayre et al. 1997; Lee et al. 1999; Arsenijevic et al. 2000; Yang et al. 2000; Li et al. 2001; Pecqueur et al. 2001) possibly by decreasing mitochondrial membrane potential (Skulachev 1998).”
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“Consistent with these latter findings, knockout of UCP2 was found to be protective in a model of cerebral ischemic injury (110).”
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“Interestingly, a role for UCP2 in the transport of mGSH has been described in neurons, suggesting that the transport of protons back into the matrix by UCP2 may favor the movement of GSH (de Bilbao et al., 2004).”
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“Whether UCP2 directly affects levels of reactive oxygen species, or regulates glutathione, which in turn affects the levels of reactive oxygen species, has been the subject of discussion (de Bilbao et al. 2004).”
BackgroundSelf-citationThe Emerging Functions of UCP2 in Health, Disease, and Therapeutics
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“Finally Finally, the role of UCP2 as a potential target for the treatment of these conditions will be addressed.”
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“SIRT1 inhibitor sirtinol prevented UCP2 upregulation, which in conjunction with a study of enhanced neuroprotection in microglia from UCP2−/− mice (De Bilbao et al., 2004), supports a role for SIRT1 in mitochondrial preservation during ischemia.”
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“Interestingly, a role for UCP2 in the transport of mitochondrial glutathione has been reported in neurons (de Bilbao et al., 2004).”
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“One important question remains to be answered: how does UCP2 modulate mitochondrial ROS production and consequently trigger signalling cascades? In a cerebral ischemic model, UCP2 was proposed as a regulator of mitochondrial glutathione levels [44].”
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“regulation of MnSOD and lowered consumption of GSH after ischemia have been proposed as compensatory mechanisms (19).”
InfluentialUCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism?
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“These further strengthen the argument that the negative effect of UCP2 observed by de Bilbao et al (2004) is probably ascribed to the permanent MCAO model being used.”
BackgroundResultHaines, B. A., Mehta, S. L., Pratt, S. M., Warden, C. H., & Li, P. A. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.52 · Cited by 78
“Contradictorily, de Bilbao et al (2004) observed that deletion of UCP2 gene in mice conferred resistance to ischemic brain damage in a permanent middle cerebral arterial occlusion (MCAO) model.”
BackgroundResultThe mitochondrial uncoupling protein‐2 is a master regulator of both M1 and M2 microglial responses
Simone, R. D., Ajmone‐Cat, M. A., Pandolfi, M., Bernardo, A., Nuccio, C. D., Minghetti, L., & Visentin, S. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13244 · Cited by 72
“…as a superoxide-permeable channel from the matrix to the intermembrane space (Mattiasson et al. 2003), regulate mitochondrial glutathione levels (de Bilbao et al. 2004) or impede the mitochondrial utilization of pyruvate derived from glucose in the so-called ‘metabolic hypothesis’ (Bouillaud 2009).”
BackgroundResveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain
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“The UCP2 KO mice (C57BL/6J, weight 19 to 21 g) and their WT colittermates (weight 19 to 22 g) were also used as described previously (de Bilbao et al, 2004).”
BackgroundMethodResultInfluentialSelf-citationThe genomic response of the ipsilateral and contralateral cortex to stroke in aged rats
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“Therefore, the elimination of ROS might be accomplished with glutathione in the reduced state in the matrix [34].”
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Caron, A., Baraboi, E., Laplante, M., & Richard, D. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23668 · Cited by 21
Self-citationEvans, Z. P., Palanisamy, A. P., Sutter, A. G., Ellett, J. D., Ramshesh, V. K., Attaway, H. H., Schmidt, M. G., Schnellmann, R. G., & Chavin, K. D. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00049.2011 · Cited by 20
UCP2 protects against amyloid beta toxicity and oxidative stress in primary neuronal culture
Jun, Z., Ibrahim, M. M., dezheng, G., Yuan, B., Wu, Q., & Zou, Y. (2015) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2015.08.001 · Cited by 18
Kambe, Y., Nakamichi, N., Takarada, T., Fukumori, R., Nakazato, R., Hinoi, E., & Yoneda, Y. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.03.018 · Cited by 18
“In UCP2-null mice with permanent middle cerebral artery occlusion, significant alleviation is seen in the infarct size, the number of apoptotic cells and lipid peroxidation levels in the peri-infarct areas (de Bilbao et al., 2004).”
Cheng, H., Munro, D., Huynh, K. W., & Pamenter, M. E. (2021) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2021.110596 · Cited by 19
Fukumori, R., Takarada, T., Nakazato, R., Fujikawa, K., Kou, M., Hinoi, E., & Yoneda, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069718 · Cited by 16
“In UCP2-null mice with permanent middle cerebral artery occlusion, significant ameliorations are seen in the infarct size, the number of apoptotic cells and lipid peroxidation levels in the periinfarct areas [35].”
BackgroundZhang, X., Li, L., Zhang, L., Borowitz, J. L., & Isom, G. E. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.03.020 · Cited by 16
“In this study, UCP-2 up-regulation enhanced cyanide depletion of mtGSH. UCP-2 knockdown significantly reduced the mtGSH depletion, thus indicating a role of UCP-2 in mtGSH depletion (de Bilbao et al., 2004).”
BackgroundUncoupling Protein 2 Increases Blood Pressure in DJ‐1 Knockout Mice
Miguel, C. D., Hamrick, W. C., Sedaka, R., Jagarlamudi, S., Asico, L. D., Jose, P. A., & Cuevas, S. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.011856 · Cited by 14
Arsenijevic, D., Clavel, S., Sanchı́s, D., Plamondon, J., Huang, Q., Ricquier, D., Rouger, L., & Richard, D. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.03.013 · Cited by 15
“Recent studies by our group have demonstrated that Ucp2 gene expression can be induced in neuronal as well as in microglial cells following exposure to kainic acid or in cerebral ischemia (Clavel et al., 2003; de Bilbao et al., 2004).”
BackgroundInfluentialSelf-citationSreekumar, P. G., Wang, M., Spee, C. K., Sadda, S. R., & Kannan, R. (2020) · Antioxidants · doi:10.3390/antiox9050411 · Cited by 14
Arsenijevic, D., de Bilbao, F., Vallet, P., Hemphill, A. F., Gottstein, B., Richard, D., Giannakopoulos, P., & Langhans, W. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.09.080 · Cited by 14
“…mM) and then processed for microglia immunohistochemistry using the anti-Iba-1 antibody (1 mg/ml, from Dr. Y. Imai, National Center of Neurology and Psychiatry, Japan) which was detected by the fluorescent goat-anti-rabbit immunoglobulin Alexa Fluor 568 (Molecular Probes) (de Bilbao et al., 2004).”
BackgroundMethodInfluentialSelf-citationLi, L., Prabhakaran, K., Zhang, X., Borowitz, J. L., & Isom, G. E. (2006) · Toxicological Sciences · doi:10.1093/toxsci/kfl039 · Cited by 13
“On the other hand, overexpression and activation may sensitize the cell to apoptotic or necrotic cell death through depletion of mitochondrial GSH and/or a decrease in efficiency of cellular ATP synthesis (de Bilbao et al., 2004; Li et al., 2005; Prabhakaran et al., 2005).”
BackgroundDíaz-Maroto Cicuéndez, I., Fernández-Díaz, E., García-García, J., Jordán, J., Fernández-Cadenas, I., Montaner, J., Serrano-Heras, G., & Segura, T. (2017) · NeuroMolecular Medicine · doi:10.1007/s12017-017-8470-x · Cited by 12
Tognocchi, M., Conte, M., Testai, L., Martucci, M., Serra, A., Salvioli, S., Calderone, V., Mele, M. L., & Conte, G. (2022) · Foods · doi:10.3390/foods11030398 · Cited by 12
“UCP2 deficiency has been shown to cause an increase in resistance to cerebral ischemia, with an increase in cerebral neuronal antioxidant status [73].”
BackgroundMitochondrial Impairments in Peripheral Blood Mononuclear Cells of Multiple Sclerosis Patients
Domínguez‐Mozo, M. I., García-Frontini, M. C., Gómez-Calcerrada, M. I., Pérez‐Pérez, S., García‐Martínez, M. Á., Villar, L. M., Villarrubia, N., Costa‐Frossard, L., Arroyo, R., & Álvarez‐Lafuente, R. (2022) · Biology · doi:10.3390/biology11111633 · Cited by 11
“This increase in cellular superoxide production has also been described in cardiovascular diseases [20] and neurodegenerative diseases such as amyotrophic lateral sclerosis [21], Alzheimer’s [22], and Parkinson’s diseases [23].”
BackgroundArsenijevic, D., Gallmann, E., Moses, W. W., Lutz, T. A., Erlanson‐Albertsson, C., & Langhans, W. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00367.2004 · Cited by 11
“Protein was precipitated by metaphosphoric acid, and the supernatant was used to quantify GSH. Total GSH levels were measured using a method based on the formation of a chromophoric product resulting from the reaction of 5,5 -dithiobis(2-nitrobenzoic acid) (DTNB, Sigma Chemicals) with GSH.”
BackgroundMethodInfluentialSelf-citationRole for nerve growth factor in the in vivo regulation of glutathione in response to LPS in mice.
Arsenijevic, D., Hernádfalvy, N., von Meyenburg, C., Onteniente, B., Richard, D., & Langhans, W. (2007) · PubMed · doi:10.1684/ecn.2007.0091 · Cited by 10
“Louis, MO, USA) and GSH (G4251, Sigma, Buchs, Switzerland) [21].”
InfluentialSelf-citationBrągoszewski, P., Habior, A., Walewska‐Zielecka, B., & Ostrowski, J. (2007) · Acta Biochimica Polonica · doi:10.18388/abp.2007_3255 · Cited by 10
“…et al., 2002), the involvement of UCP2 in a host of metabolic processes including regulation of metabolic pathways, ROS production, and response to tissue injury is generally accepted (Saleh et al., 2002; Mattiasson et al., 2003; de Bilbao et al., 2004; Horimoto et al., 2004; Krauss & Zhang, 2005).”
Chen, Y., Xu, Y., Zheng, H., Fu, J., Hou, Y., Wang, H., Zhang, Q., Yamamoto, M. P., & Pi, J. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.07.088 · Cited by 9
Cardoso, S., Santos, R. X., Carvalho, C., Correia, S. C., Santos, M. S., & Moreira, P. I. (2011) · Free Radicals and Antioxidants · doi:10.5530/ax.2011.2.3 · Cited by 8
Nino‐Fong, R., Fatehi‐Hassanabad, Z., Lee, S. C., Lu, H., Wheeler, M. B., & Chan, C. B. (2011) · Journal of Molecular Endocrinology · doi:10.1530/jme-10-0117 · Cited by 8
“Likewise, in the central nervous system, induction of UCP2 protects neurons from oxidative stress (Sullivan et al. 2004) but not all studies show this effect (de Bilbao et al. 2004, Prabhakaran et al. 2005).”
BackgroundWu, Q., Gong, D., Tian, N., Zhu, L., Guan, L., Yang, M., Yuan, B., Qiu, Q., Lv, H., & Zou, Y. (2008) · Digestive Diseases and Sciences · doi:10.1007/s10620-008-0650-y · Cited by 8
“UCP2 allowed transport of GSH into the matrix and the consumption of GSH in the efficient elimination of ROS [ 29 ].”
BackgroundFukumori, R., Takarada, T., Kambe, Y., Nakazato, R., Fujikawa, K., & Yoneda, Y. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.03.019 · Cited by 7
“In UCP2-null mice with permanent middle cerebral artery occlusion, for example, significant alleviations are seen in the infarct size, the number of apoptotic cells and lipid peroxidation levels in the peri-infarct areas (de Bilbao et al., 2004).”
BackgroundPoppy seed oil protection of the hippocampus after cerebral ischemia and re-perfusion in rats
Çevik-Demirkan, A., Öztaşan, N., Oguzhan, E., Çil, N., & Cevher, Ş. C. (2012) · Biotechnic & Histochemistry · doi:10.3109/10520295.2012.701763 · Cited by 6
“21 : 283 – 289 . and increased cerebral neuronal antioxidant state (Bilbao et al. 2004).”
BackgroundRole for glutathione in the hyposensitivity of LPS-pretreated mice to LPS anorexia.
Hernádfalvy, N., Langhans, W., von Meyenburg, C., Onteniente, B., Richard, D., & Arsenijevic, D. (2007) · PubMed · doi:10.1684/ecn.2007.0090 · Cited by 4
“From this an aliquot was taken and the trGSH tissue levels were measured using a method based on the formation of a chromophoric product resulting from the reaction with 0.04% 5,5-dithiobis-2-nitrobenzoic acid (D8130, DTNB, Sigma Chemicals, St. Louis, MO, USA) and GSH (G4251, Sigma, Buchs, Switzerland) [11].”
MethodInfluentialSelf-citationEffects of 2,4-dinitrophenol on ischemia-induced blood-brain barrier disruption
Ennis, S. R., & Keep, R. F. (2006) · Springer eBooks · doi:10.1007/3-211-30714-1_63 · Cited by 3
“[1] found that knockout mice without uncoupling protein 2 (UCP2), an endogenous”
BackgroundFree Cholesterol — A Double-Edge Sword in Alzheimer Disease
Fernández-Checa, J. C. (2015) · InTech eBooks · doi:10.5772/59935 · Cited by 3
Mitochondrial Uncoupling Proteins: Therapeutic Targets in Neurodegeneration?
Cardoso, S., Carvalho, C., Correia, S. C., Santos, R. X., Santos, M. S., & Moreira, P. I. (2010) · Cited by 2
Microglial Mitochondrial Dysfunction: The Storm Center of Post‐Stroke Neuroinflammation
Fan, R., Wang, C., Lin, Z. B., Chen, S., Pan, C., Nie, H., Qin, C., Wu, X., & Tang, Z. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.71060 · Cited by 1
“Among them, UCP2 is highly expressed in neurons and microglia [47], which was shown to downregulate IL-1β and TNF-α, upregulate IL-10 and TGF-β via the AMPKα/ NRF1 pathway, and protect against ferroptosis in experimental stroke [48].”
Metadata
- Authors
- De Bilbao, F., Arsenijevic, D., Vallet, P., Hjelle, O. P., Ottersen, O. P., Bouras, C., Raffin, Y., Abou, K., Langhans, W., Collins, S., Plamondon, J., Alves‐Guerra, M., Haguenauer, A., Garcia, I., Richard, D., Ricquier, D., & Giannakopoulos, P.
- Affiliations
- ETH Zurich (CH)
- University Hospital of Geneva (CH)
- Duke University (US)
- Université Laval (CA)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Arsenijevic, Denis
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2004-04-26
- Volume
- 89
- Issue
- 5
- Pages
- 1283-1292
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2032327447
- Cited by
- 108
- References
- 61
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 8 · 2014: 9 · 2013: 5 · 2012: 6
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- UCP2, cerebral ischemia, middle cerebral artery occlusion, microglia, mitochondrial glutathione, oxidative stress, manganese superoxide dismutase, lipid peroxidation, neuroprotection, UCP2 knockout mice, lipopolysaccharide-induced inflammation, peritoneal macrophages, reactive oxygen species
- MeSH terms
- Uncoupling Protein 2, Animals, Antioxidants, Cell Count, Brain Ischemia, Disease Models, Animal, Glutathione, Ion Channels, Lipopolysaccharides, Male, Mitochondria, RNA, Messenger, Superoxide Dismutase, Microglia, Macrophages, Peritoneal, Mice, Knockout, Oxidative Stress, Genetic Predisposition to Disease, In Situ Nick-End Labeling, Protein Transport, Mitochondrial Proteins, Membrane Transport Proteins, Cytochromes c, Mice
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