Nature Medicine
9, 1062 - 1068 (2003)
Published online: 13 July 2003; | doi:10.1038/nm903
Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain traumaGustav Mattiasson1, 5, Mehrdad Shamloo2, 5, Gunilla Gido1, Kavitha Mathi2, Gregor Tomasevic1, Saili Yi2, Craig H. Warden3, Roger F. Castilho4, Thorsten Melcher2, Mirella Gonzalez-Zulueta2, Karoly Nikolich2
& Tadeusz Wieloch11
Wallenberg Neuroscience Center, BMC A13, 221 84 Lund, Sweden. 2
AGY Therapeutics Inc., 290 Utah Ave, South San Francisco, California 94080, USA. 3
Section of Neurobiology, Physiology and Behavior, Division of Biological Sciences, School of Medicine, University of California, Davis, California 95616, USA. 4
Department of Clinical Pathology, School of Medical Sciences, State University of Campinas, Campinas, São Paulo 13083-970, Brazil. 5
These authors contributed equally to this work.
Correspondence should be addressed to Tadeusz Wieloch Tadeusz.Wieloch@Expbr.lu.seWhereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.
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