title: Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma.
abstract: Whereas 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.
authors.affiliation: Wallenberg Neuroscience Center, BMC A13, 221 84 Lund, Sweden.
authors.forename: Gustav
authors.initials: G
authors.lastname: Mattiasson
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.forename: Gunilla
authors.initials: G
authors.lastname: Gido
authors.forename: Kavitha
authors.initials: K
authors.lastname: Mathi
authors.forename: Gregor
authors.initials: G
authors.lastname: Tomasevic
authors.forename: Saili
authors.initials: S
authors.lastname: Yi
authors.forename: Craig H
authors.initials: CH
authors.lastname: Warden
authors.forename: Roger F
authors.initials: RF
authors.lastname: Castilho
authors.forename: Thorsten
authors.initials: T
authors.lastname: Melcher
authors.forename: Mirella
authors.initials: M
authors.lastname: Gonzalez-Zulueta
authors.forename: Karoly
authors.initials: K
authors.lastname: Nikolich
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D007473:Ion Channels; D007511:Ischemia / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D014475:Uncoupling Agents / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D011506:Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases