Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma

Gustav Mattiasson, Mehrdad Shamloo, Gunilla Gido, Kavitha Mathi, Gregor Tomasevic, Saili Yi, Craig H Warden, Roger F. Castilho, Thorsten Melcher, Mirella Gonzalez-Zulueta, Karoly Nikolich, Tadeusz Wieloch

Research output: Contribution to journalArticle

404 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1062-1068
Number of pages7
JournalNature Medicine
Volume9
Issue number8
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Mattiasson, G., Shamloo, M., Gido, G., Mathi, K., Tomasevic, G., Yi, S., Warden, C. H., Castilho, R. F., Melcher, T., Gonzalez-Zulueta, M., Nikolich, K., & Wieloch, T. (2003). Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Medicine, 9(8), 1062-1068. https://doi.org/10.1038/nm903