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

Nature Medicine volume 9, pages 1062–1068 (2003)Cite this article

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.

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Figure 1: Sublethal insults induce UCP-2.
Figure 2: UCP-2 is neuroprotective in models of neuronal damage in vitro and in vivo.
Figure 3: UCP-2 preserves mitochondrial membrane potential and inhibits activation of caspase-3 after OGD.
Figure 4: UCP-2 alters generation of ROS in mitochondria from transgenic and wild-type mice.
Figure 5

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Acknowledgements

We thank K. Beirup, S. Barry and S. Bennett for expert technical assistance. This work was supported by the Swedish Science Council (Project No. 08644), a grant from AGY Therapeutics, the Swedish National Network in Neuroscience, Fundação de Amparo a Pesquisa do Estado de São Paulo, Brazil, the Swedish Association of Neurologically Disabled, The Mattson foundation, the Royal Physiographic Society and National Institutes of Health grant RO1 DK53993.

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Author notes

  1. Gustav Mattiasson and Mehrdad Shamloo: These authors contributed equally to this work.

Authors and Affiliations

  1. Wallenberg Neuroscience Center, BMC A13, Lund, 221 84, Sweden

    Gustav Mattiasson, Gunilla Gido, Gregor Tomasevic & Tadeusz Wieloch

  2. AGY Therapeutics Inc., 290 Utah Ave, South San Francisco, 94080, California, USA

    Mehrdad Shamloo, Kavitha Mathi, Saili Yi, Thorsten Melcher, Mirella Gonzalez-Zulueta & Karoly Nikolich

  3. Division of Biological Sciences, Section of Neurobiology, Physiology and Behavior, School of Medicine, University of California, Davis, California, 95616, USA

    Craig H. Warden

  4. Department of Clinical Pathology, School of Medical Sciences, State University of Campinas, Campinas, 13083-970, São Paulo, Brazil

    Roger F. Castilho

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Correspondence to Tadeusz Wieloch.

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Competing interests

This work was supported by a grant from AGY Therapeutics. AGY Therapeutics has filed a patent on the use of UCP-2 as a neuroprotectant.

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Mattiasson, G., Shamloo, M., Gido, G. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9, 1062–1068 (2003). https://doi.org/10.1038/nm903

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