Metabolism and functions of copper in brain
Introduction
Copper is an indispensable element for all organisms that have an oxidative metabolism. Copper is after iron and zinc the third most abundant essential transition metal in human liver (Lewinska-Preis et al., 2011). Although some compounds exist with copper in the oxidation states Cu3+ and Cu4+, copper biochemistry is largely dominated by Cu+ and Cu2+ compounds, as these ions form numerous complexes with both organic and inorganic ligands. The soft Cu+ ion prefers ligands that have large polarizable electron clouds, such as sulfur ligands or unsaturated nitrogen donors. Such ligands usually exert coordination numbers from two to four with linear, trigonal or tetrahedral coordination, while the hard Cu2+ ion prefers sp3 hybridized nitrogen and oxygen ligands (Crichton and Pierre, 2001, Kaim and Rall, 1996, Rubino and Franz, 2012, Tisato et al., 2010, Wadas et al., 2007). The reduction potential of the Cu2+/Cu+ redox pair varies dramatically depending on the ligand environment and the pH. For example, the one electron oxidation of various Cu+-complexes toward dioxygen has been reported to vary between −1.5 and +1.3 V (Tisato et al., 2010), while in copper proteins the reduction potential for Cu2+/Cu+ ranges from +0.32 V to +0.78 V (Rubino and Franz, 2012).
The brain concentrates heavy metals including copper for metabolic use (Bush, 2000). Copper is of great importance for the normal development and function of the brain. As a cofactor of several enzymes and/or as structural component, copper is involved in many physiological pathways in the brain. This review will summarize the functions of copper in the brain for various biochemical pathways and will describe the current knowledge on the copper homeostasis by addressing copper transport, storage and export in brain cells. Finally, disturbances in the copper homeostasis that have been connected with neurodegenerative disorders will be discussed.
Section snippets
Importance of copper for brain function
Copper is utilized in the brain for general metabolic as well as for more brain specific functions (Lutsenko et al., 2010). Copper is an essential cofactor and/or a structural component of a number of important enzymes (Scheiber and Dringen, 2013) which are involved in redox reactions (Kaim and Rall, 1996, Rubino and Franz, 2012). The relatively high reduction potential of the Cu2+/Cu+ system enables many of the copper enzymes to directly oxidize their substrates, for example superoxide by
Copper uptake into the brain
Brain copper is derived from peripheral copper that is transported across the blood–brain barrier (BBB) and/or the blood–cerebrospinal fluid barrier (BCB), which separate the brain interstitial space from blood and cerebrospinal fluid (CSF), respectively (Zheng and Monnot, 2012). At both barriers copper is transported primarily as free ion (Choi and Zheng, 2009). Although the copper uptake into cerebral capillaries is much slower than into the choroid plexus, the copper acquired by cerebral
Astrocyte-neuron coupling in copper metabolism
Astrocytes, which constitute the main class of neuroglia, are the most abundant cells in the brain (Markiewicz and Lukomska, 2006, Sofroniew and Vinters, 2010). These cells are distributed throughout the entire brain and fulfill a range of important functions essential for brain physiology (Nedergaard et al., 2003, Parpura et al., 2012, Sofroniew and Vinters, 2010). Among other functions, astrocytes have been proposed to be involved in the control of brain extracellular ion homeostasis,
Copper and neurodegenerative diseases
Menkes and Wilson's disease (Kodama et al., 2011, Lorincz, 2010) are the best examples for pathological conditions that are connected with an impaired copper homeostasis that leads to neurodegeneration. While many of the clinical symptoms associated with the severe copper deficiency in Menkes disease can be attributed to a decrease in the activities of copper-dependent enzymes, copper toxicity in Wilson's disease is most likely a consequence of the redox activity of copper (Britton, 1996,
Conclusions and outlook
Within the last decade the knowledge on the metabolism and functions of copper in brain has dramatically increased. Most of the key players that are known to be involved in uptake, distribution, storage and export of copper in peripheral cell types and contribute to peripheral copper homeostasis are also present in brain cells. However, substantial parts of information on the function and the regulation of the various proteins that contribute to the copper metabolism of the different types of
Acknowledgments
Ivo F. Scheiber would like to thank the European Social Fund and the State Budget of the Czech Republic for financing (Project no. CZ.1.07/2.3.00/30.0061). Ralf Dringen and Julian Mercer would like to thank the Deakin University for financial support by the Thinkers in Residence Program.
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