Abstract
Recent immunohistochemical characterization of the copper transport protein, Ctr1, reported enriched levels in mouse choroid plexus, and enhancement by copper deficiency. To extend and confirm this, experiments were conducted with Holtzman rats. Following perinatal copper deficiency there was an 80% reduction in brain copper of 24–27 day old copper-deficient (Cu-) rat pups compared to copper-adequate (Cu+) controls. Choroid plexus immunoblot analysis with rabbit anti-hCtr1 demonstrated a 50% higher Ctr1 protein expression in Cu-samples. However, levels of copper chaperone for superoxide dismutase (CCS) were unchanged, suggesting that Ctr1 buffers the choroid plexus against copper deficiency, since CCS normally is much higher in Cu-tissues. There were 13% lower levels of cytochrome c oxidase subunit IV (COX IV) detected in Cuchoroid plexus. In contrast, in cerebellum of Cu-rats CCS was 2-fold higher and COXIV 1.7-fold lower than Cu+ rats consistent with severe copper deficiency. Brain mitochondria from Cu-rats had severe reductions in COXIV content and CCO activity and modest but significant elevations in CCS and reductions in Cu, Zn-superoxide dismutase. COXIV may be a more sensitive marker for copper deficiency than CCS and may prove useful to assess copper status.
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Bertinato J. and L’Abbe M. R. (2003) Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome.Journal of Biological Chemistry 278, 35071–35078.
Bertinato J., Iskandar M. and L’Abbe M. R. (2003) Copper deficiency induces the upregulation of the copper chaperone for Cu/Zn superoxide dismutase in weanling male rats.Journal of Nutrition 133, 28–31.
Chao J. C., Medeiros D. M., Davidson J. and Shiry L. (1994) Low levels of ATP synthase and cytochrome c oxidase subunit peptide from hearts of copper-deficient rats are not altered by the administration of dimethyl sulfoxide.Journal of Nutrition 124, 789–803.
Danks D. M., Campbell P. E., Stevens B. J., Mayne V. and Cartwright E. (1972) Menkes’s kinky hair syndrome. An inherited defect in copper absorption with widespread effects.Pediatrics 50, 188–201.
Eisses J. F. and Kaplan J. H. (2002) Molecular characterization of hCTR1, the human copper uptake protein.Journal of Biological Chemistry 277, 29162–29171.
Eisses J. F., Chi Y. and Kaplan J. H. (2005) Stable plasma membrane levels of hCTR1 mediate cellular copper uptake.Journal of Biological Chemistry 280, 9635–9639.
Failla M. L., Johnson M. A. and Prohaska J. R. (2001) Copper. In: Bowman B. A. and RussellR.M., (Eds), Present Knowledge in Nutrition, Eighth Edition (Washington, DC: ILSI Press), pp 373–383.
Gitlin J. D., Schroeder J. J., Lee-Ambrose L. M. and Cousins R. J. (1992) Mechanisms of caeruloplasmin biosynthesis in normal and copper-deficient rats.Biochemical Journal 282, 835–839.
Glowinski J. and Iversen L. L. (1966) Regional studies of catecholamines in the rat brain.Journal of Neurochemistry 13, 655–669.
Gybina A. A. and Prohaska J. R. (2003) Increased rat brain cytochrome c correlates with degree of perinatal copper deficiency rather than apoptosis.Journal of Nutrition 133, 3361–3368.
Johnson W. T. and Brown-Borg H. M. (2006) Cardiac cytochrome-c oxidase deficiency occurs during late postnatal development in progeny of copper-deficient rats.Experimental Biology and Medicine 231, 172–180.
Kelleher S. L. and Lonnerdal B. (2003) Marginal maternal Zn intake in rats alters mammary gland Cu transporter levels and milk Cu concentration and affects neonatal Cu metabolism.Journal of Nutrition 133, 2141–2148.
Klomp A. E., Tops B. B., Van Denberg I. E., Berger R. and Klomp L. W. (2002) Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1).Biochemical Journal 364, 497–505.
Kuo Y. M., Zhou B., Cosco D. and Gitschier J. (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development.Proceedings National Academy of Sciences USA 98, 6836–6841.
Kuo Y. M., Gybina A. A., Pyatskowit J. W., Gitschier J. and ProhaskaJ. R. (2006) Copper transport protein (ctr1) levels in mice are tissue specific and dependent on copper status.Journal of Nutrition 136, 21–26.
Lee C. P., Sciamanna M. and Peterson P. L. (1993) Intact rat brain mitochondria from a single animal: Preparation and properties.Methods in Toxicology 2, 41–50.
Lee J., Prohaska J. R. and Thiele D. J. (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development.Proceedings National Academy of Sciences USA 98, 6842–6847.
Lee J., Petris M. J. and Thiele D. J. (2002a) Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system.Journal of Biological Chemistry 277, 40253–40259.
Lee J., Pena M. M., Nose Y. and Thiele D. J. (2002b) Biochemical characterization of the human copper transporter Ctr1.Journal of Biological Chemistry 277, 4380–4387.
Lee J., Prohaska J. R., Dagenais S. L., Glover T. W. and Thiele D. J. (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant.Gene 254, 87–96.
Lehmann H. P., Schosinsky K. H. and Beeler M. F. (1974) Standardization of serum ceruloplasmin concentrations in international enzyme units with o-dianisidine dihydrochloride as substrate.Clinical Chemistry 20, 1564–1567.
Markwell M. A., Haas S. M., Bieber L. L. and Tolbert N. E. (1978) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples.Analytical Biochemistry 87, 206–210.
Marzullo L., Tosco A., Capone R., Andersen H. S., Capasso A. and Leone A. (2004) Identification of dietary copper- and iron-regulated genes in rat intestine.Gene 338, 225–233.
Medeiros D. M., Davidson J. and Jenkins J. E. (1993) A unified perspective on copper deficiency and cardiomyopathy.Proceedings of the Society for Experimental Biology and Medicine 203, 262–273.
Meyer L. A., Durley A. P., Prohaska J. R. and Harris Z. L. (2001) Copper transport and metabolism are normal in aceruloplasminemic mice.Journal of Biological Chemistry 276, 36857–36861.
Nittis T. and Gitlin J. D. (2004) Role of copper in the proteo some-mediated degradation of the multicopper oxidase hephaestin.Journal of Biological Chemistry 279, 25696–25702.
Okado-Matsumoto A. and Fridovich I. (2001) Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria.Journal of Biological Chemistry 276, 38388–38393.
Peterson D. J. and Prohaska J. R. (1999) Evaluation of rat white blood cell and plasma petidylglycine a-amidating monooxygenase activity as indicators of copper status.Nutrition Research 19, 1041–1047.
Petris M. J., Smith K., Lee J. and Thiele D. J. (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1.Journal of Biological Chemistry 278, 9639–9646.
Prohaska J. R. (1991) Changes in Cu,Zn-superoxide dismutase, cytochrome c oxidase, glutathione peroxidase and glutathione transferase activities in copper-deficient mice and rats.Journal of Nutrition 121, 355–363.
Prohaska J. R. and Wells W. W. (1975) Copper deficiency in the developing rat brain: evidence for abnormal mitochondria.Journal of Neurochemistry 25, 221–228.
Prohaska J. R. and Brokate B. (2001a) Lower copper, zinc-superoxide dismutase protein but not mRNA in organs of copper-deficient rats.Archives ofBiochemistry and Biophysics 393, 170–176.
Prohaska J. R. and Brokate B. (2001b) Dietary copper deficiency alters protein levels of rat dopamine-β-monooxygenase and tyrosine monooxygenase.Experimental Biology and Medicine 226, 199–207.
Prohaska J. R. and Gybina A. A. (2004) Intracellular copper transport in mammals.Journal of Nutrition 134, 1003–1006.
Prohaska J. R. and Broderius M. (2006) Plasma peptidylglycine alpha-amidating monooxygenase (PAM) and ceruloplasmin are affected by age and copper-status in rats and mice.Comparative Biochemistry and Physiology Part B 143, 360–366.
Prohaska J. R., Broderius M. and Brokate B. (2003a) Metallochaperone for Cu,Zn-superoxide dismutase (CCS) protein but not mRNA is higher in organs from copper-deficient mice and rats.Archives of Biochemistry and Biophysics 417, 227–234.
Prohaska J. R., Geissler J., Brokate B. and Broderius M. (2003b) Copper,Zinc-superoxide dismutase protein but not mRNA is lower in copper-deficient mice and mice lacking the copper chaperone for superoxide dismutase.Experimental Biology and Medicine 228, 959–966.
Prohaska J. R., Gybina A. A., Broderius M. and Brokate B. (2005) Peptidylglycine-alpha-amidating monooxygenase activity and protein are lower in copper-deficient rats and suckling copper-deficient mice.Archives of Biochemistry and Biophysics 434, 212–220.
Reeves P. G., Demars L. C., Johnson W. T. and Lukaski H. C. (2005) Dietary copper deficiency reduces iron absorption and duodenal enterocyte hephaestin protein in male and female rats.Journal of Nutrition 135, 92–98.
Rossi L., Lippe G., Marchese E., De Martino A., Mavelli I., Rotilio G. and Ciriolo M. R. (1998) Decrease of cytochrome c oxidase protein in heart mitochondria of copper-deficient rats.Biometals 11, 207–212.
Schaefer M., Hopkins R. G., Failla M. L. and Gitlin J. D. (1999) Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver.American Journal of Physiology 276, G639-G646.
Suzuki K. T., Someya A., Komada Y. and Ogra Y. (2002) Roles of metallothionein in copper homeostasis: responses to Cu-deficient diets in mice.Journal of Inorganic Biochemistry 88, 173–182.
Tosco A., Siciliano R. A., Cacace G., Mazzeo M. F., Capone R., Malorni A., Leone A. and Marzullo L. (2005) Dietary effects of copper and iron deficiency on rat intestine: a differential display proteome analysis.Journal Proteome Research 4, 1781–1788.
Trumbo P., Yates A. A., Schlicker S. and Poos M. (2001) Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc.Journal American Dietetic Association 101, 294–301.
Wang Y. R., Wu J. Y., Reaves S. K. and Lei K. Y. (1996) Enhanced expression of hepatic genes in copper-deficient rats detected by the messenger RNA differential display method.Journal of Nutrition 126, 1772–1781.
West E. C. and Prohaska J. R. (2004) Cu,Zn-superoxide dismutase is lower and copper chaperone CCS is higher in erythrocytes of copper-deficient rats and mice.Experimental Biology and Medicine 229, 756–764.
Zeng H., Saari J. T. and Dahlen G. M. (2006) Copper deficiency increases fibulin-5 (DANCE/EVEC) but decreases cytochrome C oxidase VIb subunit expression in rat heart.Journal of Inorganic Biochemistry 100, 186–191.
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Gybina, A.A., Prohaska, J.R. Variable response of selected cuproproteins in rat choroid plexus and cerebellum following perinatal copper deficiency. Genes Nutr 1, 51–59 (2006). https://doi.org/10.1007/BF02829936
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DOI: https://doi.org/10.1007/BF02829936