Abstract
Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu+ from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu+ can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.
Similar content being viewed by others
References
Acevedo K, Masaldan S, Opazo CM, Bush AI (2019) Redox active metals in neurodegenerative diseases. J Biol Inorg Chem 24:1141–1157
Aigner E, Strasser M, Haufe H, Sonnweber T, Hohla F, Stadlmayr A, Solioz M, Tilg H, Patsch W, Weiss G, Stickel F, Datz C (2010) A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol 105:1978–1985
Angeletti B, Waldron KJ, Freeman KB, Bawagan H, Hussain I, Miller CC, Lau KF, Tennant ME, Dennison C, Robinson NJ, Dingwall C (2005) BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. J Biol Chem 280:17930–17937
Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem 75:1219–1233
Barry AN, Shinde U, Lutsenko S (2010) Structural organization of human Cu-transporting ATPases: learning from building blocks. J Biol Inorg Chem 15:47–59
Becuwe C, Dalle S, Ronger-Savle S, Skowron F, Balme B, Kanitakis J, Thomas L (2005) Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson’s disease with penicillamine. Dermatology 210:60–63
Bhattacharjee A, Chakraborty K, Shukla A (2017) Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases. Metallomics 9:1376–1388
Blaby-Haas CE, Merchant SS (2014) Lysosome-related organelles as mediators of metal homeostasis. J Biol Chem 289:28129–28136
Boullata J, Muthukumaran G, Piarulli A, Labarre J, Compher C (2017) Oral copper absorption in men with morbid obesity. J Trace Elem Med Biol 44:146–150
Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, Knapp S, Xiao K, Campbell SL, Thiele DJ, Counter CM (2014) Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492–496
Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC (1999) Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum Mol Genet 8:1665–1671
Bush AI, Curtain CC (2008) Twenty years of metallo-neurobiology: where to now? Eur Biophys J 37:241–245
Calvo J, Jung H, Meloni G (2017) Copper metallothioneins. IUBMB Life 69:236–245. https://doi.org/10.1002/iub.1618
Cameron NE, Cotter MA (1995) Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents. J Clin Invest 96:1159–1163
Chambers A, Krewski D, Birkett N, Plunkett L, Hertzberg R, Danzeisen R, Aggett PJ, Starr TB, Baker S, Dourson M, Jones P, Keen CL, Meek B, Schoeny R, Slob W (2010) An exposure-response curve for copper excess and deficiency. J Toxicol Environ Health B Crit Rev 13:546–578
Chen GF, Sudhahar V, Youn SW, Das A, Cho J, Kamiya T, Urao N, McKinney RD, Surenkhuu B, Hamakubo T, Iwanari H, Li S, Christman JW, Shantikumar S, Angelini GD, Emanueli C, Ushio-Fukai M, Fukai T (2015) Copper transport protein antioxidant-1 promotes inflammatory neovascularization via chaperone and transcription factor function. Sci Rep 5:14780
Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676
Cherukuri S, Tripoulas NA, Nurko S, Fox PL (2004) Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice. Blood Cells Mol Dis 33:346–355
Choi EH, Strum W (2010) Hypocupremia-related myeloneuropathy following gastrojejunal bypass surgery. Ann Nutr Metab 57:190–192
Chojnacka M, Gornicka A, Oeljeklaus S, Warscheid B, Chacinska A (2015) Cox17 Protein is an auxiliary factor involved in the control of the mitochondrial contact site and cristae organizing system. J Biol Chem 290:15304–15312
Choo XY, Liddell JR, Huuskonen MT, Grubman A, Moujalled D, Roberts J, Kysenius K, Patten L, Quek H, Oikari LE, Duncan C, James SA, McInnes LE, Hayne DJ, Donnelly PS, Pollari E, Vahatalo S, Lejavova K, Kettunen MI, Malm T, Koistinaho J, White AR, Kanninen KM (2018) Cu(II)(atsm) attenuates neuroinflammation. Front Neurosci 12:668
Cooper GJ, Phillips AR, Choong SY, Leonard BL, Crossman DJ, Brunton DH, Saafi L, Dissanayake AM, Cowan BR, Young AA, Occleshaw CJ, Chan YK, Leahy FE, Keogh GF, Gamble GD, Allen GR, Pope AJ, Boyd PD, Poppitt SD, Borg TK, Doughty RN, Baker JR (2004) Regeneration of the heart in diabetes by selective copper chelation. Diabetes 53:2501–2508
Cooper GJ, Young AA, Gamble GD, Occleshaw CJ, Dissanayake AM, Cowan BR, Brunton DH, Baker JR, Phillips AR, Frampton CM, Poppitt SD, Doughty RN (2009) A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study. Diabetologia 52:715–722
Coronado V, Nanji M, Cox DW (2001) The Jackson toxic milk mouse as a model for copper loading. Mamm Genome 12:793–795
Cosimo QC, Daniela L, Elsa B, Carlo DV, Giuseppe F (2011) Kinky hair, kinky vessels, and bladder diverticula in Menkes disease. J Neuroimaging 21:e114–e116
Cousins RJ (1985) Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev 65:238–309
Cox DW, Moore SD (2002) Copper transporting P-type ATPases and human disease. J Bioenerg Biomembr 34:333–338
Crouch PJ, Hung LW, Adlard PA, Cortes M, Lal V, Filiz G, Perez KA, Nurjono M, Caragounis A, Du T, Laughton K, Volitakis I, Bush AI, Li QX, Masters CL, Cappai R, Cherny RA, Donnelly PS, White AR, Barnham KJ (2009) Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation. Proc Natl Acad Sci U S A 106:381–386
Czlonkowska A, Litwin T, Dusek P, Ferenci P, Lutsenko S, Medici V, Rybakowski JK, Weiss KH, Schilsky ML (2018) Wilson disease. Nat Rev Dis Primers 4:21
De Freitas J, Wintz H, Kim JH, Poynton H, Fox T, Vulpe C (2003) Yeast, a model organism for iron and copper metabolism studies. Biometals 16:185–197
Deutscher J, Kiess W, Scheerschmidt G, Willgerodt H (1999) Potential hepatotoxicity of penicillamine treatment in three patients with Wilson’s disease. J Pediatr Gastroenterol Nutr 29:628. https://doi.org/10.1097/00005176-199911000-00031
Eid C, Hemadi M, Ha-Duong NT, El Hage Chahine JM (2014) Iron uptake and transfer from ceruloplasmin to transferrin. Biochim Biophys Acta 1840:1771–1781
Eipper BA, Stoffers DA, Mains RE (1992) The biosynthesis of neuropeptides: peptide alpha-amidation. Annu Rev Neurosci 15:57–85
Eisses JF, Chi Y, Kaplan JH (2005) Stable plasma membrane levels of hCTR1 mediate cellular copper uptake. J Biol Chem 280:9635–9639
Engle TE (2011) Copper and lipid metabolism in beef cattle: a review. J Anim Sci 89:591–596
Failla ML, Kiser RA (1981) Altered tissue content and cytosol distribution of trace metals in experimental diabetes. J Nutr 111:1900–1909
Festa RA, Thiele DJ (2011) Copper: an essential metal in biology. Curr Biol 21:R877–R883
Finney L, Mandava S, Ursos L, Zhang W, Rodi D, Vogt S, Legnini D, Maser J, Ikpatt F, Olopade OI, Glesne D (2007) X-ray fluorescence microscopy reveals large-scale relocalization and extracellular translocation of cellular copper during angiogenesis. Proc Natl Acad Sci U S A 104:2247–2252
Fleming CR, Hodges RE, Hurley LS (1976) A prospective study of serum copper and zinc levels in patients receiving total parenteral nutrition. Am J Clin Nutr 29:70–77
Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15:569–589
Fox JH, Kama JA, Lieberman G, Chopra R, Dorsey K, Chopra V, Volitakis I, Cherny RA, Bush AI, Hersch S (2007) Mechanisms of copper ion mediated Huntington’s disease progression. PLoS One 2:e334
Freedman JH, Ciriolo MR, Peisach J (1989) The role of glutathione in copper metabolism and toxicity. J Biol Chem 264:5598–5605
Fukai T, Ushio-Fukai M, Kaplan JH (2018) Copper transporters and copper chaperones: roles in cardiovascular physiology and disease. Am J Phys Cell Phys 315:C186–C201. https://doi.org/10.1152/ajpcell.00132.2018
Gacheru S, McGee C, Uriu-Hare JY, Kosonen T, Packman S, Tinker D, Krawetz SA, Reiser K, Keen CL, Rucker RB (1993) Expression and accumulation of lysyl oxidase, elastin, and type I procollagen in human Menkes and mottled mouse fibroblasts. Arch Biochem Biophys 301:325–329
Genoud S, Roberts BR, Gunn AP, Halliday GM, Lewis SJG, Ball HJ, Hare DJ, Double KL (2017) Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson’s disease brain. Metallomics 9:1447–1455
Godwin SC, Shawker T, Chang B, Kaler SG (2006) Brachial artery aneurysms in Menkes disease. J Pediatr 149:412–415
Goldstein DS, Holmes CS, Kaler SG (2009) Relative efficiencies of plasma catechol levels and ratios for neonatal diagnosis of menkes disease. Neurochem Res 34:1464–1468
Gong D, Lu J, Chen X, Reddy S, Crossman DJ, Glyn-Jones S, Choong YS, Kennedy J, Barry B, Zhang S, Chan YK, Ruggiero K, Phillips AR, Cooper GJ (2008) A copper(II)-selective chelator ameliorates diabetes-evoked renal fibrosis and albuminuria, and suppresses pathogenic TGF-beta activation in the kidneys of rats used as a model of diabetes. Diabetologia 51:1741–1751
Graham SF, Nasaruddin MB, Carey M, Holscher C, McGuinness B, Kehoe PG, Love S, Passmore P, Elliott CT, Meharg AA, Green BD (2014) Age-associated changes of brain copper, iron, and zinc in Alzheimer’s disease and dementia with Lewy bodies. J Alzheimers Dis 42:1407–1413
Grimes A, Hearn CJ, Lockhart P, Newgreen DF, Mercer JF (1997) Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease. Hum Mol Genet 6:1037–1042
Grochowski C, Blicharska E, Baj J, Mierzwinska A, Brzozowska K, Forma A, Maciejewski R (2019) Serum iron, magnesium, copper, and manganese levels in alcoholism: a systematic review. Molecules 24
Grossi C, Francese S, Casini A, Rosi MC, Luccarini I, Fiorentini A, Gabbiani C, Messori L, Moneti G, Casamenti F (2009) Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 17:423–440
Gualandi F, Sette E, Fortunato F, Bigoni S, De Grandis D, Scotton C, Selvatici R, Neri M, Incensi A, Liguori R, Storbeck M, Karakaya M, Simioni V, Squarzoni S, Timmerman V, Wirth B, Donadio V, Tugnoli V, Ferlini A (2019) Report of a novel ATP7A mutation causing distal motor neuropathy. Neuromuscul Disord 29:776–785
Gupta A, Lutsenko S (2009) Human copper transporters: mechanism, role in human diseases and therapeutic potential. Future Med Chem 1:1125–1142
Gupte A, Mumper RJ (2009) Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat Rev 35:32–46
Ha C, Ryu J, Park CB (2007) Metal ions differentially influence the aggregation and deposition of Alzheimer’s beta-amyloid on a solid template. Biochemistry 46:6118–6125
Haddad MR, Patel KD, Sullivan PH, Goldstein DS, Murphy KM, Centeno JA, Kaler SG (2014) Molecular and biochemical characterization of Mottled-dappled, an embryonic lethal Menkes disease mouse model. Mol Genet Metab 113:294–300
Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD (2001) The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A 98:6848–6852
Hansel DE, May V, Eipper BA, Ronnett GV (2001) Pituitary adenylyl cyclase-activating peptides and alpha-amidation in olfactory neurogenesis and neuronal survival in vitro. J Neurosci 21:4625–4636
Harris ED (2004) A requirement for copper in angiogenesis. Nutr Rev 62:60–64. https://doi.org/10.1111/j.1753-4887.2004.tb00025.x
Harris ZL, Durley AP, Man TK, Gitlin JD (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci U S A 96:10812–10817
Hermann W (2019) Classification and differential diagnosis of Wilson’s disease. Ann Transl Med 7:S63
Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE (1987) Treatment of Wilson’s disease with zinc. I. Oral zinc therapy regimens. Hepatology 7:522–528
Hodgkinson VL, Dale JM, Garcia ML, Weisman GA, Lee J, Gitlin JD, Petris MJ (2015) X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron. J Pathol 236:241–250
Huster D, Finegold MJ, Morgan CT, Burkhead JL, Nixon R, Vanderwerf SM, Gilliam CT, Lutsenko S (2006) Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice. Am J Pathol 168:423–434
Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D (2013) Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci U S A 110:19507–19512. https://doi.org/10.1073/pnas.1318431110
Itoh S, Kim HW, Nakagawa O, Ozumi K, Lessner SM, Aoki H, Akram K, McKinney RD, Ushio-Fukai M, Fukai T (2008) Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J Biol Chem 283:9157–9167
Jeremy JY, Shukla N, Angelini GD, Day A, Wan IY, Talpahewa SP, Ascione R (2002) Sustained increases of plasma homocysteine, copper, and serum ceruloplasmin after coronary artery bypass grafting. Ann Thorac Surg 74:1553–1557. https://doi.org/10.1016/s0003-4975(02)03807-9
Jiang Y, Reynolds C, Xiao C, Feng W, Zhou Z, Rodriguez W, Tyagi SC, Eaton JW, Saari JT, Kang YJ (2007) Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice. J Exp Med 204:657–666. https://doi.org/10.1084/jem.20061943
Juarez-Rebollar D, Rios C, Nava-Ruiz C, Mendez-Armenta M (2017) Metallothionein in brain disorders. Oxidative Med Cell Longev 2017:5828056
Kaler SG (1994) Menkes disease. Adv Pediatr Infect Dis 41:263–304
Kaler SG (1996) Menkes disease mutations and response to early copper histidine treatment. Nat Genet 13:21–22
Kaler SG (2011) ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol 7:15–29
Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, Liew CJ, Sato S, Patronas N (2008) Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 358:605–614
Kamiya T, Takeuchi K, Fukudome S, Hara H, Adachi T (2018) Copper chaperone antioxidant-1, Atox-1, is involved in the induction of SOD3 in THP-1 cells. Biometals 31:61–68. https://doi.org/10.1007/s10534-017-0067-1
Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet 86:343–352
Kim BE, Turski ML, Nose Y, Casad M, Rockman HA, Thiele DJ (2010) Cardiac copper deficiency activates a systemic signaling mechanism that communicates with the copper acquisition and storage organs. Cell Metab 11:353–363
Klevay LM (2000) Cardiovascular disease from copper deficiency—a history. J Nutr 130:489S–492S. https://doi.org/10.1093/jn/130.2.489S
Krishnamoorthy L, Cotruvo JA Jr, Chan J, Kaluarachchi H, Muchenditsi A, Pendyala VS, Jia S, Aron AT, Ackerman CM, Wal MN, Guan T, Smaga LP, Farhi SL, New EJ, Lutsenko S, Chang CJ (2016) Copper regulates cyclic-AMP-dependent lipolysis. Nat Chem Biol 12:586–592
Kuo YM, Zhou B, Cosco D, Gitschier J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci U S A 98:6836–6841
La Fontaine S, Theophilos MB, Firth SD, Gould R, Parton RG, Mercer JF (2001) Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase. Hum Mol Genet 10:361–370
Lamb DJ, Avades TY, Ferns GA (2001) Biphasic modulation of atherosclerosis induced by graded dietary copper supplementation in the cholesterol-fed rabbit. Int J Exp Pathol 82:287–294. https://doi.org/10.1046/j.1365-2613.2001.00200.x
Lamb DJ, Mitchinson MJ, Leake DS (1995) Transition metal ions within human atherosclerotic lesions can catalyse the oxidation of low density lipoprotein by macrophages. FEBS Lett 374:12–16. https://doi.org/10.1016/0014-5793(95)01068-p
Landriscina M, Bagala C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T (2001) Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress. J Biol Chem 276:25549–25557. https://doi.org/10.1074/jbc.M102925200
Lee J, Prohaska JR, Thiele DJ (2001) Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci U S A 98:6842–6847
Levenson CW (1998) Mechanisms of copper conservation in organs. Am J Clin Nutr 67:978S–981S
Levenson CW, Janghorbani M (1994) Long-term measurement of organ copper turnover in rats by continuous feeding of a stable isotope. Anal Biochem 221:243–249
Levinson B, Packman S, Gitschier J (1997) Deletion of the promoter region in the Atp7a gene of the mottled dappled mouse. Nat Genet 16:224–225
Li C, Wang J, Zhou B (2010) The metal chelating and chaperoning effects of clioquinol: insights from yeast studies. J Alzheimers Dis 21:1249–1262
Linder MC (2016) Ceruloplasmin and other copper binding components of blood plasma and their functions: an update. Metallomics 8:887–905
Litwin T, Dziezyc K, Czlonkowska A (2019) Wilson disease-treatment perspectives. Ann Transl Med 7:S68
Lob HE, Marvar PJ, Guzik TJ, Sharma S, McCann LA, Weyand C, Gordon FJ, Harrison DG (2010) Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. Hypertension 55:277–283, 276p following 283. https://doi.org/10.1161/HYPERTENSIONAHA.109.142646
Lob HE, Vinh A, Li L, Blinder Y, Offermanns S, Harrison DG (2011) Role of vascular extracellular superoxide dismutase in hypertension. Hypertension 58:232–239. https://doi.org/10.1161/HYPERTENSIONAHA.111.172718
Lowndes SA, Harris AL (2005) The role of copper in tumour angiogenesis. J Mammary Gland Biol Neoplasia 10:299–310. https://doi.org/10.1007/s10911-006-9003-7
Lu SC (2009) Regulation of glutathione synthesis. Mol Asp Med 30:42–59
Malinouski M, Hasan NM, Zhang Y, Seravalli J, Lin J, Avanesov A, Lutsenko S, Gladyshev VN (2014) Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism. Nat Commun 5:3301. https://doi.org/10.1038/ncomms4301
Mandinova A, Soldi R, Graziani I, Bagala C, Bellum S, Landriscina M, Tarantini F, Prudovsky I, Maciag T (2003) S100A13 mediates the copper-dependent stress-induced release of IL-1alpha from both human U937 and murine NIH 3 T3 cells. J Cell Sci 116:2687–2696. https://doi.org/10.1242/jcs.00471
Mansoor MA, Bergmark C, Haswell SJ, Savage IF, Evans PH, Berge RK, Svardal AM, Kristensen O (2000) Correlation between plasma total homocysteine and copper in patients with peripheral vascular disease. Clin Chem 46:385–391
Maryon EB, Molloy SA, Kaplan JH (2013) Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1. Am J Phys Cell Phys 304:C768–C779
Maselbas W, Czlonkowska A, Litwin T, Niewada M (2019) Persistence with treatment for Wilson disease: a retrospective study. BMC Neurol 19:278. https://doi.org/10.1186/s12883-019-1502-4
Matzuk MM, Dionne L, Guo Q, Kumar TR, Lebovitz RM (1998) Ovarian function in superoxide dismutase 1 and 2 knockout mice. Endocrinology 139:4008–4011
McInerney MP, Pan Y, Volitakis I, Bush AI, Short JL, Nicolazzo JA (2019) The effects of clioquinol on P-glycoprotein expression and biometal distribution in the mouse brain microvasculature. J Pharm Sci 108:2247–2255
Medici V, LaSalle JM (2019) Genetics and epigenetic factors of Wilson disease. Ann Transl Med 7:S58
Medici V, Trevisan CP, D’Inca R, Barollo M, Zancan L, Fagiuoli S, Martines D, Irato P, Sturniolo GC (2006) Diagnosis and management of Wilson’s disease: results of a single center experience. J Clin Gastroenterol 40:936–941
Mohr I, Weiss KH (2019) Biochemical markers for the diagnosis and monitoring of Wilson disease. Clin Biochem Rev 40:59–77
Molloy SA, Kaplan JH (2009) Copper-dependent recycling of hCTR1, the human high affinity copper transporter. J Biol Chem 284:29704–29713
Murakami H, Kodama H, Nemoto N (2002) Abnormality of vascular elastic fibers in the macular mouse and a patient with Menkes’ disease: ultrastructural and immunohistochemical study. Med Electron Microsc 35:24–30
Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H (2018) Copper deficiency anemia: review article. Ann Hematol 97:1527–1534
Nose Y, Kim BE, Thiele DJ (2006) Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab 4:235–244
Nose Y, Wood LK, Kim BE, Prohaska JR, Fry RS, Spears JW, Thiele DJ (2010) Ctr1 is an apical copper transporter in mammalian intestinal epithelial cells in vivo that is controlled at the level of protein stability. J Biol Chem 285:32385–32392
Ogata R, Chong PF, Maeda K, Imagi T, Nakamura R, Kawamura N, Kira R (2019) Long surviving classical Menkes disease treated with weekly intravenous copper therapy. J Trace Elem Med Biol 54:172–174
Ohgami RS, Campagna DR, McDonald A, Fleming MD (2006) The Steap proteins are metalloreductases. Blood 108:1388–1394
Ozumi K, Sudhahar V, Kim HW, Chen GF, Kohno T, Finney L, Vogt S, McKinney RD, Ushio-Fukai M, Fukai T (2012) Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase. Hypertension 60:476–486
Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, Krishna S, Walker W, Selby J, Glerum DM, Coster RV, Lyon G, Scalais E, Lebel R, Kaplan P, Shanske S, De Vivo DC, Bonilla E, Hirano M, DiMauro S, Schon EA (1999) Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23:333–337
Petris MJ, Smith K, Lee J, Thiele DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 278:9639–9646
Pierson H, Yang H, Lutsenko S (2019) Copper transport and disease: what can we learn from organoids? Annu Rev Nutr 39:75–94
Polishchuk EV, Concilli M, Iacobacci S, Chesi G, Pastore N, Piccolo P, Paladino S, Baldantoni D, van ISC, Chan J, Chang CJ, Amoresano A, Pane F, Pucci P, Tarallo A, Parenti G, Brunetti-Pierri N, Settembre C, Ballabio A, Polishchuk RS (2014) Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Dev Cell 29:686–700
Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, Scott RW, Snider WD (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47
Reed V, Boyd Y (1997) Mutation analysis provides additional proof that mottled is the mouse homologue of Menkes’ disease. Hum Mol Genet 6:417–423
Rembach A, Doecke JD, Roberts BR, Watt AD, Faux NG, Volitakis I, Pertile KK, Rumble RL, Trounson BO, Fowler CJ, Wilson W, Ellis KA, Martins RN, Rowe CC, Villemagne VL, Ames D, Masters CL, group Ar, Bush AI (2013) Longitudinal analysis of serum copper and ceruloplasmin in Alzheimer’s disease. J Alzheimers Dis 34:171–182
Repiscak P, Erhardt S, Rena G, Paterson MJ (2014) Biomolecular mode of action of metformin in relation to its copper binding properties. Biochemistry 53:787–795
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691
Roberts BR, Lim NK, McAllum EJ, Donnelly PS, Hare DJ, Doble PA, Turner BJ, Price KA, Lim SC, Paterson BM, Hickey JL, Rhoads TW, Williams JR, Kanninen KM, Hung LW, Liddell JR, Grubman A, Monty JF, Llanos RM, Kramer DR, Mercer JF, Bush AI, Masters CL, Duce JA, Li QX, Beckman JS, Barnham KJ, White AR, Crouch PJ (2014) Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 34:8021–8031
Roberts EA, Schilsky ML (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47:2089–2111
Roos PM, Vesterberg O, Nordberg M (2006) Metals in motor neuron diseases. Exp Biol Med (Maywood) 231:1481–1487
Savir Y, Martynov A, Springer M (2017) Achieving global perfect homeostasis through transporter regulation. PLoS Comput Biol 13:e1005458. https://doi.org/10.1371/journal.pcbi.1005458
Schilsky ML, Blank RR, Czaja MJ, Zern MA, Scheinberg IH, Stockert RJ, Sternlieb I (1989) Hepatocellular copper toxicity and its attenuation by zinc. J Clin Invest 84:1562–1568
Schlief ML, West T, Craig AM, Holtzman DM, Gitlin JD (2006) Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci U S A 103:14919–14924
Schrag M, Mueller C, Oyoyo U, Smith MA, Kirsch WM (2011) Iron, zinc and copper in the Alzheimer’s disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog Neurobiol 94:296–306
Sedjahtera A, Gunawan L, Bray L, Hung LW, Parsons J, Okamura N, Villemagne VL, Yanai K, Liu XM, Chan J, Bush AI, Finkelstein DI, Barnham KJ, Cherny RA, Adlard PA (2018) Targeting metals rescues the phenotype in an animal model of tauopathy. Metallomics 10:1339–1347
Shawki A, Anthony SR, Nose Y, Engevik MA, Niespodzany EJ, Barrientos T, Ohrvik H, Worrell RT, Thiele DJ, Mackenzie B (2015) Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am J Physiol Gastrointest Liver Physiol 309:G635–G647
Shiono Y, Wakusawa S, Hayashi H, Takikawa T, Yano M, Okada T, Mabuchi H, Kono S, Miyajima H (2001) Iron accumulation in the liver of male patients with Wilson’s disease. Am J Gastroenterol 96:3147–3151
Simunkova M, Alwasel SH, Alhazza IM, Jomova K, Kollar V, Rusko M, Valko M (2019) Management of oxidative stress and other pathologies in Alzheimer’s disease. Arch Toxicol 93:2491–2513
Singleton WC, McInnes KT, Cater MA, Winnall WR, McKirdy R, Yu Y, Taylor PE, Ke BX, Richardson DR, Mercer JF, La Fontaine S (2010) Role of glutaredoxin1 and glutathione in regulating the activity of the copper-transporting P-type ATPases, ATP7A and ATP7B. J Biol Chem 285:27111–27121
Skopp A, Boyd SD, Ullrich MS, Liu L, Winkler DD (2019) Copper-zinc superoxide dismutase (Sod1) activation terminates interaction between its copper chaperone (Ccs) and the cytosolic metal-binding domain of the copper importer Ctr1. Biometals 32:695–705. https://doi.org/10.1007/s10534-019-00206-3
Song MO, Mattie MD, Lee CH, Freedman JH (2014) The role of Nrf1 and Nrf2 in the regulation of copper-responsive transcription. Exp Cell Res 322:39–50
Stankovic RK, Chung RS, Penkowa M (2007) Metallothioneins I and II: neuroprotective significance during CNS pathology. Int J Biochem Cell Biol 39:484–489
Starkebaum G, Harlan JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77:1370–1376. https://doi.org/10.1172/JCI112442
Stremmel W, Merle U, Weiskirchen R (2019) Clinical features of Wilson disease. Ann Transl Med 7:S61
Sudhahar V, Okur MN, Bagi Z, O’Bryan JP, Hay N, Makino A, Patel VS, Phillips SA, Stepp D, Ushio-Fukai M, Fukai T (2018) Akt2 (Protein Kinase B Beta) stabilizes ATP7A, a copper transporter for extracellular superoxide dismutase, in vascular smooth muscle: novel mechanism to limit endothelial dysfunction in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 38:529–541
Sudhahar V, Urao N, Oshikawa J, McKinney RD, Llanos RM, Mercer JF, Ushio-Fukai M, Fukai T (2013) Copper transporter ATP7A protects against endothelial dysfunction in type 1 diabetic mice by regulating extracellular superoxide dismutase. Diabetes 62:3839–3850
Svensson PA, Englund MC, Markstrom E, Ohlsson BG, Jernas M, Billig H, Torgerson JS, Wiklund O, Carlsson LM, Carlsson B (2003) Copper induces the expression of cholesterogenic genes in human macrophages. Atherosclerosis 169:71–76. https://doi.org/10.1016/s0021-9150(03)00145-x
Tanaka YK, Ogra Y (2019) Evaluation of copper metabolism in neonatal rats by speciation analysis using liquid chromatography hyphenated to ICP mass spectrometry. Metallomics 11:1679–1686
Tay SK, Shanske S, Kaplan P, DiMauro S (2004) Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch Neurol 61:950–952
Theophilos MB, Cox DW, Mercer JF (1996) The toxic milk mouse is a murine model of Wilson disease. Hum Mol Genet 5:1619–1624
Tsai CY, Finley JC, Ali SS, Patel HH, Howell SB (2012) Copper influx transporter 1 is required for FGF, PDGF and EGF-induced MAPK signaling. Biochem Pharmacol 84:1007–1013
Tumer Z (2013) An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Hum Mutat 34:417–429
Tumer Z, Horn N, Tonnesen T, Christodoulou J, Clarke JT, Sarkar B (1996) Early copper-histidine treatment for Menkes disease. Nat Genet 12:11–13
Turski ML, Brady DC, Kim HJ, Kim BE, Nose Y, Counter CM, Winge DR, Thiele DJ (2012) A novel role for copper in Ras/mitogen-activated protein kinase signaling. Mol Cell Biol 32:1284–1295
Urso E, Maffia M (2015) Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J Vasc Res 52:172–196. https://doi.org/10.1159/000438485
Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208
Vanisova M, Burska D, Krizova J, Danhelovska T, Dosoudilova Z, Zeman J, Stiburek L, Hansikova H (2019) Stable COX17 Downregulation leads to alterations in mitochondrial ultrastructure, decreased copper content and impaired cytochrome c oxidase biogenesis in HEK293 cells. Folia Biol (Praha) 65:181–187
Waggoner DJ, Bartnikas TB, Gitlin JD (1999) The role of copper in neurodegenerative disease. Neurobiol Dis 6:221–230
Walshe JM (1973) Copper chelation in patients with Wilson’s disease. A comparison of penicillamine and triethylene tetramine dihydrochloride. Q J Med 42:441–452
Walshe JM (1989) Wilson’s disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients. Q J Med 70:253–263
Watanabe S, Nagano S, Duce J, Kiaei M, Li QX, Tucker SM, Tiwari A, Brown RH Jr, Beal MF, Hayward LJ, Culotta VC, Yoshihara S, Sakoda S, Bush AI (2007) Increased affinity for copper mediated by cysteine 111 in forms of mutant superoxide dismutase 1 linked to amyotrophic lateral sclerosis. Free Radic Biol Med 42:1534–1542
Watts JC, Balachandran A, Westaway D (2006) The expanding universe of prion diseases. PLoS Pathog 2:e26
Wiernicka A, Janczyk W, Dadalski M, Avsar Y, Schmidt H, Socha P (2013) Gastrointestinal side effects in children with Wilson’s disease treated with zinc sulphate. World J Gastroenterol 19:4356–4362
Wong PC, Waggoner D, Subramaniam JR, Tessarollo L, Bartnikas TB, Culotta VC, Price DL, Rothstein J, Gitlin JD (2000) Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. Proc Natl Acad Sci U S A 97:2886–2891
Wyman S, Simpson RJ, McKie AT, Sharp PA (2008) Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett 582:1901–1906
Xiao G, Fan Q, Wang X, Zhou B (2013) Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding. Proc Natl Acad Sci U S A 110:14995–15000
Yarandi SS, Griffith DP, Sharma R, Mohan A, Zhao VM, Ziegler TR (2014) Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery. J Clin Gastroenterol 48:862–865
Yi L, Kaler S (2014) ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. Ann N Y Acad Sci 1314:49–54
Yi L, Kaler SG (2018) Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration. J Biol Chem 293:7606–7617
Zhou X, Xiao X, Li XH, Qin HL, Pu XY, Chen DB, Wu C, Feng L, Liang XL (2020) A study of susceptibility-weighted imaging in patients with Wilson disease during the treatment of metal chelator. J Neurol
Zimnicka AM, Maryon EB, Kaplan JH (2007) Human copper transporter hCTR1 mediates basolateral uptake of copper into enterocytes: implications for copper homeostasis. J Biol Chem 282:26471–26480
Zimnicka AM, Tang H, Guo Q, Kuhr FK, Oh MJ, Wan J, Chen J, Smith KA, Fraidenburg DR, Choudhury MS, Levitan I, Machado RF, Kaplan JH, Yuan JX (2014) Upregulated copper transporters in hypoxia-induced pulmonary hypertension. PLoS One 9:e90544. https://doi.org/10.1371/journal.pone.0090544
Funding
This work was supported by National Natural Science Foundation of China (91749121 to Li), the Outstanding Young and Middle-aged Scientific and Technological Innovation Team Program of Colleges and Universities in Hubei Province (T201819 to Jiang), and the Fundamental Research Funds for the Central Universities (SCU2019D013).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chen, J., Jiang, Y., Shi, H. et al. The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch - Eur J Physiol 472, 1415–1429 (2020). https://doi.org/10.1007/s00424-020-02412-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-020-02412-2