The biology of mammalian multi-copper ferroxidases

Helman, Sheridan L; Zhou, Jie; Fuqua, Brie K.; Lu, Yan; Collins, James F.; Chen, Huijun; Vulpe, Chris D.; Anderson, Gregory J.; Frazer, David M.

doi:10.1007/s10534-022-00370-z

Cited by 34 publications

(26 citation statements)

References 155 publications

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“…Overall, these results attest that slight variation of its expression result in a moderate but significant role for CP in GB cell. The moderate response could be explained by a compensation with the CP homologue, the hephaestin, ferroxidase, also converting ferrous iron to ferric iron for the transport of dietary iron in the circulatory system [ 27 ]. Because hephaestin is a membrane-bound ferroxidase that partners with FPN1 to facilitate iron efflux and was reported to be expressed in human brain astrocytes and in mouse brain, it may partially compensate for loss of the GPI-CP form [ 39 , 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…As first identified by Holmberg and Laurell, CP is the major copper-carrying protein in the blood [ 26 ]. CP is expressed in both a secreted and GPI-anchored form and exerts broad functions ranging from iron and copper homeostasis, oxidation of organic amines, to anti and pro-oxidant activities [ 27 ]. Interestingly, through its ferroxidase activity, it is also involved in iron metabolism converting ferrous iron Fe 2+ to ferric iron Fe 3+ [ 28 ] which is internalized by cells via transferrin (Tf) [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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A role for ceruloplasmin in the control of human glioblastoma cell responses to radiation

et al. 2022

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Background Glioblastoma (GB) is the most common and most aggressive malignant brain tumor. In understanding its resistance to conventional treatments, iron metabolism and related pathways may represent a novel avenue. As for many cancer cells, GB cell growth is dependent on iron, which is tightly involved in red-ox reactions related to radiotherapy effectiveness. From new observations indicating an impact of RX radiations on the expression of ceruloplasmin (CP), an important regulator of iron metabolism, the aim of the present work was to study the functional effects of constitutive expression of CP within GB lines in response to beam radiation depending on the oxygen status (21% O2 versus 3% O2). Methods and results After analysis of radiation responses (Hoechst staining, LDH release, Caspase 3 activation) in U251-MG and U87-MG human GB cell lines, described as radiosensitive and radioresistant respectively, the expression of 9 iron partners (TFR1, DMT1, FTH1, FTL, MFRN1, MFRN2, FXN, FPN1, CP) were tested by RTqPCR and western blots at 3 and 8 days following 4 Gy irradiation. Among those, only CP was significantly downregulated, both at transcript and protein levels in the two lines, with however, a weaker effect in the U87-MG, observable at 3% O2. To investigate specific role of CP in GB radioresistance, U251-MG and U87-MG cells were modified genetically to obtain CP depleted and overexpressing cells, respectively. Manipulation of CP expression in GB lines demonstrated impact both on cell survival and on activation of DNA repair/damage machinery (γH2AX); specifically high levels of CP led to increased production of reactive oxygen species, as shown by elevated levels of superoxide anion, SOD1 synthesis and cellular Fe2 + . Conclusions Taken together, these in vitro results indicate for the first time that CP plays a positive role in the efficiency of radiotherapy on GB cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A role for ceruloplasmin in the control of human glioblastoma cell responses to radiation

et al. 2022

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“…The export of Fe 2+ is coupled to its extracellular oxidation to Fe 3+ , mediated by the plasma membrane multicopper ferroxidase hephaestin (HEPH) expressed in the duodenum ( Figure 1 A). Other ferroxidases with a similar function are ceruloplasmin (CP), expressed in macrophages and hepatocytes, and zyklopen (ZP), mainly expressed in the placenta [ 7 ]. The machinery that regulates dietary iron absorption is coordinated by hypoxia-inducible factor 2α (HIF2), a transcription factor whose levels are under the control of oxygen tension and iron [ 8 , 9 ].…”

Section: Iron Absorptionmentioning

confidence: 99%

Managing the Dual Nature of Iron to Preserve Health

Silvestri

Pettinato

Furiosi

et al. 2023

IJMS

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Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.

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“…Therefore, Cu is involved in normal brain functions such as neurotransmitter synthesis, myelination, and neuroprotection [38]. Cu is also involved in Fe homeostasis since ceruloplasmin and other ferroxidases, termed 'multi-copper ferroxidases,' convert Fe 2+ to Fe 3+ [39]. Similar to Zn 2+ , a considerable amount of Cu is stored in synaptic vesicles.…”

Section: Coppermentioning

confidence: 99%

Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases

2023

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Trace elements such as iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) are absorbed from food via the gastrointestinal tract, transported into the brain, and play central roles in normal brain functions. An excess of these trace elements often produces reactive oxygen species and damages the brain. Moreover, increasing evidence suggests that the dyshomeostasis of these metals is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, prion diseases, and Lewy body diseases. The disease-related amyloidogenic proteins can regulate metal homeostasis at the synapses, and thus loss of the protective functions of these amyloidogenic proteins causes neurodegeneration. Meanwhile, metal-induced conformational changes of the amyloidogenic proteins contribute to enhancing their neurotoxicity. Moreover, excess Zn and Cu play central roles in the pathogenesis of vascular-type senile dementia. Here, we present an overview of the intake, absorption, and transport of four essential elements (Fe, Zn, Cu, Mn) and one non-essential element (aluminum: Al) in food and their connections with the pathogenesis of neurodegenerative diseases based on metal–protein, and metal–metal cross-talk.

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The biology of mammalian multi-copper ferroxidases

Cited by 34 publications

References 155 publications

A role for ceruloplasmin in the control of human glioblastoma cell responses to radiation

A role for ceruloplasmin in the control of human glioblastoma cell responses to radiation

Managing the Dual Nature of Iron to Preserve Health

Dietary Trace Elements and the Pathogenesis of Neurodegenerative Diseases

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