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16 pages, 1278 KiB

Open AccessArticle

Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

by Jennifer K. Lee, Jung-Heun Ha and James F. Collins

Biomedicines 2021, 9(4), 338; https://doi.org/10.3390/biomedicines9040338 - 27 Mar 2021

Cited by 11 | Viewed by 3650

Abstract

Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high [...] Read more.

Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with ⁶⁴Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue ⁶⁴Cu accumulation were lower in dams consuming excess iron, and tissue ⁶⁴Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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11 pages, 17576 KiB

Open AccessArticle

Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells

by Dirk Reinhold, Karina Guttek, Annika Reddig, Linda Voss, Claudia Schubert, Sascha Kahlfuss, Kurt Grüngreiff, Burkhart Schraven and Annegret Reinhold

Biomedicines 2021, 9(3), 246; https://doi.org/10.3390/biomedicines9030246 - 1 Mar 2021

Cited by 5 | Viewed by 2411

Abstract

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine [...] Read more.

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells. To understand the suppressive effect of zinc on T cell function, we here investigated the influence of zinc aspartate on human T cells focusing on the secretion of immunosuppressive cytokines, induction of apoptosis, and caspase 3/7 activity. To this end, we monitored either freshly stimulated or pre-activated human T cells in the presence of zinc aspartate from 40–140 µM over a period of 72 h. Under both experimental conditions, we observed a dose-dependent suppression of human T cell proliferation. While IL-1ra, latent TGF-β1, and IL-10 were dose-dependently reduced, we, unexpectedly, detected elevated levels of IL-16 upon zinc supplementation. In addition, the number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis, steadily increased at zinc aspartate concentrations exceeding 100 µM. Taken together, our findings suggest that zinc aspartate impairs T cell fitness and might be beneficial for the treatment of T cell-mediated autoimmune diseases. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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13 pages, 4481 KiB

Open AccessArticle

Accurate Measurement of Copper Overload in an Experimental Model of Wilson Disease by Laser Ablation Inductively Coupled Plasma Mass Spectrometry

by Philipp Kim, Chengcheng Christine Zhang, Sven Thoröe-Boveleth, Sabine Weiskirchen, Nadine Therese Gaisa, Eva Miriam Buhl, Wolfgang Stremmel, Uta Merle and Ralf Weiskirchen

Biomedicines 2020, 8(9), 356; https://doi.org/10.3390/biomedicines8090356 - 16 Sep 2020

Cited by 9 | Viewed by 3046

Abstract

Wilson disease is a rare inherited autosomal recessive disorder. As a consequence of genetic alterations in the ATP7B gene, copper begins to accumulate in the body, particularly in the liver and brain. Affected persons are prone to develop liver cancer and severe psychiatric [...] Read more.

Wilson disease is a rare inherited autosomal recessive disorder. As a consequence of genetic alterations in the ATP7B gene, copper begins to accumulate in the body, particularly in the liver and brain. Affected persons are prone to develop liver cancer and severe psychiatric and neurological symptoms. Clinically, the development of corneal Kayser-Fleischer rings and low ceruloplasmin concentrations (<20 mg/dL) are indicative of Wilson disease. However, the detection of elevated hepatic copper content (>250 µg/g dry weight) alone is still considered as the best but not exclusive diagnostic test for Wilson disease. Presently, specific copper stains (e.g., rhodanine) or indirect staining for copper-associated proteins (e.g., orcein) are widely used to histochemically visualize hepatic copper deposits. However, these procedures only detect lysosomal copper, while cytosolic copper is not detectable. Similarly, elemental analysis in scanning electron microscope with energy dispersive X-ray analysis (EDX) often leads to false negative results and inconsistencies. Here, we tested the diagnostic potential of laser ablation inductively-coupled mass spectrometry (LA-ICP-MS) that allows quantitative analysis of multiple elements. Comparative studies were performed in wild type and the Atp7b null mouse model. We propose LA-ICP-MS as a versatile and powerful method for the accurate determination of hepatic copper in people with Wilson disease with high spatial resolution. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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Review

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21 pages, 1088 KiB

Open AccessReview

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

by Hilary Y. Liu, Jenna R. Gale, Ian J. Reynolds, John H. Weiss and Elias Aizenman

Biomedicines 2021, 9(5), 489; https://doi.org/10.3390/biomedicines9050489 - 29 Apr 2021

Cited by 24 | Viewed by 4140

Abstract

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy [...] Read more.

Zinc is a highly abundant cation in the brain, essential for cellular functions, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential (MMP), leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and excitotoxic calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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38 pages, 536 KiB

Open AccessReview

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

by Nina Horn and Pernilla Wittung-Stafshede

Biomedicines 2021, 9(4), 391; https://doi.org/10.3390/biomedicines9040391 - 6 Apr 2021

Cited by 40 | Viewed by 4311

Abstract

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to [...] Read more.

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

20 pages, 785 KiB

Open AccessReview

Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease

by R. G. Barber, Zoey A. Grenier and Jason L. Burkhead

Biomedicines 2021, 9(3), 316; https://doi.org/10.3390/biomedicines9030316 - 20 Mar 2021

Cited by 30 | Viewed by 5231

Abstract

Essential metals such as copper (Cu) and zinc (Zn) are important cofactors in diverse cellular processes, while metal imbalance may impact or be altered by disease state. Cu is essential for aerobic life with significant functions in oxidation-reduction catalysis. This redox reactivity requires [...] Read more.

Essential metals such as copper (Cu) and zinc (Zn) are important cofactors in diverse cellular processes, while metal imbalance may impact or be altered by disease state. Cu is essential for aerobic life with significant functions in oxidation-reduction catalysis. This redox reactivity requires precise intracellular handling and molecular-to-organismal levels of homeostatic control. As the central organ of Cu homeostasis in vertebrates, the liver has long been associated with Cu storage disorders including Wilson Disease (WD) (heritable human Cu toxicosis), Idiopathic Copper Toxicosis and Endemic Tyrolean Infantile Cirrhosis. Cu imbalance is also associated with chronic liver diseases that arise from hepatitis viral infection or other liver injury. The labile redox characteristic of Cu is often discussed as a primary mechanism of Cu toxicity. However, work emerging largely from the study of WD models suggests that Cu toxicity may have specific biochemical consequences that are not directly attributable to redox activity. This work reviews Cu toxicity with a focus on the liver and proposes that Cu accumulation specifically impacts Zn-dependent processes. The prospect that Cu toxicity has specific biochemical impacts that are not entirely attributable to redox may promote further inquiry into Cu toxicity in WD and other Cu-associated disorders. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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15 pages, 3030 KiB

Open AccessReview

Apoceruloplasmin: Abundance, Detection, Formation, and Metabolism

by Maria C. Linder

Biomedicines 2021, 9(3), 233; https://doi.org/10.3390/biomedicines9030233 - 25 Feb 2021

Cited by 17 | Viewed by 2785

Abstract

Ceruloplasmin, the main copper-binding protein in blood and some other fluids, is well known for its copper-dependent enzymatic functions and as a source of copper for cells. What is generally unknown or ignored is that, at least in the case of blood plasma [...] Read more.

Ceruloplasmin, the main copper-binding protein in blood and some other fluids, is well known for its copper-dependent enzymatic functions and as a source of copper for cells. What is generally unknown or ignored is that, at least in the case of blood plasma and serum, about half of ceruloplasmin is in the apo (copper-free) form. This has led to some misconceptions about the amounts and variations of other copper-binding proteins and so-called “free copper” in the blood that might be indicators of disease states. What is known about the levels, sources, and metabolism of apo versus holo ceruloplasmin and the problems associated with measurements of the two forms is reviewed here. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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25 pages, 4085 KiB

Open AccessReview

Zinc: Multidimensional Effects on Living Organisms

by Math P. Cuajungco, Maria Soledad Ramirez and Marcelo E. Tolmasky

Biomedicines 2021, 9(2), 208; https://doi.org/10.3390/biomedicines9020208 - 22 Feb 2021

Cited by 40 | Viewed by 4450

Abstract

Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a [...] Read more.

Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes, ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as an antimicrobial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented, and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing number of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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13 pages, 1019 KiB

Open AccessReview

Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family

by Daniel J. Styrpejko and Math P. Cuajungco

Biomedicines 2021, 9(2), 220; https://doi.org/10.3390/biomedicines9020220 - 21 Feb 2021

Cited by 12 | Viewed by 3041

Abstract

A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, [...] Read more.

A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, has similar characteristics in both predicted transmembrane domain structure and function to the cation diffusion facilitator (CDF) protein superfamily. This review discusses past and present data indicating that TMEM163 is a zinc binding protein that transports zinc in cells. We provide a brief background on TMEM163’s discovery, transport feature, protein interactome, and similarities, as well as differences, with known SLC30 (ZnT) protein family. We also examine recent reports that implicate TMEM163 directly or indirectly in various human diseases such as Parkinson’s disease, Mucolipidosis type IV and diabetes. Overall, the role of TMEM163 protein in zinc metabolism is beginning to be realized, and based on current evidence, we propose that it is likely a new CDF member belonging to mammalian SLC30 (ZnT) zinc efflux transporter proteins. Full article

(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)

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