Copper Homeostasis in Mammals, with Emphasis on Secretion and Excretion. A Review

Linder, Maria C.

doi:10.3390/ijms21144932

Cited by 72 publications

(69 citation statements)

References 92 publications

(165 reference statements)

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“…Alternately, Cu exits hepatocytes via the basolateral membrane as a cofactor of the ferroxidase ceruloplasmin [ 11 ]. Blood circulating Cu can be acquired by other tissues including the brain, kidney, heart, connective tissue, and pancreas [ 12 ]. Although most whole-body Cu regulation is attributed to ATP7B, the Cu exporter ATP7A has central roles in intestinal Cu acquisition and mobilization across the blood–brain barrier [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

2021

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“…Lastly, copper binds to the transcription factors and regulates gene expression, mostly involved in copper storage and buffering [ 1 ]. To maintain copper physiological levels, copper homeostasis is tightly regulated [ 4 ]. Its alterations are often linked with various diseases.…”

Section: Introductionmentioning

confidence: 99%

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

Soczewka

Tribouillard-Tanvier

Rago

et al. 2021

IJMS

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Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A-D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases.

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“…Copper enters the hepatocytes via CTR1. Intracellularly, copper is sequestered by metallothionein and glutathione after which copper chaperones COX17, CCS and ATOX1 shuttle copper to their respective intracellular target proteins CcO in the mitochondria, SOD1 in the cytoplasm and ATP7B in the trans-Golgi network (TGN) [4]. COMMD1 and ATP7B are involved in copper excretion into the bile.…”

Section: Introductionmentioning

confidence: 99%

“…Under high intracellular copper conditions, ATP7B traffics into late endosomes/lysosomes, and COMMD1, as a complex with CCD22-CCDC93, binds to ATP7B and mediates ATP7B trafficking and plays a role in ATP7B stability and fidelity [4,5]. Additionally, ATP7B incorporates copper into apo-ceruloplasmin to form holo-ceruloplasmin in the TGN, which is subsequently excreted into the plasma [4]. Ceruloplasmin is a copper-carrying protein in the blood, which is also involved in iron metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers

Boer

Vos-Loohuis

et al. 2020

Life

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Copper toxicosis is a complex genetic disorder in Labrador retrievers characterized by hepatic copper accumulation eventually leading to liver cirrhosis. The variation of hepatic copper levels in Labrador retrievers has been partly explained by mutations in ATP7A c.980C>T and ATP7B c.4358G>A. To further elucidate the genetic background of this disease, we used targeted Next Generation Sequencing (NGS) in a cohort of 95 Labrador retrievers to analyze 72 potential modifier genes for variations associated with hepatic copper levels. Variants associated with copper levels were subsequently evaluated in a replication cohort of 144 Labrador retrievers. A total of 44 variants in 25 different genes were identified, of which four showed significant association with copper levels. Of the four variants found associated with hepatic copper levels in the NGS cohort, one was validated in the replication cohort. The non-reference allele of the variant NC_006602.3.g.52434480C>T in RETN resulting in amino-acid change p.Leu7Phe was associated with decreased hepatic copper levels. In humans, resistin is associated with severity of non-alcoholic fatty liver disease, fibrosis, cirrhosis and mitochondrial dysfunction in hepatocytes. Further studies are needed to investigate the biological function of RETN p.Leu7Phe in the development of copper toxicosis in Labrador retrievers.

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Copper Homeostasis in Mammals, with Emphasis on Secretion and Excretion. A Review

Cited by 72 publications

References 92 publications

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

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

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers

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