The molecular and cellular basis of copper dysregulation and its relationship with human pathologies

Abstract

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu + -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in K E Y W O R D S cancer, copper, copper-dependent diseases, cuproproteins, Menkes disease, mitochondrial myopathies, Wilson disease

Angiogenin and Copper Crossing in Wound Healing

“…Copper enters the cell through the copper transporters 1 and 2 (CTR1 and CTR2), which are membrane proteins with a channel-like structure, widely present in several cell types and tissues [89][90][91]. Before its transfer, to ensure efficient transport across the cell membrane, Cu 2+ is reduced to Cu + , by membrane metal reductases [92], and within the cell, copper's distribution to mitochondrial, nuclear and vesicular targets is mediated by several metal chaperones, namely glutathione (GSH), Menkes protein, copper chaperone for superoxide dismutase (SOD) and antioxidant-1 (ATOX-1) [93].…”

A Deeper Insight in Metal Binding to the hCtr1 N-terminus Fragment: Affinity, Speciation and Binding Mode of Binuclear Cu2+ and Mononuclear Ag+ Complex Species

“…A defective absorption of the metal ion is linked to a series of pathologies, while an excessive copper accumulation may cause degenerative disorders [ 4 , 5 ].…”

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

“…The main copperstorage organ in the body is the liver (Figure 6). Wilson's disease is an autosomal recessive genetic disorder caused by mutation of gene ATP7B on chromosome 13 with incidence regionally varying in the range of 1-4 cases per 100,000 (but the genetic prevalence is considerably higher, even 1:7000) [85][86][87]. Impaired function of the corresponding protein leads to high accumulation of copper in the Wilson's disease is an autosomal recessive genetic disorder caused by mutation of gene ATP7B on chromosome 13 with incidence regionally varying in the range of 1-4 cases per 100,000 (but the genetic prevalence is considerably higher, even 1:7000) [85][86][87].…”

“…Wilson's disease is an autosomal recessive genetic disorder caused by mutation of gene ATP7B on chromosome 13 with incidence regionally varying in the range of 1-4 cases per 100,000 (but the genetic prevalence is considerably higher, even 1:7000) [85][86][87]. Impaired function of the corresponding protein leads to high accumulation of copper in the Wilson's disease is an autosomal recessive genetic disorder caused by mutation of gene ATP7B on chromosome 13 with incidence regionally varying in the range of 1-4 cases per 100,000 (but the genetic prevalence is considerably higher, even 1:7000) [85][86][87]. Impaired function of the corresponding protein leads to high accumulation of copper in the organism, especially in the liver and central neural system, as the product of this gene is responsible for copper elimination from the liver into bile, the main regulated physiological way of excessive copper elimination from the organism.…”