Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1

Abstract

Maryon EB, Molloy SA, Kaplan JH. Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1.

Copper signaling in the brain and beyond

“…In mammalian systems, intracellular copper trafficking is influenced by the cell's redox state (95), and changes in redox state may be able to trigger mobilization of copper signals. Other storage sites for copper, which may serve as the origin of copper signals, include the copper chaperones (96) or small molecules such as glutathione (6). Continued efforts to develop new technologies to image and characterize copper pools in living systems will aid in addressing these outstanding questions (14,18,97,98).…”

“…Copper is an essential mineral that must be acquired through the diet and trafficked to the organs, cells, and proteins that require copper for health (4). The majority (70%) of copper import into mammalian cells occurs through copper transporter 1 (CTR1), (5) from which copper is passed to intracellular chaperone proteins or small molecules, such as glutathione, which carry copper through the cytoplasm (6,7). The copper chaperone Atox1 delivers copper to the Cu-transporting ATPases ATP7A and ATP7B, copper exporters typically located on the Golgi apparatus and responsible for loading copper into cuproenzymes including ceruloplasmin and dopamine β-hydroxylase (8,9).…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…Among cytosolic copper-binding proteins, the antioxidant tripeptide GSH is expected to significantly influence the endothelial activation by different mechanisms, ranging from the modulation of the cell oxidative status [167,168] to copper chaperoning [169,170]. Interestingly, findings made by Maryon et al [169] subverted the traditional notion that direct protein-protein interactions are required for copper insertion into cuproenzymes (the CCS-SOD axis) and ion excess removal (the ATOX1- ATP7A axis), and proposed that GSH first accepts copper from human CTR1 membrane transporters before conveying it to specific chaperones (ATOX1 and CCS).…”

“…Interestingly, findings made by Maryon et al [169] subverted the traditional notion that direct protein-protein interactions are required for copper insertion into cuproenzymes (the CCS-SOD axis) and ion excess removal (the ATOX1- ATP7A axis), and proposed that GSH first accepts copper from human CTR1 membrane transporters before conveying it to specific chaperones (ATOX1 and CCS). In contrast to the latter, GSH has been demonstrated to severely affect copper uptake, when its expression is reduced [169]. The potential positive impact of GSH on endothelial copper management must be considered net of its negative effects on vascularization, likely exerted through the scavenging of ROS, acting as second messengers in endothelial signalling [144].…”

Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system

“…However, because of its ready non-specific reaction with many amino acid side chains and ability to undergo Fenton chemistry and generate reactive oxygen species, Cu can be damaging at excessive levels. The cellular homeostasis of Cu is accomplished by a Cu proteome consisting of uptake transporter(s), specific metallochaperones, and glutathione (GSH) that deliver cellular Cu to its target proteins and exporters that protect against excess accumulation (Harrison et al, 2000;Maryon et al, 2013b). The main high-affinity Cu uptake protein, CTR1, delivers Cu to the intracellular milieu, whereas under low (normal) cellular Cu the export proteins ATP7A and ATP7B, Cu-activated Ptype ATPases, are responsible for delivering Cu to the proteins in the secretory pathway.…”