Functional Partnership of the Copper Export Machinery and Glutathione Balance in Human Cells

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

“…28 In this study, we identified that 5-bromo-2-deoxyuridine (BrdU) incorporation in VSMCs from SM22α −/− mice increased after PDGF-BB stimulation and decreased after reexpression of SM22α WT but not K21R mutant protein (Online Figure VIIIE). However, TUNEL staining showed that the number of cells undergoing apoptosis were markedly increased in VSMCs from SM22α −/− mice compared with those from WT mice (1.8±0.8% versus 8.2±2.7%), and reduced after the expression of exogenous SM22α WT but not K21R mutant protein ( Figure 5D and 5E).…”

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

“…The effects of lowering GSH levels with BSO include an effect on the redox status of ATOX1 thiols (22). If it were assumed that ATOX1 directly receives copper from hCTR1, the BSO inhibition of copper transport may seem to point to a mechanism in which copper binding by ATOX1 protein is impaired by oxidation, leading to the reduction in copper uptake we observed in the presence of BSO.…”

“…This result led to the suggestion that ATP7A can obtain the metal from some other donor (20). Interestingly, moderate levels of BSO are toxic to Atox1 Ϫ/Ϫ MEF cells but not to the parental Atox1 ϩ/ϩ MEF line (22). This toxicity might be explained by a large reduction in (copper-bound) GSH by BSO, which could be the unknown ATP7A copper donor in Atox1 Ϫ/Ϫ cells.…”

“…Specifically, it is not known whether copper is exchanged directly from the transporter to the chaperones via specific transporter: chaperone interactions (22,43) or via an intermediate ligand.…”

An Expanding Range of Functions for the Copper Chaperone/Antioxidant Protein Atox1

“…Mice and flies with the genetically deleted Atox1 are born and develop into adulthood, whereas this does not happen if they lack active copper transporters (34,72). New data have emerged showing a protective effect of Atox1 on cells' growth in low GSH (30) along with the studies illustrating the dual role of Atox1 in maintaining the mRNA levels for the secreted Cu/Zndependent superoxide dismutase 3, SOD3 along with transferring copper to SOD3 during biosynthesis (42). Altogether, these observations suggest that Atox1 may play a key role at the intersection of several metabolic pathways by contributing to both copper homeostasis and cellular redox balance.…”