title: Glutaredoxin1 protects neuronal cells from copper-induced toxicity.
abstract: Glutaredoxin1 (GRX1) is a glutathione (GSH)-dependent thiol oxidoreductase. The GRX1/GSH system is important for the protection of proteins from oxidative damage and in the regulation of protein function. Previously we demonstrated that GRX1/GSH regulates the activity of the essential copper-transporting P1B-Type ATPases (ATP7A, ATP7B) in a copper-responsive manner. It has also been established that GRX1 binds copper with high affinity and regulates the redox chemistry of the metallochaperone ATOX1, which delivers copper to the copper-ATPases. In this study, to further define the role of GRX1 in copper homeostasis, we examined the effects of manipulating GRX1 expression on copper homeostasis and cell survival in mouse embryonic fibroblasts and in human neuroblastoma cells (SH-SY5Y). GRX1 knockout led to cellular copper retention (especially when cultured with elevated copper) and reduced copper tolerance, while in GRX1-overexpressing cells challenged with elevated copper, there was a reduction in both intracellular copper levels and copper-induced reactive oxygen species, coupled with enhanced cell proliferation. These effects are consistent with a role for GRX1 in regulating ATP7A-mediated copper export, and further support a new function for GRX1 in neuronal copper homeostasis and in protection from copper-mediated oxidative injury.
authors.affiliation: School of Life and Environmental Sciences, Deakin University, Burwood, VIC, 3125, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cater
authors.forename: Stephanie
authors.initials: S
authors.lastname: Materia
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Xiao
authors.forename: Kamil
authors.initials: K
authors.lastname: Wolyniec
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ackland
authors.forename: Yann W
authors.initials: YW
authors.lastname: Yap
authors.forename: Nam Sang
authors.initials: NS
authors.lastname: Cheung
authors.forename: Sharon
authors.initials: S
authors.lastname: La Fontaine
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003300:Copper / Q000378:metabolism* / Q000633:toxicity; D054477:Glutaredoxins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000201:enzymology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C516005:GLRX protein, human; D054477:Glutaredoxins; D017382:Reactive Oxygen Species; D003300:Copper