Copper transport into the secretory pathway is regulated by oxygen in macrophages.
Copper is an essential nutrient for a variety of biochemical processes; however, the redox properties of copper also make it potentially toxic in the free form. Consequently, the uptake and intracellular distribution of this metal is strictly regulated. This raises the issue of whether specific pathophysiological conditions can promote adaptive changes in intracellular copper distribution. In this study, we demonstrate that oxygen limitation promotes a series of striking alterations in copper homeostasis in RAW264.7 macrophage cells. Hypoxia was found to stimulate copper uptake and to increase the expression of the copper importer, CTR1. This resulted in increased copper delivery to the ATP7A copper transporter and copper-dependent trafficking of ATP7A to cytoplasmic vesicles. Significantly, the ATP7A protein was required to deliver copper into the secretory pathway to ceruloplasmin, a secreted copperdependent enzyme, the expression and activity of which were stimulated by hypoxia. However, the activities of the alternative targets of intracellular copper delivery, superoxide dismutase and cytochrome c oxidase, were markedly reduced in response to hypoxia. Collectively, these findings demonstrate that copper delivery into the biosynthetic secretory pathway is regulated by oxygen availability in macrophages by a selective increase in copper transport involving ATP7A.
White
Carine
C
Department of Nutritional Sciences, University of Missouri, Columbia, MO 65211, USA.
Kambe
Taiho
T
Fulcher
Yan G
YG
Sachdev
Sherri W
SW
Bush
Ashley I
AI
Fritsche
Kevin
K
Lee
Jaekwon
J
Quinn
Thomas P
TP
Petris
Michael J
MJ
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D006706:Homeostasis; D000860:Hypoxia / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D055571:Secretory Pathway / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; C490077:Slc31a1 protein, mouse; D003300:Copper; D002570:Ceruloplasmin; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D010100:Oxygen