Copper transport into the secretory pathway is regulated by oxygen in macrophages

Carine White, Taiho Kambe, Yan G. Fulcher, Sherri W. Sachdev, Ashley I. Bush, Kevin Fritsche, Jaekwon Lee, Thomas P. Quinn, Michael J. Petris

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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 copper-dependent 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.

Original languageEnglish (US)
Pages (from-to)1315-1321
Number of pages7
JournalJournal of Cell Science
Volume122
Issue number9
DOIs
StatePublished - May 1 2009

Fingerprint

Secretory Pathway
Copper
Macrophages
Oxygen
Biochemical Phenomena
Cytoplasmic Vesicles
Ceruloplasmin
Poisons
Biosynthetic Pathways
Electron Transport Complex IV
Superoxide Dismutase
Oxidation-Reduction
Homeostasis

Keywords

  • ATP7A
  • Copper
  • Hypoxia
  • Macrophage
  • Oxygen
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology

Cite this

White, C., Kambe, T., Fulcher, Y. G., Sachdev, S. W., Bush, A. I., Fritsche, K., ... Petris, M. J. (2009). Copper transport into the secretory pathway is regulated by oxygen in macrophages. Journal of Cell Science, 122(9), 1315-1321. https://doi.org/10.1242/jcs.043216

Copper transport into the secretory pathway is regulated by oxygen in macrophages. / White, Carine; Kambe, Taiho; Fulcher, Yan G.; Sachdev, Sherri W.; Bush, Ashley I.; Fritsche, Kevin; Lee, Jaekwon; Quinn, Thomas P.; Petris, Michael J.

In: Journal of Cell Science, Vol. 122, No. 9, 01.05.2009, p. 1315-1321.

Research output: Contribution to journalArticle

White, C, Kambe, T, Fulcher, YG, Sachdev, SW, Bush, AI, Fritsche, K, Lee, J, Quinn, TP & Petris, MJ 2009, 'Copper transport into the secretory pathway is regulated by oxygen in macrophages', Journal of Cell Science, vol. 122, no. 9, pp. 1315-1321. https://doi.org/10.1242/jcs.043216
White C, Kambe T, Fulcher YG, Sachdev SW, Bush AI, Fritsche K et al. Copper transport into the secretory pathway is regulated by oxygen in macrophages. Journal of Cell Science. 2009 May 1;122(9):1315-1321. https://doi.org/10.1242/jcs.043216
White, Carine ; Kambe, Taiho ; Fulcher, Yan G. ; Sachdev, Sherri W. ; Bush, Ashley I. ; Fritsche, Kevin ; Lee, Jaekwon ; Quinn, Thomas P. ; Petris, Michael J. / Copper transport into the secretory pathway is regulated by oxygen in macrophages. In: Journal of Cell Science. 2009 ; Vol. 122, No. 9. pp. 1315-1321.
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