Role for copper in the cellular and regulatory effects of heme-hemopexin

Ann Smith, Kimberly R. Rish, Rachel Lovelace, Jennifer F. Hackney, Rachel M. Helston

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Hemopexin (HPX) binds heme tightly, thus protecting cells from heme toxicity during hemolysis, trauma and ischemia-reperfusion injury. Heme uptake via endocytosis of heme-HPX followed by heme catabolism by heme oxygenase-1 (HMOX1) raises regulatory iron pools, thus linking heme metabolism with that of iron. Normal iron homeostasis requires copper-replete cells. When heme-HPX induces HMOX1, the copper-storing metallothioneins (MTs) are also induced whereas the copper-responsive copper chaperone that delivers copper to Cu, Zn superoxide dismutase, CCS1, is decreased; both are known responses when cellular copper levels rise. Endocytosis of heme-HPX is needed to regulate CCS1 since the signaling ligand cobalt-protoporphyrin (CoPP)-HPX, which does not induce HMOX1 but does co-localize with heme-HPX in endosomes, also decreased CCS1. These observations support that heme-HPX mobilizes copper in cells. The regulation of both hmox1 and mt1 is prevented by the copper-chelator, bathocuproinedisulfonate (BCDS), but not uptake of heme-AlexaFluor-labeled HPX into endosomes. Supporting a role for copper in HMOX1 regulation by heme-HPX, nutritional copper deficiency generated by tetraethylene pentamine or 232 tetraamine prevented HMOX1 induction. Using conditions that mimic maturing endosomes, we found that copper prevents rebinding of heme to apo-HPX. A model is presented in which copper endocytosis together with that of heme-HPX provides a means to facilitate heme export from HPX in the maturing endosomes: heme is needed for hmox1 transcription, while cytosolic copper and CCS1 provide a link for the known simultaneous regulation of hmox1 and mt1 by heme-HPX.

Original languageEnglish (US)
Pages (from-to)421-437
Number of pages17
JournalBioMetals
Volume22
Issue number3
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

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Keywords

  • CCS1
  • Cobalt protoporphyrin IX
  • Copper
  • Endocytosis
  • Endosomes
  • Heme
  • Heme oxygenase
  • Hemopexin
  • Iron
  • Metallothionein

ASJC Scopus subject areas

  • Biomaterials
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Metals and Alloys

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