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

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 2009
Externally publishedYes

Fingerprint

Hemopexin
heme
Heme
Copper
copper
heme oxygenase (biliverdin-producing)
Heme Oxygenase-1
endosomes
Endosomes
endocytosis
Endocytosis
Iron
pentamine
iron
Transcription
uptake mechanisms
Metabolism

Keywords

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

ASJC Scopus subject areas

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

Cite this

Role for copper in the cellular and regulatory effects of heme-hemopexin. / Smith, Ann; Rish, Kimberly R.; Lovelace, Rachel; Hackney Price, Jennifer; Helston, Rachel M.

In: BioMetals, Vol. 22, No. 3, 06.2009, p. 421-437.

Research output: Contribution to journalArticle

Smith, Ann ; Rish, Kimberly R. ; Lovelace, Rachel ; Hackney Price, Jennifer ; Helston, Rachel M. / Role for copper in the cellular and regulatory effects of heme-hemopexin. In: BioMetals. 2009 ; Vol. 22, No. 3. pp. 421-437.
@article{e8f60cf2d7a54244b6a8580bf5e5beac,
title = "Role for copper in the cellular and regulatory effects of heme-hemopexin",
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.",
keywords = "CCS1, Cobalt protoporphyrin IX, Copper, Endocytosis, Endosomes, Heme, Heme oxygenase, Hemopexin, Iron, Metallothionein",
author = "Ann Smith and Rish, {Kimberly R.} and Rachel Lovelace and {Hackney Price}, Jennifer and Helston, {Rachel M.}",
year = "2009",
month = "6",
doi = "10.1007/s10534-008-9178-z",
language = "English (US)",
volume = "22",
pages = "421--437",
journal = "BioMetals",
issn = "0966-0844",
publisher = "Springer Netherlands",
number = "3",

}

TY - JOUR

T1 - Role for copper in the cellular and regulatory effects of heme-hemopexin

AU - Smith, Ann

AU - Rish, Kimberly R.

AU - Lovelace, Rachel

AU - Hackney Price, Jennifer

AU - Helston, Rachel M.

PY - 2009/6

Y1 - 2009/6

N2 - 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.

AB - 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.

KW - CCS1

KW - Cobalt protoporphyrin IX

KW - Copper

KW - Endocytosis

KW - Endosomes

KW - Heme

KW - Heme oxygenase

KW - Hemopexin

KW - Iron

KW - Metallothionein

UR - http://www.scopus.com/inward/record.url?scp=67349257454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67349257454&partnerID=8YFLogxK

U2 - 10.1007/s10534-008-9178-z

DO - 10.1007/s10534-008-9178-z

M3 - Article

VL - 22

SP - 421

EP - 437

JO - BioMetals

JF - BioMetals

SN - 0966-0844

IS - 3

ER -