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

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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.

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Acknowledgments

The authors wish to thank Dr. M. Ferrari (University of Missouri-K.C.) for his help with confocal microscopy; and are greatly indebted to Dr. J. Prohaska (University of Minnesota) for affinity purified antibodies to CCS1 and to Dr. R.C. Hider (Kings College, London, UK.) for the physical constants for the metal chelators, for the characterization of Cu-NTA complexes (speciation plots and the calculations of free copper from Cu-NTA complexes at different pHs). Drs. G. Anderson (QMIR, Brisbane, Australia), R.C. Hider and J. Price (University of Missouri-K.C.) are also thanked for reading the manuscript and for their helpful comments. This research was supported by the National Institutes of Health (R21DK 64363 to A.S.) and by a grant from the University of Missouri Research Board (A.S.). The authors declare no competing financial interest.

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  1. Division of Molecular Biology & Biochemistry, School of Biological Sciences, University of Missouri-K.C., 5007 Rockhill Road, Kansas City, MO, 64110, USA

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

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  1. Ann Smith
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  2. Kimberly R. Rish
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Correspondence to Ann Smith.

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R.L. and K.R. carried out experiments, participated in the data statistical analyses and helped set up the figures; R.H. and J.H. carried out the fluorescence microscopy experiments and R.H. made the microscopy figures. A.S. defined the experimental strategy, designed and supervised the research, interpreted data and wrote the manuscript.

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Smith, A., Rish, K.R., Lovelace, R. et al. Role for copper in the cellular and regulatory effects of heme-hemopexin. Biometals 22, 421–437 (2009). https://doi.org/10.1007/s10534-008-9178-z

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