Abstract
Studies with patients, animal models of human disease and hemopexin null mice have shown that the heme-binding protein hemopexin is vital for the protection of a variety of cell types and tissues against heme toxicity. The presence of hemopexin in all biological fluids examined to date indicates wide roles in abrogating heme toxicity in human tissues; and, thus, is clinically relevant. Heme-hemopexin endocytosis leads to coordinated trafficking of heme, iron and copper as heme traffics from endosomes to heme oxygenases (HOs) in the smooth endoplasmic reticulum and to the nucleus. This is safe redox-metal trafficking, without oxidative stress, as iron released from heme catabolism by HOs as well as copper taken up with heme-hemopexin move through the cell. To our knowledge, this coordinated metal trafficking has been described only for the hemopexin system and differs from the cell’s response to non-protein bound heme, which can be toxic. We propose that defining how cells respond to heme-hemopexin endocytosis, a natural cytoprotective system, will aid our understanding of how cells adapt as they safely respond to increases in heme, Fe(II) and copper. This is relevant for many genetic hemolytic diseases and conditions, stroke and hemorrhage as well as neurodegeneration. Such analyses will help to define a pattern of events that can be utilized to characterize how dysfunctional redox and transition metal handling is linked to the development of pathology in disease states such as Alzheimer’s disease when metal homeostasis is not restored; and potentially provide novel targets and approaches to improve therapies.
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Acknowledgements
We acknowledge Drs. Peter Koulen and Jeffrey Price (School of Biological Sciences, University of Missouri-Kansas City) for help with the preparation of the manuscript, and Dr. Tamas Kapros (School of Biological Sciences, University of Missouri-Kansas City) for his help generating the final figures. We also acknowledge the expert technical help of members of the Smith research team Dr. Rachel M. Helston, Kimberley Rish, Rachel Hunt (formerly Lovelace) and Peter Hahl. This research was supported in part by the National Institutes of Health (R21 DK64363 to A.S.), by a grant from University of Missouri Research Board (A.S.) and Research Incentive Funds UMKC (A.S.).
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Vanacore, R., Eskew, J.D., Sung, L. et al. Safe coordinated trafficking of heme and iron with copper maintain cell homeostasis: modules from the hemopexin system. Biometals 32, 355–367 (2019). https://doi.org/10.1007/s10534-019-00194-4
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DOI: https://doi.org/10.1007/s10534-019-00194-4