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Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc

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Abstract

The essential role of transferrin in mammalian iron metabolism is firmly established. Integral to our understanding of transferrin, studies in hypotransferrinemic mice, a model of inherited transferrin deficiency, have demonstrated that transferrin is essential for iron delivery for erythropoiesis and in the regulation of expression of hepcidin, a hormone that inhibits macrophage and enterocyte iron efflux. Here we investigate a potential role for transferrin in the distribution of three other physiologic metals, manganese, copper, and zinc. We first assessed metal content in transferrin-rich fractions of wild-type mouse sera and demonstrate that although both iron and manganese cofractionated predominantly with transferrin, the absolute levels of manganese are several orders of magnitude lower than those of iron. We next measured metal content in multiple tissues in wild-type and hypotransferrinemic mice of various ages. Tissue metal imbalances were severe for iron and minimal to moderate for some metals in some tissues in hypotransferrinemic mice. Metal levels measured in a transferrin-replete yet hepcidin-deficient and iron-loaded mouse strain suggested that the observed imbalances in tissue copper, zinc, and manganese levels were not all specific to hypotransferrinemic mice or caused directly by transferrin deficiency. Overall, our results suggest that transferrin does not have a primary role in the distribution of manganese, copper, or zinc to tissues and that the abnormalities observed in tissue manganese levels are not attributable to a direct role for transferrin in manganese metabolism but rather are attributable to an indirect effect of transferrin deficiency on hepcidin expression and/or iron metabolism.

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Abbreviations

BPS:

Bathophenanthrolinedisulfonic acid

CCS:

Copper chaperone for superoxide dismutase

CV:

Column volume

DMT1:

Divalent metal transporter 1

GF-AAS:

Graphite furnace atomic absorption spectrometry

Hjv:

Hemojuvelin

hpx:

Hypotransferrinemic

ICP-AES:

Inductively coupled plasma atomic emission spectroscopy

SOD1:

Copper/zinc superoxide dismutase

SOD2:

Manganese superoxide dismutase

Tris:

Tris(hydroxymethyl)aminomethane

wt:

Wild type

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Acknowledgments

This work was supported by NIH grant K99/R00 DK084122 to T.B.B. We thank Joseph Orchardo and David Murray at the Environmental Chemistry Facility at Brown University for providing assistance with ICP-AES and GF-AAS, Joe Prohaska for providing an aliquot of rabbit anti-CCS antibody for use in immunoblots, and Rick Eisenstein for providing samples of SOD1-deficient mouse tissue.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, 02912, USA

    Carolina Herrera, Michael A. Pettiglio & Thomas B. Bartnikas

Authors
  1. Carolina Herrera
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  2. Michael A. Pettiglio
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  3. Thomas B. Bartnikas
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Correspondence to Thomas B. Bartnikas.

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Herrera, C., Pettiglio, M.A. & Bartnikas, T.B. Investigating the role of transferrin in the distribution of iron, manganese, copper, and zinc. J Biol Inorg Chem 19, 869–877 (2014). https://doi.org/10.1007/s00775-014-1118-5

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