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Blood. 2019 Oct 24;134(17):1373-1384. doi: 10.1182/blood.2018893099.

Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis.

Author information

1
Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO.
2
Division of Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
3
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and.
4
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO.

Abstract

Transferrin, the major plasma iron-binding molecule, interacts with cell-surface receptors to deliver iron, modulates hepcidin expression, and regulates erythropoiesis. Transferrin binds and releases iron via either or both of 2 homologous lobes (N and C). To test the hypothesis that the specificity of iron occupancy in the N vs C lobe influences transferrin function, we generated mice with mutations to abrogate iron binding in either lobe (TfN-bl or TfC-bl). Mice homozygous for either mutation had hepatocellular iron loading and decreased liver hepcidin expression (relative to iron concentration), although to different magnitudes. Both mouse models demonstrated some aspects of iron-restricted erythropoiesis, including increased zinc protoporphyrin levels, decreased hemoglobin levels, and microcytosis. Moreover, the TfN-bl/N-bl mice demonstrated the anticipated effect of iron restriction on red cell production (ie, no increase in red blood cell [RBC] count despite elevated erythropoietin levels), along with a poor response to exogenous erythropoietin. In contrast, the TfC-bl/C-bl mice had elevated RBC counts and an exaggerated response to exogenous erythropoietin sufficient to ameliorate the anemia. Observations in heterozygous mice further support a role for relative N vs C lobe iron occupancy in transferrin-mediated regulation of iron homeostasis and erythropoiesis.

Comment in

PMID:
31434707
PMCID:
PMC6839954
[Available on 2020-10-24]
DOI:
10.1182/blood.2018893099
[Indexed for MEDLINE]

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