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Lobe Specificity of Iron Binding to Transferrin Modulates Murine Erythropoiesis and Iron Homeostasis

Lobe Specificity of Iron Binding to Transferrin Modulates Murine Erythropoiesis and Iron Homeostasis

Nermi L Parrow, Yihang Li, Maria Feola, Amaliris Guerra, Carla Casu, Princy Prasad, Luke Mammen, Faris Ali, Edvinas Vaicikauskas, Stefano Rivella, Yelena Z Ginzburg, Robert E Fleming

Blood. 2019 Oct 24;134(17):1373-1384.

PMID: 31434707

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413264	Erythropoietin from mouse			Price

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