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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Erythrocyte Count
  • Erythropoiesis*
  • Erythropoietin / metabolism
  • Female
  • Homeostasis
  • Iron / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transferrin / chemistry
  • Transferrin / genetics
  • Transferrin / metabolism*


  • Transferrin
  • Erythropoietin
  • Iron
  • Proto-Oncogene Proteins c-akt