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

Transferrin, the major plasma iron binding molecule, interacts with cell surface receptors to deliver iron, modulate hepcidin expression, and regulate erythropoiesis. Transferrin binds and releases iron via either or both of two homologous lobes (N and C). To test the hypothesis that the specificity of iron occupancy in N vs. C lobe influences transferrin function, we generated mice with mutations to abrogate iron-binding in either lobe (TfN-blor TfC-bl). Mice homozygous for either mutation have hepatocellular iron loading and decreased liver hepcidin expression (relative to iron concentration), although to different magnitudes. Both mouse models demonstrate some aspects of iron-restricted erythropoiesis, including increased zinc protoporphyrin levels, decreased hemoglobin levels, and microcytosis. The TfN-bl/N-bl mice moreover demonstrate the anticipated effect of iron restriction on red cell production (i.e., no increase in RBC count despite elevated erythropoietin levels) along with a poor response to exogenous erythropoietin. In contrast, the TfC-bl/C-bl mice have 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.