Key Points
FPN on erythroid cells contributes a significant amount of iron to the blood.
FPN deficiency predisposes RBCs to oxidative injury.
Visual Abstract
Abstract
Ferroportin (FPN), the only known vertebrate iron exporter, transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues and cells in vivo. Most of the circulating iron is consumed by erythroid cells to synthesize hemoglobin. Here we found that erythroid cells not only consumed large amounts of iron, but also returned significant amounts of iron to the blood. Erythroblast-specific Fpn knockout (Fpn KO) mice developed lower serum iron levels in conjunction with tissue iron overload and increased FPN expression in spleen and liver without changing hepcidin levels. Our results also showed that Fpn KO mice, which suffer from mild hemolytic anemia, were sensitive to phenylhydrazine-induced oxidative stress but were able to tolerate iron deficiency upon exposure to a low-iron diet and phlebotomy, supporting that the anemia of Fpn KO mice resulted from erythrocytic iron overload and resulting oxidative injury rather than a red blood cell (RBC) production defect. Moreover, we found that the mean corpuscular volume (MCV) values of gain-of-function FPN mutation patients were positively associated with serum transferrin saturations, whereas MCVs of loss-of-function FPN mutation patients were not, supporting that erythroblasts donate iron to blood through FPN in response to serum iron levels. Our results indicate that FPN of erythroid cells plays an unexpectedly essential role in maintaining systemic iron homeostasis and protecting RBCs from oxidative stress, providing insight into the pathophysiology of FPN diseases.
- Submitted April 6, 2018.
- Accepted September 6, 2018.
- © 2018 by The American Society of Hematology
To view this item, select one of the options below.
ASH Members and Subscribers
If you already have a subscription, you may gain access using your ASH username and password.
Purchase Short-Term Access
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$75.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
OpenAthens Users
Log in through your institution
Sign Up
Subscribe to the Journal - Subscribe to the print and/or online journal.