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Am J Physiol Cell Physiol 293: C641-C649, 2007. First published April 25, 2007; doi:10.1152/ajpcell.00599.2006
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RECEPTORS AND SIGNAL TRANSDUCTION

Ferritin: a novel mechanism for delivery of iron to the brain and other organs

J. Fisher,1 K. Devraj,2 J. Ingram,1 B. Slagle-Webb,1 A. B. Madhankumar,1 X. Liu,1 M. Klinger,2 I. A. Simpson,2 and J. R. Connor1

1Department of Neurosurgery and 2Department of Neural and Behavioral Science, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Submitted 4 December 2006 ; accepted in final form 14 April 2007

Traditionally, transferrin has been considered the primary mechanism for cellular iron delivery, despite suggestive evidence for additional iron delivery mechanisms. In this study we examined ferritin, considered an iron storage protein, as a possible delivery protein. Ferritin consists of H- and L-subunits, and we demonstrated iron uptake by ferritin into multiple organs and that the uptake of iron is greater when the iron is delivered via H-ferritin compared with L-ferritin. The delivery of iron via H-ferritin but not L-ferritin was significantly decreased in mice with compromised iron storage compared with control, indicating that a feedback mechanism exists for H-ferritin iron delivery. To further evaluate the mechanism of ferritin iron delivery into the brain, we used a cell culture model of the blood-brain barrier to demonstrate that ferritin is transported across endothelial cells. There are receptors that prefer H-ferritin on the endothelial cells in culture and on rat brain microvasculature. These studies identify H-ferritin as an iron transport protein and suggest the presence of an H-ferritin receptor for mediating iron delivery. The relative amount of iron that could be delivered via H-ferritin could make this protein a predominant player in cellular iron delivery.

blood-brain barrier; iron transport; H-ferritin


Address for reprint requests and other correspondence: J. R. Connor, Dept. of Neurosurgery (H110), Pennsylvania State Univ., Milton S. Hershey Medical Center, 500 Univ. Drive, PO Box 850, Hershey, PA 17033-0850 (e-mail: jconnor{at}psu.edu)




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