Ferritin: a novel mechanism for delivery of iron to the brain and other organs.
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.
Fisher
J
J
Dept of Neurosurgery, Pennsylvania State University, Milton S Hershey Medical Center, Hershey, PA 17033-0850, USA.
Devraj
K
K
Ingram
J
J
Slagle-Webb
B
B
Madhankumar
A B
AB
Liu
X
X
Klinger
M
M
Simpson
I A
IA
Connor
J R
JR
D000818:Animals; D001052:Apoferritins; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006736:Horses; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010088:Oxidoreductases; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012171:Retinal Vessels / Q000166:cytology / Q000378:metabolism; D013154:Spleen / Q000737:chemistry / Q000378:metabolism
C507433:FTL protein, human; D033862:Iron-Binding Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C027293:ferritin receptor; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; C454461:FTH1 protein, human; D010088:Oxidoreductases