Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2).
Iron regulatory protein 2 (IRP2)-deficient mice have been reported to suffer from late-onset neurodegeneration by an unknown mechanism. We report that young adult Irp2-/- mice display signs of iron mismanagement within the central iron recycling pathway in the mammalian body, the liver-bone marrow-spleen axis, with altered body iron distribution and compromised hematopoiesis. In comparison with wild-type littermates, Irp2-/- mice are mildly microcytic with reduced serum hemoglobin levels and hematocrit. Serum iron and transferrin saturation are unchanged, and hence microcytosis is not due to an overt decrease in systemic iron availability. The liver and duodenum are iron loaded, while the spleen is iron deficient, associated with a reduced expression of the iron exporter ferroportin. A reduction in transferrin receptor 1 (TfR1) mRNA levels in the bone marrow of Irp2-/- mice can plausibly explain the microcytosis by an intrinsic defect in erythropoiesis due to a failure to adequately protect TfR1 mRNA against degradation. This study links a classic regulator of cellular iron metabolism to systemic iron homeostasis and erythropoietic TfR1 expression. Furthermore, this work uncovers aspects of mammalian iron metabolism that can or cannot be compensated for by the expression of IRP1.
Galy
Bruno
B
European Molecular Biology Laboratory, Heidelberg, Germany.
Ferring
Dunja
D
Minana
Belen
B
Bell
Oliver
O
Janser
Heinz G
HG
Muckenthaler
Martina
M
Schümann
Klaus
K
Hentze
Matthias W
MW
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D004386:Duodenum / Q000378:metabolism; D004920:Erythropoiesis; D005293:Ferritins / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics* / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D012333:RNA, Messenger; D014168:Transferrin; D012313:RNA; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2