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Mammalian regulation of iron circulation


Iron is an essential mineral. Both excess and lack of iron are detrimental to life-function. In mammals highest iron use is in the red blood cell (RBC), and iron from senescent RBCs is recycled for erythropoiesis through the macrophage (MP). Understanding the regulation of systemic iron recycling has made progress through the detection of hepcidin that regulates iron release from MPs and intestinal iron import.

Cellular iron metabolism is regulated in mammals mainly post-transcriptionally by the two iron regulatory proteins (IRPs). IRPs sense cellular iron status and regulate proteins of iron metabolism by binding to an RNA stem loop structure when cells are iron deplete. In mice with targeted deletions of IRP2 misregulation of proteins involved in iron metabolism, including ferritin, leads to improper iron distribution, anaemia, high serum ferritin and late onset neurodegeneration.

Our preliminary finding that ferritin in bone marrow resident MPs of IRP2-/- mice is low, while ferritin content in bone marrow de rived MPs cultured from IRP2-/- mice is high suggests that ferritin is secreted from MPs by a systemically regulated pathway that is disrupted in IRP2-/- mice. This implies a tight link between cellular and systemic regulation of iron metabolism. My lab will focus on two very different aspects of systemic iron distribution and effects of its disruption.

One project will characterize the mechanism of ferritin trafficking in wild type and IRP2-/- mice. We will explore the possibility that secreted ferritin is involved in cell to cell iron distribution and that ferritin plays an active role in the neuropathology of the IRP2-/- mice and in other neurodegenerative diseases where homeostasis of brain iron distribution is disrupted such as Parkinson's disease.

The second project will characterize the immunologic response of MPs to erythrophagocytosis and will explore the effect of the MP state after this daily event on immune homeostasis and iron recycling.

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