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C H A P T E R 35

PATHOPHYSIOLOGY OF IRON HOMEOSTASIS

Gary M. Brittenham

Each cell in the body needs iron, not too much and not too each cell is the number of transferrin receptors expressed on the cell
little. Iron is an essential element required for energy production, surface. Within each cell, iron self-regulates its intracellular avail-
oxygen use, and cellular proliferation. Iron, able to act as both an ability, at least in part, through the iron regulatory proteins 1 and 2
electron donor and an electron acceptor by readily interconverting that function as sensors of intracellular iron (Fig. 35.2). The iron
2+
3+
between ferric (Fe ) and ferrous (Fe ) forms, is an irreplaceable regulatory proteins recognize and bind to RNA stem−loop structures
component of oxygen transport (hemoglobin); oxygen storage (myo- called iron-responsive elements when iron is absent and dissociate
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globin); sensing molecules, cytochromes, iron-sulfur clusters, and when iron is present. When the iron-responsive elements are within
heme and nonheme enzymes. The ease with which iron can gain and the 3′ untranslated region of a messenger (m) RNA (e.g., transferrin
lose electrons also makes it able to catalyze the formation of highly receptor 1 mRNA), binding prevents mRNA degradation, increasing
reactive oxygen species that can damage lipids, proteins, and DNA protein expression when iron is lacking. In contrast, when the iron-
and injure subcellular organelles, resulting in cellular dysfunction, responsive elements are located in the 5′ untranslated region of an
apoptosis, and necrosis. Consequently, both the total body iron mRNA (e.g., cytosolic ferritin mRNA), binding of the iron regulatory
and the amount within each cell are carefully controlled to ensure proteins interferes with ribosomal assembly, decreasing protein
adequate iron availability but avoid excess iron toxicity. Humans expression when iron is absent. Accordingly, a decrease in intracellular
have no regulated means for iron excretion, and obligatory losses are iron availability enhances transferrin receptor 1 protein synthesis,
normally minuscule, less than 0.05% of the total body iron each day. increasing iron import, and reduces cytosolic ferritin protein produc-
As a result, the amount of body iron is determined by control of iron tion and iron storage. Conversely, an increase in intracellular iron
absorption, and human iron homeostasis is distinguished by efficient availability reduces transferrin receptor 1 protein synthesis, inhibiting
recycling of iron (Fig. 35.1). iron import, and augments cytosolic ferritin protein production and
Although all cells require iron, quantitatively most of the iron iron storage. In iron-replete cells with sufficient oxygen, F box and
in the body is found within erythroid cells, and most of the daily leucine-rich repeat protein 5 (FBXL5), a subunit of a ubiquitin ligase
movement of iron (approximately 80%) cycles through the erythroid complex, monitors cytosolic iron and leads to iron-dependent degra-
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compartment. External exchange of iron through absorption of iron dation of iron regulatory protein 2. The presence of two distinct iron
from the gastrointestinal tract and through obligatory losses is very regulatory proteins provides for adaptation to cytosolic iron and
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limited. Physiologically, iron is carried into the erythroid marrow oxygen over a wide range of concentrations. Altogether, regulation of
and incorporated into hemoglobin, and it enters the circulation intracellular iron homeostasis is provided principally through iron
within red blood cells (RBCs) dedicated to oxygen transport. At the regulatory proteins 1 and 2 by translational control of the synthesis
end of their lifespan, RBCs are phagocytized by a select population of transferrin receptor and ferritin and, in specialized cells, of other
of macrophages in the bone marrow, liver, and spleen that then essential proteins involved in iron homeostasis, including erythroid
promptly renders up most of the catabolized iron for return to the δ-aminolevulinic acid synthase 2 (eALAS), mitochondrial aconitase,
erythroid marrow. Any surplus is stored within macrophages or hypoxia-inducible factor 2α (HIF-2α), intestinal divalent metal
hepatocytes. After examining the intricate interrelationship between transporter 1 (DMT1) isoform I, and ferroportin. 7
intracellular and systemic iron homeostasis, this chapter considers in Regulation of systemic iron homeostasis is accomplished by control
1–4
turn each portion of the pathway of iron transport, use, storage, and of the entry of iron into plasma for transport by transferrin. Cir-
absorption (see Fig. 35.1). Altogether, iron homeostasis is maintained culating transferrin iron is derived from specialized cells that can
by effective use of iron for erythropoiesis, efficient recycling of iron export iron, primarily reticuloendothelial macrophages that recycle
from senescent erythrocytes, controlled storage of iron by macro- iron from senescent RBCs, hepatocytes that can mobilize iron from
phages and hepatocytes, and careful regulation of intestinal iron stores, and duodenal enterocytes that provide iron absorbed from the
absorption. 1–4 diet. To enter plasma, iron in these cells must pass through ferroportin
(SLC40A1), a multitransmembrane-spanning protein that is the sole
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REGULATION OF CELLULAR AND SYSTEMIC known cellular iron export channel. Hepcidin, a small 25-amino acid
peptide hormone secreted principally by the liver, provides post-
IRON HOMEOSTASIS translational control of ferroportin expression by binding to and
inducing its internalization, ubiquitination, and degradation, thereby
2
Each cell in the body needs just enough iron, at just the right time. inhibiting iron entry into plasma (Fig. 35.3). Hepatic hepcidin
Iron is required in precise, carefully timed amounts for growth, synthesis is stimulated by increases in body iron stores, infection,
development, and function. Within the systemic circulation, the inflammation, or malignancy and inhibited by hypoxemia and
3
varied and varying cellular requirements are met by the transport increased erythropoietic demand. Increments in plasma hepcidin
protein transferrin, the physiologic carrier of iron through the plasma reduce the amount of ferroportin in cell membranes, causing a
and extracellular fluid. Each cell obtains its share of circulating prompt fall in plasma iron concentration. Conversely, decrements in
transferrin-bound iron by expressing transferrin receptor 1, a glyco- plasma hepcidin concentration increase the amount of ferroportin,
protein on cell membranes that binds the transferrin−iron complex producing a rise in plasma iron concentration.
and is internalized in an endocytic vesicle, where iron is released, and MicroRNAs, short (approximately 22 nucleotides), noncoding
then returns to the cell membrane, liberating apotransferrin into the RNAs that act as antisense regulators of target RNAs, provide a
1,5
plasma. Within the cell, the iron released from the endosome is further degree of control of both cellular and systemic iron homeo-
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either used or sequestered with cytosolic ferritin, an iron storage stasis. MicroRNAs help regulate the expression of genes involved in
protein that holds iron in a nontoxic form ready for prompt mobiliza- hepcidin expression (HFE, hemojuvelin: miR-122), iron uptake
1,6
tion in time of need. A prime determinant of the iron supply to (transferrin receptor 1: miR-320; divalent metal transporter 1:
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