Erythropoiesis in animals is a synchronized process of erythroid cell differentiation that depends on successful acquisition of iron. model. GLRX5 is involved in the production and ABCB7 in the export of an unknown factor that may function as a gauge of mitochondrial iron status which may GS-9350 indirectly modulate activity of iron regulatory proteins (IRPs). ALAS2 the enzyme catalyzing the first step in heme synthesis is translationally controlled by IRPs. GLRX5 may also provide Fe-S cofactor for ferrochelatase the last enzyme in heme synthesis. ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase the enzyme producing lipoate for pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA a substrate for heme biosynthesis. Thus many steps of heme synthesis depend GS-9350 on Fe-S cluster assembly. 1 Erythropoiesis Erythropoiesis the manufacture of red blood cells (or erythrocytes) mainly occurs within bone marrow in human adults for review see [1]. In erythropoiesis there is a stepwise differentiation of cell types beginning with multipotent hematopoietic stem cells which successively mature into common myeloid progenitor cells proerythroblasts erythroblasts and finally into mature erythrocytes [2]. Erythropoiesis is stimulated by the hormone erythropoietin (EPO) for review see [3] which enhances proliferation and differentiation of the erythroid cells by blocking apoptosis of erythroid progenitors as is reviewed elsewhere for review see [4-8].Hemoglobinization results from the production of hemoglobin which requires synthesis of heme. Heme is synthesized by an eight step enzyme-catalyzed pathway in which the final step is the insertion of an iron into protoporphyrin IX to form a protoheme for review see [9 10 The substantial manufacture of heme for hemoglobin in red blood cells consumes 70% of body iron in humans. Iron homeostasis during erythropoiesis is highly regulated to synchronize synthesis of heme and globin and to avoid the potential toxicity caused by accumulation of excess iron or heme. 2 Systemic Iron Metabolism and Regulation of Hepcidin Expression by EPO and Other Factors Iron in food is absorbed in the duodenum from which it is released into the GS-9350 circulation via ferroportin the iron exporter on basolateral membranes of duodenal enterocytes. Most of the daily iron supply in the human body comes from phagocytosis of senescent red blood cells by macrophages in the spleen liver and bone marrow. Macrophages recycle iron by metabolizing heme and releasing the free iron into the circulation via the membrane-bound ferrous iron transporter ferroportin [11-13]. The ferroportin-mediated release of iron is therefore a key regulation point of systemic iron metabolism. Hepcidin is a small peptide synthesized mainly in the liver that modulates the abundance of ferroportin at the cellular membrane of GS-9350 cells that release iron for review see [14-16]. Hepcidin is the master regulator of systemic iron homeostasis: low levels of hepcidin increase iron release into plasma whereas high hepcidin levels decrease iron release into plasma. The transcription of hepcidin is complex and is finely tuned by a number of different signal transduction pathways KCTD18 antibody for review see [14 17 To coordinate iron metabolism to meet the demands of erythropoiesis hepcidin expression is regulated by EPO the erythropoiesis stimulator and also possibly by growth differentiation factor 15 (GDF15) and twisted gastrulation (TWSG1) soluble peptides which are directly produced by erythroblasts [20 21 In cultured liver cells (primary hepatocytes and HepG2) hepcidin transcription is regulated by EPO which mediates its effect through EPO receptor signaling and C/EBP transcription factor [22]. GDF15 GS-9350 secretion from maturing erythroblasts may inhibit hepcidin mRNA expression in hepatocytes which would therefore allow more release of iron into plasma from the duodenum and macrophages to support erythropoiesis. However this potential role of GDF15 remains unproven as GDF15 has failed to suppress hepcidin expression in cellular models [23.