Abstract
In mammals over 65% of the total body iron is located within erythrocytes in the heme moieties of hemoglobin. Iron homeostasis requires iron absorbed from the diet by the gut as well as recycling of iron after the destruction of senescent erythrocytes. Senescent erythrocytes are engulfed by reticuloendothelial system macrophages where hemoglobin is broken down in the lysosomes, releasing heme for iron recovery in the cytoplasm. We recently showed that the SLC48A1 protein is responsible for transporting heme from the lysosome to the cytoplasm. CRISPR generated SLC48A1-deficient mice accumulate heme in their reticuloendothelial system macrophages as hemozoin crystals. Here we describe additional features of SLC48A1-deficient mice. We show that visible hemozoin first appears in the reticuloendothelial system macrophages of SLC48A1-deficient mice at 8 days of age, indicating the onset of erythrocyte recycling. Evaluation of normal and SLC48A1-deficient mice on iron-controlled diets show that SLC48A1-mediated iron recycling is equivalent to at least 10 parts per million of dietary iron. We propose that mutations in human SLC48A1 could contribute to idiopathic iron disorders.
Highlights
Hemoglobin within erythrocytes of an average adult human male contain about 2.5 g of iron, representing about 65% of the total body iron
We demonstrate that hemozoin begins to accumulate in reticuloendothelial system (RES) macrophages 8 days after birth, which we propose correlates with the beginning of erythrocyte recycling in the mouse
Prior to our discovery of hemozoin in SLC48A1-deficient RES macrophages, hemozoin had only been observed in the lysosomal-like organelles of blood-feeding organisms that digest hemoglobin such as malaria parasites of the genus Plasmodium (Francis et al, 1997; Egan, 2008; Pek et al, 2019)
Summary
Hemoglobin within erythrocytes of an average adult human male contain about 2.5 g of iron, representing about 65% of the total body iron. Absorbed iron is bound to transferrin, which enters the circulation from where it is imported into developing orthochromic erythroblasts (Andrews, 2008; Giger and Kalfa, 2015). The majority of iron is recovered from hemoglobin by reticuloendothelial system (RES) macrophages. RES macrophages digest the hemoglobin, releasing heme. The enzyme heme oxygenase processes heme to remove the iron atom, which is exported from the cell by ferroportin and bound by transferrin for passage to the bone marrow to produce new erythrocytes (Kong et al, 2013). In erythroblasts, imported transferrin-bound iron is subsequently incorporated into heme by a series of enzymes associated with the mitochondrial membrane (Chung et al, 2012; Kong et al, 2013). From there heme rapidly associates with nascent alpha and beta globin chains which are assembled into a heterotetrameric hemoglobin molecule (2 alpha chains with their associated heme molecules and 2 beta chains with their associated heme molecules)
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