The recycling of hemoglobin from damaged or senescent red blood cells (RBCs)

contributes almost 90% of daily body iron requirements in humans for bone marrow

erythropoiesis. Previously, our cell biological studies have shown that HRG1, a four

transmembrane protein first discovered in C. elegans, facilitates the transport of heme

within reticuloendothelial system (RES) macrophages during the turnover of RBCs, a

process termed erythrophagocytosis. HRG1 transports heme from the

phagolysosomes into the cytosol where heme is degraded to liberate iron for

erythropoiesis. Here we show that mice deficient for HRG1 are defective in heme-

iron recycling by RES macrophages, resulting in over ten-fold excess heme

accumulation as visible dark pigments within lysosomal compartments that are 10-

100 times larger than normal. The sequestered heme is tolerated by macrophages

through polymerization into crystallized hemozoin, a phenomenon typically observed

in blood-feeding parasites as a detoxification method to protect against heme toxicity.

HRG1-/- mice display ineffective bone marrow erythropoiesis which results in a

reduction in hematocrit and extramedullary erythropoiesis in the spleen. Under iron-

deficient conditions HRG1-/- mice are unable to utilize hemozoin as an iron source to

sustain erythropoiesis, causing severe anemia and lethality. Our studies establish that

polymerizing cytotoxic heme into hemozoin is a previously-unanticipated heme

tolerance pathway in mammals.