Erythropoiesis requires rapid and extensive
hemoglobin production.
Heme activates
globin transcription and translation; therefore,
heme synthesis must precede
globin synthesis. As free
heme is a potent inducer of oxidative damage, its levels within cellular compartments require stringent regulation. Mice lacking the
heme exporter FLVCR1 have a severe
macrocytic anemia; however, the mechanisms that underlie erythropoiesis dysfunction in these animals are unclear. Here, we determined that erythropoiesis failure occurs in these animals at the CFU-E/proerythroblast stage, a point at which the
transferrin receptor (CD71) is upregulated,
iron is imported, and
heme is synthesized--before ample
globin is produced. From the CFU-E/proerythroblast (CD71(+) Ter119(-) cells) stage onward, erythroid progenitors exhibited excess
heme content, increased cytoplasmic ROS, and increased apoptosis. Reducing
heme synthesis in FLVCR1-defient animals via genetic and biochemical approaches improved the
anemia, implying that
heme excess causes, and is not just associated with, the erythroid marrow failure. Expression of the cell surface FLVCR1
isoform, but not the mitochondrial FLVCR1
isoform, restored normal rbc production, demonstrating that cellular
heme export is essential. Together, these studies provide insight into how
heme is regulated to allow effective erythropoiesis, show that erythropoiesis fails when
heme is excessive, and emphasize the importance of evaluating Ter119(-) erythroid cells when studying erythroid marrow failure in murine models.