Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload

Abstract

Erythroid 5-aminolevulinate synthase (ALAS-E) catalyzes the first step of heme biosynthesis in erythroid cells. Mutation of human ALAS-E causes the disorder X-linked sideroblastic anemia. To examine the roles of heme during hematopoiesis, we disrupted the mouse ALAS-E gene. ALAS-E-null embryos showed no hemoglobinized cells and died by embryonic day 11.5, indicating that ALAS-E is the principal isozyme contributing to erythroid heme biosynthesis. In the ALAS-E-null mutant embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. In contrast, we found typical ring sideroblasts that accumulated iron mostly in mitochondria in adult mice chimeric for ALAS-E-null mutant cells, indicating that the mode of iron accumulation caused by the lack of ALAS-E is different in primitive and definitive erythroid cells. These results demonstrate that ALAS-E, and hence heme supply, is necessary for differentiation and iron metabolism of erythroid cells.

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

“…In addition, as discussed before, the IRE motif of ALAS2 mRNA in the 5´-protein noncoding region is involved in regulating the translation of mRNA to protein (Bekri et al 2003). Mice lacking ALAS2 died in the embryonic stage (Nakajima et al 1999). Male hemizygous null mutants could not support fetal hematopoiesis and were not viable after embryonic stage E11.5.…”

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

“…In fact, the lower level of succinyl-CoA in the mitochondria, a product of the KGDH complex, may be the cause of erythropoietic failure because heme biosynthesis requires condensation of succinyl-CoA and glycine. Heme deficiency caused by disruption of the murine gene for this enzyme in erythroid cells (ALAS-E) caused anemia and death by E11.5 (17). In contrast to the Slc25a19 Ϫ/Ϫ mutant, the ALAS-E-null embryos had some immature primitive nonhemoglobinized erythrocytes, suggesting that reduction of heme synthesis cannot solely be responsible for the lack of red cell development in the Slc25a19 Ϫ/Ϫ embryos.…”

Mitochondria in hematopoiesis and hematological diseases

“…In some families, the ALAS2 gene mutation either decreases the processing or the stability of the enzyme, leading to reduction of its level (Furuyama et al, 1997), or abrogates its interaction with protein partners (Furuyama and Sassa, 2000), thus rendering patients resistant to pyridoxine supplementation (Astner et al, 2005). Animal models for XLSA have been developed in mice and zebrafish by disruption of ALAS2 gene homolog (Nakajima et al, 1999;Yamamoto and Nakajima, 2000). An intriguing and still unexplained difference between the human disease and the mouse model is the absence of ring sideroblasts in the mouse models of ALAS2 deficiency (Harigae et al, 2003).…”