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

Osamu Nakajima, Satoru Takahashi, Hideo Harigae, Kazumichi Furuyama, Norio Hayashi, Shigeru Sassa, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6282-6289
Number of pages8
JournalEMBO Journal
Volume18
Issue number22
DOIs
Publication statusPublished - 1999 Nov 15

Keywords

  • ALAS-E
  • Heme
  • Iron metabolism
  • Transferrin receptors
  • X-linked sideroblastic anemia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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