Heme metabolism and erythropoiesis

Abstract

Purpose of review: Heme biosynthesis requires a series of enzymatic reactions that take place in the cytosol and the mitochondria as well as the proper intercellular and intracellular trafficking of iron. Heme can also be acquired by intestinal absorption and intercellular transport. The purpose of this review is to highlight recent work on heme and iron transport with an emphasis on their relevance in erythropoiesis.

Recent findings: Whereas the enzymes responsible for heme biosynthesis have been identified, transport mechanisms for iron, heme, or heme synthesis intermediates are only emerging. Recent studies have shed light on how these molecules are transported among various cellular compartments, as well as tissues. Much of this progress can be attributed to the use of model organisms such as S. cerevisiae, C. elegans, D. rerio, and M. musculus. Genetic studies in these models have led to the identification of several new genes involved in heme metabolism. Although our understanding has greatly improved, it is highly likely that other regulators exist and additional work is required to characterize the pathways by which heme and iron are transported within the erythron.

Summary: The identification of heme and iron transport mechanisms will improve our understanding of blood development and provide new insight into human blood disorders.

Figure 1. Transcriptional regulation of MFRN1

In early erythropoiesis, GATA-2 binds to two GATA-sites (−37.5 kb and −20.4 kb) in the MFRN1 distal transcriptional enhancer, but does not activate gene transcription (top panel). As erythroblasts mature, GATA-1 becomes expressed and the GATA-1/FOG-1 complex displaces GATA-2 from both DNA-binding sites in the MFRN1 distal enhancer (bottom panel) and triggers MFRN1 transcription. Reprinted with permission from J.D. Amigo et al. (ref. 9) and The American Society of Microbiology.

Figure 2. FECH, ABCB10, and MFRN1 form an oligomeric complex to import mitochondrial Fe²⁺ and its utilization for heme biogenesis

FECH, ABCB10, and MFRN1 form a macromolecular complex at the inner mitochondrial membrane to facilitate the import of Fe²⁺. ABCB10 increases the protein half-life of MFRN1 in differentiating erythroblasts to accommodate the increase demand for Fe²⁺ for heme biosynthesis. Binding of MFRN1 to FECH suggests that the import of Fe²⁺ may be coupled to Fe²⁺ incorporation into porphyrins. Reprinted with permission from W. Chen et al. (ref. 22) and The American Society of Hematology.