Mitochondria are crucial to iron metabolism, being the unique site for heme synthesis and the major site for iron–sulfur ([Fe–S]) cluster biosynthesis.
Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe–S cluster protein assembly during red cell development.
In murine erythroblasts it is suggested that iron is transported into the mitochondrion by the recently characterized iron transporter mitoferrin [Shaw GC et al, 2006]. Murine mitoferrin is a homolog of the zebrafish protein frascati [Ransom DG et al, 1996] and the yeast proteins MRS3 and MRS4.
Fig 1 Model of mitoferrin (Mfrn) function in importing iron into the mitochondrial matrix for haem synthesis and haemoglobin production in developing erythroblasts. The iron delivered to the mitochondria by Mfrn would be released to ferrochelatase, catalysing the insertion of Fe(II) into protoporphyrin IX to make haem, which is exported to the cytoplasm.
Once iron is transported across the mitochondrial membrane, it can be used for a variety of metabolic processes, in particular heme and [Fe–S] synthesis (Figure 2). Heme is then transported out of the mitochondrion for insertion into protein, such as cytochromes. However, the heme transporters(s)responsible for heme release remain unclear.
Three molecules have been identified as possible mitochondrial heme exporters or transporters:
The ABCG2 and ABC-me transporters are members of the ATP-binding cassette superfamily of membrane transporters, belonging to the G and B subfamilies, respectively, and are believed to be important for the trafficking of heme. In mice, ablation of ABCG2 leads to accumulation of the heme synthesis intermediate, protoporphyrin IX.
ABCG2 has a role in heme export from the mitochondrion.
ABC-me is also suggested to traffic heme and heme intermediates across the mitochondrial membrane.
FLVCR could be required for differentiation of erythroid precursors into colony forming units, potentially protecting cells against heme toxicity by exporting excess heme that can otherwise result in oxidative stress.
However, the exact molecular mechanism and contribution of ABC-me and FLVCR to heme transport in the mitochondrion remain to be determined. [Dunn LL et al, 2006]
Fig 2 Mitochondrial iron metabolism. A mitochondrial iron importer, such as mitoferrin, transports iron into the mitochondrion. Ferrochelatase synthesizes heme from Fe(II) and protoporphyrin IX (PIX). The iron is also used for [Fe–S] cluster synthesis or potentially stored in mitochondrial ferritin. The [Fe–S] clusters can be exported from the mitochondria by ABCB7. Heme is probably exported from the mitochondrion by a transporter, with several candidates being known: the breast cancer resistance protein ABCG2, the feline leukemia virus subgroup-C receptor FLVCR and the ABC-me transporter. It has been proposed that frataxin acts as a metabolic switch between [Fe–S] cluster and heme synthesis.
- Feline leukemic virus, sub-group C receptor (FLVCR): believed to export excess heme from developing erythrocytes and other cell types
- ABCG2 : a breast cancer drug resistance protein that can protect cells from hypoxic conditions by preventing protoporphyrin IX accumulation
- Mitoferrin: a mitochondrial iron transporter that could be responsible for the transport of iron into the mitochondrion
- Sec15l1: a protein involved in the mammalian exocyst complex and suggested to be involved in the cycling of transferrincontaining endosomes and vesicle docking
- Six-transmembrane epithelial antigen of the prostate-3 (Steap3) : an endosomal ferrireductase responsible for transferrin-dependent iron uptake in erythroid cells
- ABC-mitochondrial erythroid (ABC-me) : an inner mitochondrial membrane transporter involved in heme biosynthesis in erythroid cells
- ABCB7 : a membrane transporter essential for [Fe–S] cluster transport in the mitochondria
Iron across plasma and mitochondrial membrane Fig