Iron and Porphyrin Trafficking in Heme Biogenesis

Abstract

Iron is an essential element for diverse biological functions. In mammals, the majority of iron is enclosed within a single prosthetic group: heme. In metazoans, heme is synthesized via a highly conserved and coordinated pathway within the mitochondria. However, iron is acquired from the environment and subsequently assimilated into various cellular pathways, including heme synthesis. Both iron and heme are toxic but essential cofactors. How is iron transported from the extracellular milieu to the mitochondria? How are heme and heme intermediates coordinated with iron transport? Although recent studies have answered some questions, several pieces of this intriguing puzzle remain unsolved.

Systems and Trans-System Level Analysis Identifies Conserved Iron Deficiency Responses in the Plant Lineage

“…In eukaryotic cells, there is the additional complication of subcellular compartmentation and delivery of iron or assembled cofactors across membranes, and this is exacerbated in plants where the plastid is yet another compartment (Jeong and Guerinot, 2009). In multicellular organisms, transport from sites of assimilation (roots or gastrointestinal tract) to sites of utilization (leaves, muscle, or reticulocytes) involves redox chemistry and chelation as well (Hellman and Gitlin, 2002;De Domenico et al, 2008;Schultz et al, 2010).…”

Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis

“…4,23,24 Such a complex could coordinate the correct molar ratio and sufficient, but not excessive, supply of protoporphyrin IX and Fe 2ϩ substrates for Fech to produce heme. 6,25 …”

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

“…Finally, ferrous iron is incorporated into PPIX in the mitochondrial matrix, a reaction catalyzed by ferrochelatase (FECH) (6). While all the enzymatic steps leading to the production of heme are well characterized, it is still not completely understood how the compartmentalization of these reactions between the mitochondrion and cytosol occurs, how heme is exported out of the mitochondrion, and how heme efflux from this organelle is regulated (7,8). Recently, the ATP-binding cassette transporter ABCB6 has been proposed as a porphyrin importer into the mitochondrion (9), but no mitochondrial heme exporter has been identified to date.…”