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.

FIGURE 1.

Cellular iron processing. Ferric iron (Fe³⁺) bound to Tf is taken up by cells through TfR1. The TfR1-Tf complex is internalized through endocytosis. The endosomal matrix is acidified by an ATPase proton pump, which allows dissociation of Tf and Fe³⁺ from TfR1. The ferric iron is reduced to Fe²⁺ by the STEAP family of proteins, and it can now be exported to the cytosol by DMT1. Ferrous iron can be delivered to ferritin for storage by the iron chaperone PCBP1. The larger part of iron will be transported to the mitochondrion for heme and FeS cluster synthesis. How iron is delivered to mitochondria is largely unknown. In erythrocytes, mitochondrial iron import is mediated by MFRN1 complexed with ABCB10. The MFRN1 paralog, MFRN2, is thought to import iron into mitochondria of non-erythroid cells, whether or not complexed with ABCB transporters. Factors involved in mitochondrial export of heme remain to be elucidated, whereas ABCB7 is thought to export a yet undefined component “X” needed for cytosolic FeS cluster assembly. After delivery of iron, TfR1 and Tf are recycled back to the cell surface, a pathway in which SEC15L1 plays an important role. mFerritin, mitochondrial ferritin.

FIGURE 2.

Transport of heme synthesis intermediates and heme in metazoans. A, heme is synthesized via a conserved eight-step pathway involving both mitochondrial and cytoplasmic enzymes. The intermediates ALA, CPgenIII, and PPIX and the substrate glycine need to be transported across mitochondrial membranes for the subsequent reactions. The solute carrier protein SLC25A38 may be involved in translocating glycine into mitochondria. The ATP-binding cassette transporter ABCB6 and the peripheral benzodiazepine receptor (PBR) were proposed to facilitate the import of CPgenIII into the mitochondria, whereas the 2-oxoglutarate carrier (OGC) and the adenine nucleotide translocator (ANT) may play a role in PPIX transport. The mechanisms for the export of ALA and the shuttling of heme precursors among the cytosolic enzymes are unknown. ALAS, aminolevulinic acid synthase; CPOX, coproporphyrinogen oxidase. B, the last step of heme biosynthesis occurs in the mitochondrial matrix. The nascent heme moiety must be translocated across membranes to multiple subcellular compartments where target hemoproteins reside. Heme can also be exported out of the cell or imported into the cell. The cell-surface FLVCR and the ABC transporter ABCG2 have been implicated in heme export in erythroid cells, whereas HRG-1 was identified as a heme importer. The question marks represent the presumptive heme trafficking pathways that are currently unclear. COX, cytochrome c oxidase; Cyt_b5, cytochrome b₅.