Mitochondrial Iron in Human Health and Disease

Abstract

Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

Keywords: iron; metabolism; mitochondria.

Figure 1

In eukaryotes, iron acquisition in the form of transferrin-bound or non-transferrin-bound (NTBI) iron is mediated through the metal or metal-siderophore transporter transferrin receptor, solute carrier family 39 member 8 (SLC39A8 or ZIP8), solute carrier family 39 member 14 (SLC39A14 or ZIP14), or solute carrier family 11 member 2 (SLC11A2 or DMT1). Heme-bound iron is acquired by the heme receptors/ transporters LDL receptor-related protein 1 (LRP1), solute carrier family 48 member 1 (SLC48A1 or HRG1), the hemoglobin scavenger receptor (CD163), and feline leukemia virus subgroup C cellular receptor family (FLVCR2). Heme is degraded by heme-oxygenase 1 to produce ferrous iron (Fe²⁺). Once inside the cell, transferrin-bound iron is degraded in the endosome by the metalloreductase six-transmembrane epithelial antigen of prostate 3 (STEAP3), capable of converting iron from an insoluble ferric (Fe³⁺) to a soluble ferrous (Fe²⁺) form. The labile iron pool (LIP) represents a pool of chelatable, redox-active iron, which is transitory. Iron is transported to sites of utilization such as the mitochondria (heme and Fe-S cluster synthesis) or into the iron storage proteins ferritin and mitochondrial ferritin (MTFT). Iron is exported from the cell by FPN1 (ferroportin1), which is inhibited by the iron hormone hepcidin (HAMP). Poly C-binding proteins 1/2 (PCBP1/2) act as iron chaperones that assist in the mineralization of ferritin whereas iron responsive element binding proteins 1 and 2 (IRP1/2) limit the transcription of ferritin in iron-depleted conditions. Similarly, in low-iron conditions, nuclear receptor coactivator 4 (NCOA4) protein assists in the release of iron from ferritin through an autophagy-mediated mechanism involving the lysosome.

Figure 2

In eukaryotes, iron acquisition is mediated through metal or metal-siderophore transport. Cytosolic iron must first cross the semipermeable outer mitochondrial membrane and then be imported into the mitochondrial matrix for heme and Fe-S cluster synthesis through transferrin-mediated endosome-to-mitochondrial contact, termed kiss-and-run, and/or via divalent metal transporter (DMT1). Iron is transported across the tight diffusion barrier of the inner mitochondrial membrane by hydrophobic mitochondrial carrier proteins called mitoferrins (MFRN1, MFRN2), which may form a complex with ABCB10. In mitochondria, iron is inserted into protoporphyrin IX (PPIX) by ferrochelatase (FECH) to produce heme. The first step in the heme synthesis pathway involves the production of δ-aminolevulinic acid (ALA). ALA is then transported to the cytosol where the next four steps take place to form coproporphyrinogen III (CoPIII), which is transported back into mitochondria to form PPIX. Heme is transported outside of mitochondria via the 1b isoform of FLVCR (feline leukemia virus subgroup C cellular receptor) for incorporation into hemoproteins. Mitochondrial iron is also used for Fe-S cluster synthesis, which among other factors involves frataxin (FXN) and GLRX5 (glutaredoxin-related protein 5), which are exported into the cytosol by ABCB7. Fe-S clusters are essential for the efficient functional of the electron transport chain (ETC) to generate ATP in a process called oxidative phosphorylation. Excess iron can be stored in mitochondrial ferritin (MTFT).