by Ian Napier, Prem Ponka, and Des R. Richardson Iron trafficking in the mitochondrion: novel pathways revealed by disease by Ian Napier, Prem Ponka, and Des R. Richardson Blood Volume 105(5):1867-1874 March 1, 2005 ©2005 by American Society of Hematology

Schematic illustration showing how Fe is acquired for cellular processes by the transferrin-transferrin receptor pathway in nonerythroid cells. Schematic illustration showing how Fe is acquired for cellular processes by the transferrin-transferrin receptor pathway in nonerythroid cells. Diferric transferrin (Tf) binds to the transferrin receptor 1 (TfR1) and is then internalized into cells by receptor-mediated endocytosis. After internalization, Fe is released from Tf by a decrease in endosomal pH and then transported through the endosomal membrane by the divalent metal ion transporter 1 (DMT1). Once transported into the cytosol, the Fe then becomes part of a poorly characterized labile Fe pool. The Fe can be either transported to ferritin, for storage and reutilization, or to the mitochondrion or other organelles such as the nucleus. Iron in the labile pool is thought to regulate the mRNA-binding activity of the iron-regulatory proteins (IRP1 and IRP2) that are important for regulating the expression of TfR1 and ferritin, which are critical for Fe uptake and storage, respectively. Ian Napier et al. Blood 2005;105:1867-1874 ©2005 by American Society of Hematology

Schematic illustration of a generalized overview of mitochondrial Fe metabolism. Schematic illustration of a generalized overview of mitochondrial Fe metabolism. Iron is supplied to the mitochondrion from the cytosolic labile Fe pool by an unknown mechanism. It is transported by as yet unidentified transporter(s) into the matrix where it can be directed to a number of different pathways, including storage in mitochondrial ferritin, [Fe-S] synthesis, heme metabolism, or other as yet unknown pathways (see “The mitochondrion is a major site of [Fe-S] synthesis” for further details). ALA indicates δ-aminolevulinic acid; ALAS, δ-aminolevulinic acid synthase; CoPIII, coproporphyrinogen III; Fch, ferrochelatase; [Fe-S], iron sulphur cluster; Fxn, frataxin; IRP1, iron-regulatory protein 1; m-Ferr, mitochondrial ferritin; and PIX, protoporphyrin IX. Ian Napier et al. Blood 2005;105:1867-1874 ©2005 by American Society of Hematology

Schematic illustration of the molecules involved in the genesis of [Fe-S] clusters. Schematic illustration of the molecules involved in the genesis of [Fe-S] clusters. Nfs1 supplies elemental sulphur for incorporation into a new [Fe-S] cluster with pyridoxal-5-phosphate (PLP) as a cofactor. Homodimeric IscU acts as a scaffold upon which the [Fe-S] cluster is built. Two atoms of Fe are delivered to the cluster machinery and the [Fe-S] cluster components are rearranged to form a single [2Fe-2S] cluster that is bridged between the 2 IscU subunits. Another [2Fe-2S] cluster may be formed on the cluster-containing scaffold complex, leading to the formation of a single [4Fe-4S] cluster (see “The mitochondrion is a major site of [Fe-S] synthesis” for further details). Ian Napier et al. Blood 2005;105:1867-1874 ©2005 by American Society of Hematology

Schematic illustration of heme and cluster synthesis and metabolism. Schematic illustration of heme and cluster synthesis and metabolism. (A) Schematic illustration of normal heme and [Fe-S] cluster synthesis, (B) PIX induction of heme synthesis and the inhibition of frataxin (Fxn) expression and [Fe-S] cluster metabolism, and (C) a proposed mechanism of the disrupted mitochondrial [Fe-S] cluster biosynthesis and Fe metabolism in Friedreich ataxia (FA). (A) Under physiologic conditions, Fe is used for the synthesis of heme or the genesis of [Fe-S] clusters. (B) PIX has been shown to decrease frataxin expression and we hypothesize that frataxin acts as a PIX-sensitive metabolic switch that regulates the use of Fe for heme synthesis. In this way, increased PIX levels indicate a requirement for heme synthesis that decreases frataxin expression and results in diversion of Fe to this pathway from [Fe-S] cluster assembly or Fe storage. Hence, we propose that this may be the role for frataxin under physiologic conditions. (C) Since frataxin expression is low in FA, [Fe-S] cluster synthesis is impaired. Moreover, because there is no intense demand for heme synthesis in nonerythroid tissues, the excess Fe not used for [Fe-S] cluster synthesis is incorporated into m-Ferr. Initially, the Fe accumulation in m-Ferr may be protective and would explain the delay in pathogenesis of FA until many years after birth. However, in the absence of marked Fe utilization in nonerythroid cells for the generation of heme, the m-Ferr may degrade to “hemosiderin-like” material that is redox-active and could lead to the mitochondrial damage observed in FA. Ian Napier et al. Blood 2005;105:1867-1874 ©2005 by American Society of Hematology

Transmission electron micrographs. Transmission electron micrographs. Transmission electron micrographs of (A) electron dense deposits consistent with hemosiderin and ferritin in the liver of a hemochromatosis patient (reprinted from Stal et al92 with permission); (B) electron dense deposits in sideroblasts from a patient suffering X-linked sideroblastic anemia (reprinted from Wickramasinghe et al91 with permission from S. Karger AG, Basel); and (C) electron dense deposits in the mitochondrion of a muscle creatine kinase (MCK) conditional frataxin knockout mouse (reprinted from Puccio et al63 with permission from Nature [www.nature.com], copyright 2001). Ian Napier et al. Blood 2005;105:1867-1874 ©2005 by American Society of Hematology