Mitochondrial Iron Transport

Defects in mitochondrial iron transport and utilization can result in mitochondrial iron overload. There is extensive iron accumulation in erythroblast mitochondria of both patients with X-linked sideroblastic anemia due to defective erythroid-speeifie 5-aminolevulinic acid synthase (eALAS) and those with ring sideroblasts associated with myelodysplastic syndrome. Mitochondrial iron overload has also been documented in patients with Friedreich s ataxia with defective frataxin" and in those with sideroblastic anemia with ataxia from defects in the Fe-S transporter ABC7. In addition, studies with yeast, the best studied eukaryotic model of Fe-S cluster synthesis, showed that defects in any of the enzymes of the Fe-S cluster assembly pathway caused mitochondrial iron accumulation and lack of normal mitochondrial function. ... 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Iron is also a key constitnent of many enzymes involved in electron transfer reactions, inclnding those involved in the mitochondrial electron transport chain conpled to the synthesis of ATP. 

Wharton, M., Granger, D. L., and Durack, D. T. (1988). Mitochondrial iron loss from leukemia cells injured by macrophages. A possible mechanism for electron transport chain defects. J. Immunol. 141, 1311-1317. 

Aconitase exists as both mitochondrial and cytosolic isoenzyme forms of similar structure. However, the cytosolic isoenzyme has a second function. In its apoenzyme form, which lacks the iron-sulfur cluster, it acts as the much-studied iron regulatory factor, or iron-responsive element binding protein (IRE-BP). This protein binds to a specific stem-loop structure in the messenger RNA for proteins involved in iron transport and storage (Chapter 28).86/9°... 

The high-affinity uptake system is more puzzling. It requires a permease encoded by FTRI and an additional protein encoded by FET3.30/33 35 The Fet3 protein is a copper oxidoreductase related to ceruloplasmin (Section D). The protein Frelp (encoded by FRE1) is a metalloreductase that reduces Cu2+ to Cu+, as well as Fe3+ to Fe2+. It is essential for copper uptake (Section D).33 It has long been known that ceruloplasmin is required for mobilization of iron from mammalian tissues.30 Hereditary ceruloplasmin deficiency causes accumulation of iron in tissues.36 Yeast also contains both mitochondrial and vacuolar iron transporters.37/37a b... 

During the 1940s, when it had become clear that formation of ATP in mitochondria was coupled to electron transport, the first attempts to pick the system apart and understand the molecular mechanism began. This effort led to the identification and at least partial characterization of several flavoproteins, iron-sulfur centers, ubiquinones, and cytochromes, most of which have been described in Chapters 15 and 16. It also led to the picture of mitochondrial electron transport shown in Fig. 10-5 and which has been drawn in a modem form in Fig. 18-5. 

Mitochondrial Myopathy. A general deticiency of iron may ho implicated in mitochondrial myopathy, which is a complex disorder that affects muscular activity. It lias been suspected for a number of years that the disorder is caused hy a delect of mitochondrial-protein transport. H.H.V. Sdiarpa and a team of researchers (Royal Free Hospital. London) postulate that a deficiency of an iron-sulfur protein in muscle dehydrogenase may be the specific cause. 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

It has been generally assumed that iron is transported across biological membranes in the ferrous form and that ferric iron would have to be reduced before it can be used by the organism. Thus, based on nutritional studies it has long been recognized that Fe(II) is1 more effectively absorbed than Fe(III), and this has been attributed to differences in the thermodynamic and kinetic stability of the complexes and chelates formed by these cations (for review, see Ref. 2). The experimental proof of a transport in the ferrous form has, however, not been given until quite recently in studies of iron transport in isolated mitochondria (23) as well as in enterobacteria (33). In rat liver mitochondria we have found that Fe(III) donated from a metabolically inert water soluble complex of sucrose interacts with the respiratory chain at the level of cytochrome c (and possibly cytochrome a) (23, 32) (Figure 1 B), which has a oxidation-reduction potential of around +250 mV (34) and is localized to the outer phase of the mitochondrial inner membrane (35). 

The parenchymatous liver cells (hepatocytes) hold a key position in the overall metabolism of iron (57, 58, 59, 60), and since functionally intact liver mitochondria can be conveniently prepared at high yield, these mitochondria have been most extensively studied so far. The iron transporting system discussed above for liver mitochondria is present also in mitochondria from other tissues and animal species (Table III). Quantitatively, erythroid cells of the bone marrow play the most important role in the overall metabolism of iron (61), and it was therefore not unexpected to find that the energized uptake of iron by isolated reticulocyte mitochondria exceeds that of mitochondria isolated from, for example, liver, kidney, and heart (Table IV). Thus, a relationship appears to exist between the rate and extent of heme protein turnover in mitochondria isolated from different tissues and their energized iron accumulation (30). Thus, it is evident that cellular differentiation is expressed at the mitochondrial level by modulation of the activity of essential functions related to iron transport and heme biosynthesis. 

Aerobic respiration The mitochondrial electron-transport chain incorporates cytochrome c, and the oxidation and reduction of the iron atoms in this biomolecule passes electrons through a series or chain of metabolic reactions. This is illustrated in Figure 4.3. 

A distinct electron transfer flavoprotein (ETF) is the single-electron acceptor for a variety of flavoprotein dehydrogenases, including acyl CoA, glutaryl CoA, sarcosine, and dimethylglycine dehydrogenases. It then transfers the electrons to ETF-ubiquinone reductase, the iron-sulfur flavoprotein that reduces ubiquinone in the mitochondrial electron transport chain. 

Several other iron metabolism proteins contain IREs, including ferroportin, an iron exporter, the erythrocyte form of aminolevulinic acid synthase, an enzyme important in heme biosynthesis, an alternatively spliced transcript of the iron transporter DMTl, and mammalian mitochondrial aconitase. The importance of these IREs in regulation of these transcripts is the subject of ongoing research. 

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