Mitochondrial iron metabolism

Mitochondria play a key role in iron metabolism since heme and various iron-sulfur (Fe-S)-cluster containing proteins are synthesized in them. The last step in heme biosynthesis, the insertion of Fe into protoporphyrin IX by ferrochelatase, takes place in the mitochondrial matrix. Fe-S clusters are synthesized mainly, if not entirely, in mitochondria and are combined with mitochondrial apo-proteins to form mature proteins or are exported from mitochondria for utilization by cytosolic and nuclear proteins. Table 8.2 summarizes some known proteins involved in mitochondrial iron homeostasis and utilization and their deficiency-related human disorders. 

Protein functions and deficiency related human diseases 

ALAS2/eALAS The first enz5me of heme synthesis in erythroid cells and its 

Ferrochelatase The mitochondrial protein inserts Fe into the protoporphyrin 

Frataxin It is thought to be involved in mitochondrial iron export and 

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The recent discovery of mitochondrial ferritin (MtFt) has contributed to our understanding of mitochondrial iron metabolism and sideroblastic anemia. 

Britton, R.S., O Neill, R. and Bacon, B.K (1990a). Hepatic mitochondrial malonedialdehyde metabolism in rats with chronic iron overload. Hepatology 11, 93-97. 

Friedreich s ataxia is caused by an intronic triplet repeat expansion. Friedreich s ataxia is an autosomal recessive disorder characterized by progressive ataxia, nystagmus, distal sensory polyneuropathy and corticospinal tract degeneration. It is caused by an unstable expanded GAA repeat in intron 1 of the frataxin gene on chromosome 9ql3. This diminishes expression of frataxin, a mitochondrial iron-storage protein that participates in free radical metabolism [71]. 

IL-1 also appears to inhibit insulin secretion by modulating the mitochondrial oxidative metabolism of purified P cells. Treatment of purified P cells for 18 hr with IL-1 results in nearly complete inhibition of the oxidation of [ CJ-D-glucose to C02 (Fig. 10). This inhibition is completely prevented by NMMA (Corbett et al., 1992b). Treatment of purified a cells with lL-1 has no effect on glucose oxidation, suggesting that the effects of IL-1 are specific to the endocrine P cell (Fig. 10). These findings are further supported by the observation that lL-1 induces iron-nitrosyl complex formation and the accumulation of cGMP in the... 

Alves R, Herrero E, Sorribas A (2004) Predictive reconstruction of the mitochondrial iron-sulfur cluster assembly metabolism. II. Role of glutaredoxin Grx5. Proteins Struct Funct Bioinf 57 481-492... 

Rouault , Tong WH (2005) Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol 6 345-351 Roy A, Solodovnikova N, Nicholson T, Antholine W, Walden WE (2003) A novel eukaryotic factor for cytosolic Fe-S cluster assembly. EMBO J 22 4826-4835 Schilke B, Voisine C, Beinert H, Craig E (1999) Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 96 10206-10211... 

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. 

Fig. 1. Schematic overview of copper trafficking and homeostasis inside the yeast cell. The actions of Mad and Ace 1, copper-dependent metalloregulatory transcription factors, control the production of copper import [copper transporter (Ctr) and reductase (Fre)] and detoxification/sequestration [metallothionein (MT)] machineries, respectively. Three chaperone-mediated delivery pathways are shown. Atxl shuttles Cu(I) to the secretory pathway P-type ATPase Ccc2 (right). CCS delivers Cu(I) to the cytoplasmic enzyme copper-zinc superoxide dismutase (SOD) (left). Coxl7 shuttles Cu(I) to cytochrome c oxidase (CCO) in the mitochondria (bottom). Mitochondrial proteins Scol and Sco2 may also play a role in copper delivery to the CuA and CuB sites of CCO. Copper metabolism and iron metabolism are linked through the actions of Fet3, a copper-containing ferroxidase required to bring iron into the cell (lower right) (see text).

Eide, D. J., Bridgham, J. T, Zhao, Z., and Mattoon, J. R. (1993). The vacuolar H -ATPase of Saccharomyces cerevisiae is required for efficient copper detoxification, mitochondrial function, and iron metabolism. Mol. Gen. Genet. 241, 447 56. 

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. 

Copper is necessary, together with iron, for hematopoiesis, probably partly because it is needed for the synthesis of fer-roxidase (ceruloplasmin). Many enzymes require copper for activity. Examples of some of the copper-enzymes and their functions are given in Table 37-5. Mitochondrial iron uptake may be blocked by deficiency of a cuproprotein, perhaps cytochrome oxidase. Several inherited diseases involving abnormalities in copper metabolism (Wilson s disease, Menkes syndrome) or copper enzymes (X-linked cutis laxa, albinism) occur in human and in several animal species. 

Frataxin (Figure 2) has recently been identified as a likely physiological iron donor to ISU during assembly of the [2Fe-2S] cluster core 10, 21-23), and to ferrochelatase for the final step of heme biosynthesis 24, 25), Dysfunction of fi-ataxin results in mitochondrial iron accumulation and oxidative damage to mitochondrial DNA 26, 27), as well as the potential to disrupt other cellular processes dependent on such iron cofactors. This is the first characterized example of an iron-delivery protein and it remains to be seen how relevant its functional chemistry will be, relative to cell metabolism across a spectrum of organisms. As noted later, the absence of sequence homologs in certain other organisms does not preclude the presence of structural and functional... 

Cyt c has an important role in the production of ATP in the mitochondrial respiratory electron-transfer chain, cyt c transfers electrons from the transmembrane cyt bc complex to cytochrome c oxidase." " Cyt c also delivers electrons to cytochrome c peroxidase, which facilitates the reduction of hydrogen peroxide to water. In addition to its life-sustaining electron-transfer functions, cyt c is required for activation of the cell-death protease, caspase-3, in apoptosis." " Defects in cyt c biogensis have been implicated in pathogenic responses related to copper and iron metabolism, and prokaryotic heme biosynthesis. ... 

Jenner, P. Altered mitochondrial function, iron metabolism and glutathione levels in Parkinson s disease. Acta Neurol Scand Suppl 146(1), 1993 6-13. 

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