Direct Interorganellar Transfer of Iron from Endosome to Mitochondrion.

Sheftel, Alex D.; Zhang, An-Sheng; Brown, C. K.; Ponka, Prem

doi:10.1182/blood.v108.11.268.268

Cited by 19 publications

(25 citation statements)

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“…Yet, interactions of DMT1 with COXII and Tom6 were unexpected findings, suggesting that DMT1 is localized in part in the mitochondrial envelope. Distinguishing this idea from certain alternatives-the kiss-and-run (20,21) docking of mitochondria and endosomes, the contamination of mitochondria by endosomal DMT1, or the apparent morphologic overlap of the locations of the 2 organelles-is paramount. The challenge is even greater, because docking and an OMM location for DMT1 in addition to its location in the endosome and plasma membrane are hypotheses that can coexist.…”

Section: Dmt1 Associates With Mitochondrial Proteinsmentioning

confidence: 99%

“…Therefore, it has been suggested that to prevent cytotoxicity, labile iron is transported bound to cytosolic ligands or chaperones (19). Alternatively, iron may be delivered directly from endosomes and lysosomes to iron-requiring organelles, such as mitochondria, by a "kiss-and-run" docking mechanism (20,21). Hence, we reasoned that with any of the proposed mechanisms of iron delivery to intracellular targets, endosomal and lysosomal DMT1 may be pivotal for efficient and safe transfer of iron to target sites by controlling iron egress via interactions with yet unidentified acceptor or docking proteins in the cytosol and/or the mitochondria.…”

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confidence: 99%

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Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1)

et al. 2014

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In mammalian cells, mitochondria receive most incoming iron, yet no entry pathway for iron at the outer mitochondrial membrane (OMM) has been characterized. Our results show that the divalent metal transporter 1 (DMT1) occurs in the OMM. Immunoblots detected DMT1 in mitochondria from a pneumocyte cell model in their OMM. Using the split-ubiquitin yeast 2-hybrid system, we found that cytochrome c oxidase subunit II (COXII) and the translocase of OMM 6-kDa subunit (Tom6) homologue interact with DMT1. COXII coimmunoprecipitates with DMT1. There are 4 DMT1 isoforms that differ at the N and C termini. Using HEK293 cells that inducibly express all of the 4 ends of DMT1, we found all of them in the OMM, as detected by immunoblots after cell fractionation, and in isolated mitochondria, as detected by immunofluorescence. Immunoblot analysis of purified cell fractions from rat renal cortex confirmed and extended these results to the kidney, which expressed high levels of DMT1. Immunogold labeling detected DMT1 colocalization in mitochondria with the voltage-dependent anion-selective channel protein-1, which is expressed in the OMM. We suggest that DMT1 not only exports iron from endosomes, but also serves to import the metal into the mitochondria.

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Section: Dmt1 Associates With Mitochondrial Proteinsmentioning

confidence: 99%

mentioning

confidence: 99%

Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1)

et al. 2014

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“…For instance, the 'kissand-run' hypothesis postulates a scenario in which iron, still enveloped by the endosome, is transported directly to the mitochondrion ( Figure 2). According to this model, once in close proximity, the endosome transiently docks with the mitochondrion in order to transfer the iron directly through protein-based conduits; and thereby bypassing the cytosol (Sheftel et al, 2007). The recent identification of the putative chaperone proteins human poly(rC)-binding proteins 1-4 (PCBPs; Shi et al, 2008;Leidgens et al, 2013) has elucidated another modality of intracellular iron transport.…”

Section: Cellular Iron Uptakementioning

confidence: 99%

“…This has influenced hypotheses concerning how iron is transported into the mitochondrion from the cytosol. The previously described 'kissand-run' hypothesis is one such proposed mechanism for mitochondrial iron import (Sheftel et al, 2007), although the issue of how iron traverses the mitochondrial membranes is not directly addressed by this model. Alternatively, it has been suggested that iron can be acquired directly from the cytosol without an intermediate chaperone protein to facilitate the transfer.…”

Section: Figurementioning

confidence: 99%

Fixing frataxin: ‘ironing out’ the metabolic defect in Friedreich's ataxia

Anzovino

Lane

Huang

et al. 2014

British J Pharmacology

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The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron-sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro-and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies.

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“…Studies from a zebra fish mutant, frascati helped to identify mitoferrin, which functions as a principal iron importer in vertebrate erythroblasts (46). Recently it has been shown that the endosomes come in contact with mitochondria and facilitate direct transfer of the metal from cytosol to mitochondria (47). Once inside the mitochondria, iron can be used for a variety of metabolic pathways.…”

Section: Iron and Mitochondriamentioning

confidence: 99%

Iron homeostasis: new players, newer insights

Edison

Bajel

Chandy

2008

European J of Haematology

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Iron is an essential element for virtually all-living organisms. It is required as a cofactor for a multitude of proteins of diverse biological function. Iron plays a central role in the formation of hemoglobin and myoglobin and in many vital biochemical pathways and enzyme systems including energy metabolism, neurotransmitter production, collagen formation and immune system function. As a transition metal, iron also has useful ligand-binding and redox properties. At the same time, iron poses enormous problems because of the easy inter-conversion of Fe(II) and Fe(III), the very property that makes it attractive for biological redox processes (1). The reduced iron, Fe(II) can produce highly reactive hydroxyl and lipid radicals, which can damage lipid membranes, nucleic acids and proteins. In the million years of evolution, nature has not developed a pathway for excretion of iron in humans, so the body concentration of iron can only be regulated by absorption to match losses of iron.Under normal circumstances 1-2 mg of iron enters and leaves the body each day. In the body, iron is distributed in three pools -functional, storage and transport iron. The absorbed iron circulates in the plasma bound to transferrin (Tf) (transport iron) and the excess iron gets stored in the parenchymal cells of the liver and reticuloendothelial macrophages as ferritin (storage iron). About 0.1% of total body iron is circulating bound to Tf. Nearly 80% of iron is utilized for hemoglobin synthesis in the bone marrow. Approximately 10-15% is present in muscle fibers (myoglobin) and in other tissues as enzymes and cytochromes (functional iron).Homeostatic mechanisms regulating the absorption, transport, storage and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. The last decade has seen a rapid advancement of knowledge in iron metabolism. Modern techniques in molecular biology and biochemistry are giving new insights through the identification and characterization of proteins involved in iron homeostasis. This review focuses on the current developments in the understanding of iron homeostasis and the delicate mechanisms involved in the regulation of iron in the body. AbstractAlthough iron is a relatively abundant element in the universe, it is estimated that more than 2 billion people worldwide suffer from iron deficiency anemia. Iron deficiency results in impaired production of ironcontaining proteins, the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth and subsequently leads to cell death. Hemochromatosis, an inherited disorder results in disproportionate absorption of iron and the extra iron builds up in tissues resulting in organ damage. As both iron deficiency and iron overload have adverse effects, cellular and systemic iron homeostasis is critically important. Recent advances in the field of iron metabolism have led to newer understanding of the pathways involved in iron homeostasis and the ...

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Direct Interorganellar Transfer of Iron from Endosome to Mitochondrion.

Cited by 19 publications

References 0 publications

Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1)

Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1)

Fixing frataxin: ‘ironing out’ the metabolic defect in Friedreich's ataxia

Iron homeostasis: new players, newer insights

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