Cytochemical Demonstration of Transferrin in the Mitochondria of Immature Human Erythroid Cells

Isobe, Kiyoko; Isobe, Yoshinari; Sakurami, Takehiko

doi:10.1159/000207141

Cited by 12 publications

(5 citation statements)

References 10 publications

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“…Earlier work suggested an association of Tf with mitochondria in erythroid cells, [53][54][55] leading to the proposal 1,16 that a highly efficient use of Tf-borne iron for heme synthesis may require a direct interaction of endosomes, bearing Fe 2 -Tf, with mitochondria, followed by the transfer of iron through organellar membrane-associated proteins to ferrochelatase. The main purpose of our study was to further investigate this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria

Zhang

Sheftel

Ponka

2005

Blood

113

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In erythroid cells the vast majority of iron (Fe) released from endosomes must cross both the outer and the inner mitochondrial membranes to reach ferrochelatase that inserts Fe into protoporphyrin IX. In the present study, we developed a method whereby a cohort of 59 Fe-transferrin (Tf)-laden endosomal vesicles were generated, from which we could evaluate the transfer of 59 Fe into mitochondria. Iron chelators, dipyridyl or salicylaldehyde isonicotinoyl hydrazone (SIH), were able to bind the 59 Fe when they were present during a 37°C incubation; however, addition of these agents only during lysis at 4°C chelated virtually no 59 Fe. Bafilomycin A1 (which prevents endosome acidification) and succinylacetone (an inhibitor of 5-aminolevulinate dehydratase) prevented endosomal 59 Fe incorporation into heme. Importantly, both the myosin light chain kinase inhibitor wortmannin and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), caused significant inhibition of 59 Fe incorporation from 59 Fe-Tf-labeled endosomes into heme, suggesting that myosin is required for Tf-vesicle movement. IntroductionNormal hemoglobinization of immature erythroid cells requires iron uptake from transferrin (Tf), mediated by Tf receptors, whose high levels are essential for maintaining the exceptionally rapid rates of heme synthesis. On a per-cell basis the rate of heme synthesis in immature erythroid cells is at least an order of magnitude higher than in the liver, the second highest heme producer in the organism. 1 Following the binding of Fe(III) 2 -Tf to Tf receptors on the erythroid cell membrane, the Tf-receptor complexes are internalized by endocytosis, and iron is then released from Tf by a process involving endosomal acidification. [1][2][3] The transporter, Nramp2 (also known as DMT1 4 or DCT1 5 ), has been shown to be likely responsible for the egress of iron from the endosome. [6][7][8] This protein is encoded by a gene that belongs to the "natural resistance-associated macrophage protein" (Nramp) family of genes identified by Gros and his coworkers 9 and transports Fe(II). 5 Therefore, reduction of Fe(III) must occur in endosomes; however, nothing is known about the mechanism of this process. It is generally believed that following its release from endosomes, iron enters the cytosol where it equilibrates with a low molecular weight labile iron pool. 10,11 However, the extraordinary efficiency of Fe utilization in erythroid tissues, as well as the apparent targeting of Fe to mitochondria (as discussed in the next paragraph), may be inconsistent with such a model.In hemoglobin-synthesizing cells, the vast majority of iron released from endosomes must cross both the outer and the inner mitochondrial membranes to reach ferrochelatase. 1 It is remarkable that in these cells iron acquired from Tf continues to flow into mitochondria, even when the synthesis of protoporphyrin IX is markedly compromised in vitro (by isonicotinic acid hydrazide [INH] or succinylacetone [SA]) [12][13][14][15][16] or in...

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Section: Discussionmentioning

confidence: 99%

Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria

Zhang

Sheftel

Ponka

2005

Blood

113

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“…Because Tf-bound iron is efficiently used for heme synthesis (11,30) and no low M r cytoplasmic iron-transport intermediate has been found in reticulocytes, an intimate direct transfer of iron from Tf to the mitochondrion was proposed to occur (37,38). This idea has developed in more recent years and has led to the "kiss and run" hypothesis (11) (Fig.…”

Section: Regulation Of Cellular Iron Homeostasismentioning

confidence: 99%

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

Richardson

Lane

Becker

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

439

383

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The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell ironprocessing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial ironprocessing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.iron sulfur cluster | heme | Friedreich's ataxia | frataxin | sideroblastic anemia

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“…Some believe that some of these compounds could remove iron from proteins and organelles because they chelate iron from low cytosolic M complexes [42]. An intimate direct transfer of iron from TF to the mitochondrion has been proposed to occur [43,44]. The direct transport of iron from the endosome into the mitochondrion has been described as the "kiss and run mechanism" [44,45].…”

Section: Mitochondrial Iron Metabolismmentioning

confidence: 99%

Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression; “A Tight Partnership—Was Warburg Correct?”

Elliott¹,

Head²

2012

JCT

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Over the last 30 years there have been numerous worldwide investigators involved in cancer research. Billions of dollars have been spent on drug development and cancer research; however, with all of the new agents and modalities of treatment, we have honestly not significantly improved the overall survival of the Stage IV cancer patient. There is and will not be a magic bullet treatment, thus the extensive title of this paper. We are convinced that unless we use multiple innovative therapies in combination with conventional treatment, we will never truly defeat this disease. We have attempted to address this problem by presenting in detail some of these complex mechanisms involved in tumorigenesis, progression, escape, and metastasis. Most investigators have their own special area of interest, but if we are to conquer this scourge, we must develop an extensive, multifaceted, comprehensive approach. Hopefully this article will contribute to awareness and further insight into this very serious and complicated problem, so we can improve quality of life and improve the survival of the Stage IV cancer patient.

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Cytochemical Demonstration of Transferrin in the Mitochondria of Immature Human Erythroid Cells

Cited by 12 publications

References 10 publications

Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria

Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria

Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol

Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression; “A Tight Partnership—Was Warburg Correct?”

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