Microspectrophotometric and Electron Microscopic Studies of Bone Marrow in Hereditary Sideroblastic Anaemia

Wickramasinghe, Sunitha N.; Fulker, M.J.; Losowsky, M. S.; Hall, Richard

doi:10.1159/000208630

Cited by 15 publications

(5 citation statements)

References 6 publications

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“…Interestingly, TEM analysis (Figure 4) of tumors, in which we overexpressed MtFt, revealed iron overloaded mitochondria that exhibited very similar morphology to those seen in the erythroblasts of patients with sideroblastic anemia. 47,48 Strikingly, MtFt overexpression dramatically reduced (by more than 75%) tumor burden, as compared with the control tumors ( Figure 5A). Oral administration of Dox to mice, inoculated with MtFt-expressing tumor cells, abrogated MtFt expression and dramatically decreased TfR expression ( Figure 5B); these results provided a clear link between MtFt expression and tumor growth inhibition.…”

Section: Discussionmentioning

confidence: 85%

“…TEM has revealed ( Figure 4B) that non-heme iron accumulated in B9 cell-derived tumors, and that this iron was indeed deposited in mitochondria in a form that was similar to that observed in ringed sideroblasts, 47,48 whereas there was no detectable iron in the mitochondria of parental H1299 cell-derived tumors ( Figure 4A). The accumulation of non-heme iron in mitochondria elicited some unusual mitochondrial morphology ( Figure 4B).…”

Section: Morphologic Observation Of Iron Deposition In Mitochondria Omentioning

confidence: 78%

“…These observations confirm that, in MtFt-expressing tumors, iron shunted to and accumulated in the mitochondria is stored in a form similar to the aberrant iron storage in mitochondria observed in pathologic conditions, such as sideroblastic anemia. 47,48 …”

Section: Morphologic Observation Of Iron Deposition In Mitochondria Omentioning

confidence: 99%

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In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin

Nie

Chen

Sheftel

et al. 2006

Blood

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Mitochondrial ferritin (MtFt) is a mitochondrial iron-storage protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular iron homeostasis in mammalian cells. Using tumor xenografts, we examined the effects of MtFt overexpression on tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted tumor growth in nude mice. Mitochondrial iron deposition in MtFt-expressing tumors was directly observed by transmission electron microscopy. A cytosolic iron starvation phenotype in MtFt-expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins, and concomitantly both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to decreases in total cellular heme content and heme oxygenase-1 levels. In addition, elevated MtFt in tumors was also associated with a decrease in total aconitase activity and lower frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partially deficient heme and iron-sulfur cluster synthesis. It is likely that deprivation of iron in the cytosol is the cause for the significant inhibition of xenograft tumor growth. (Blood. 2006; 108:2428-2434)

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Section: Discussionmentioning

confidence: 85%

Section: Morphologic Observation Of Iron Deposition In Mitochondria Omentioning

confidence: 78%

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In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin

Nie

Chen

Sheftel

et al. 2006

Blood

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“…These should be compared to the deposits in the mitochondrion of X-linked sideroblastic anemia patients ( Figure 5B) and in the muscle creatinine kinase (MCK) conditional frataxin knockout mouse ( Figure 5C). The Fe deposits in FA patients (reviewed in Wickramasinghe 91 ) and the conditional frataxin knockout mice stain positive using Perl stain 63 are consistent with hemosiderin rather than ferritin. Indeed, electron micrographs of the mitochondrial Fe deposits in the conditional frataxin knockout mouse ( Figure 5C) 63 are similar to those published of insoluble hemosiderin, but not cytoplasmic ferritin ( Figure 5A).…”

Section: A Hypothetical Model Of Mitochondrial Fe Metabolism: Is Fratmentioning

confidence: 99%

Iron trafficking in the mitochondrion: novel pathways revealed by disease

Napier

Ponka

Richardson

2005

Blood

251

201

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It is well known that iron (Fe) is trans- IntroductionSince its discovery, the mitochondrion has been known as an essential and dynamic component of cellular biochemistry. The complexity of the mitochondrion has been gradually revealed by the study of a variety of genetic diseases associated with its function. Thus far, it is clear that Fe plays a crucial role in many facets of mitochondrial metabolism and the consequences of disruption to these pathways are catastrophic. Therefore, it would seem clear that the mitochondrion, a site of dynamically active electron transport and redox activity, would possess sufficient measures for the safe trafficking and metabolism of Fe. However, until recently, knowledge of the Fe metabolism of the mitochondrion has been largely confined to the heme synthesis pathway (for review, see Ponka 1 ), and very little was understood concerning the trafficking and storage of Fe in this organelle.The recent discovery of a plethora of mitochondrial proteins believed to be involved in Fe metabolism has resulted in a marked increase of research in this field. Key proteins identified include frataxin, ATP-binding cassette protein B7 (ABCB7), and the more recently discovered mitochondrial ferritin. These discoveries have provided evidence to support the hypothesis that the mitochondrion is a distinct compartment of Fe metabolism. However, despite these new data, the Fe trafficking pathways within the mitochondrion remain unclear, and in this review we will attempt to analyze and integrate the most recent findings in this intriguing field. Iron transport, storage, and homeostatic regulationBefore discussing the most recent results regarding mitochondrial Fe metabolism, we will first provide a brief overview of the well-characterized molecular pathways of cellular Fe trafficking and utilization. Iron is transported within the serum bound to the Fe-binding protein, transferrin (Tf), 2-4 that binds to the transferrin receptor 1 (TfR1; Figure 1). The receptor binds 2 molecules of Fe-loaded Tf, 5 resulting in receptor-mediated endocytosis of the Tf-TfR1 complex (for reviews, see Morgan, 2 Richardson and Ponka, 3 and Hentze et al 4 ). A reduction in endosomal pH 2,3,6 mediates the release of Fe from Tf. 2,7 A protein known as the natural resistance-associated macrophage protein 2 (Nramp2) 8 was subsequently demonstrated to be the long sought-after exporter of Fe ϩ2 from endosomes. [9][10][11] This molecule is now known as divalent metal ion transporter 1 (DMT1) but has also been denoted as the divalent cation transporter 1 (DCT1) or solute carrier family 11a member 2 (Slc11a2).Within the cytosol, Fe can be stored in a large multimeric protein known as ferritin. 12 The storage of Fe in this molecule protects the cells from the damaging effects of free Fe and also keeps it sequestered in a bioavailable form. Since Fe is such an important but potentially toxic metal, its uptake, storage, and mobilization pathways are tightly regulated. This homeostatic control mechanism is largely controlled by RNA-bi...

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“…On the contrary, iron deposits in human sideroblasts and Rtc are found predominantly within the mitochondrial matrix. Deposits are described as finely granular, electron-dense material resembling ferritin micelles, or amorphous accumulations of coarser granules (6,51,54). The observation that mice have siderocytes instead of sideroblasts is seen not only in SOD2 deficiency but also in other experimental forms of SA such as pyridoxine deficiency (24).…”

Section: Hemolytic Anemias Mitochondrial Dysfunction and Oxidative Smentioning

confidence: 99%

SOD2-Deficiency Sideroblastic Anemia and Red Blood Cell Oxidative Stress

Martin

Bydlon

Friedman

2006

Antioxidants & Redox Signaling

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Iron overload is a feature of an array of human disorders such as sideroblastic anemias, a heterogeneous group of erythropoietic disorders without identified cause in most cases. However, sideroblastic anemias appear to result from a disturbance at the interface between mitochondrial function and iron metabolism. A defining feature is excessive iron deposition within mitochondria of developing red cells, the consequences of which are an increase in cellular free radicals production, increased damage to proteins, and reduced cell survival. Because of its mitochondrial location, superoxide dismutase (SOD2) is the principal defense against the toxicity of superoxide anions generated by the oxidative phosphorylation. We have used hematopoietic stem cell transplantation to study blood cells lacking SOD2. We became interested in the role SOD2 plays in the metabolism of superoxide anions during erythroid development, as anemia is the major phenotype in transplanted animals. Our exploration of this model suggests that oxidative stress-and in particular, mitochondrial- derived oxidants-plays an important role in the pathogenesis of the human disorder, sideroblastic anemia. Here we review the relation between mitochondrial dysfunction and sideroblastic anemia, describe several methods for assessing oxidative damage to mature or developing red cells, present data on, and discuss the potential of antioxidant therapy for this disorder.

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Microspectrophotometric and Electron Microscopic Studies of Bone Marrow in Hereditary Sideroblastic Anaemia

Cited by 15 publications

References 6 publications

In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin

In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin

Iron trafficking in the mitochondrion: novel pathways revealed by disease

SOD2-Deficiency Sideroblastic Anemia and Red Blood Cell Oxidative Stress

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