Commentary 1: Abnormal Mitochondrial Iron Metabolism in Friedreich Ataxia

2002 ◽  
Vol 29 (3) ◽  
pp. 548-549 ◽  
Author(s):  
Prem Ponka
Keyword(s):  
Iron Metabolism ◽  
Friedreich Ataxia ◽  
Mitochondrial Iron

scholarly journals Ironing out a therapy for Friedreich ataxia

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 1-2 ◽  
Author(s):  
Grazia Isaya
Keyword(s):  
Iron Metabolism ◽  
Inborn Error ◽  
Friedreich Ataxia ◽  
Young Patients ◽  
Iron Chelation ◽  
Positive Effects ◽  
Mitochondrial Iron

Boddaert and colleagues show the positive effects of selective iron chelation in young patients with Friedreich ataxia, a devastating inborn error of mitochondrial iron metabolism.

Targeting mitochondrial iron metabolism suppresses tumor growth and metastasis by inducing mitochondrial dysfunction and mitophagy

2021 ◽  
pp. canres.1628.2020
Author(s):  
Cristian Sandoval-Acuña ◽  
Natalia Torrealba ◽  
Veronika Tomkova ◽  
Sukanya Balkrishna Jadhav ◽  
Kristyna Blazkova ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Mitochondrial Iron ◽  
Tumor Growth And Metastasis

scholarly journals Hscb, a Mitochondrial Iron-Sulfur Cluster Assembly Co-Chaperone, Is a Novel Candidate Gene for Congenital Sideroblastic Anemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 79-79
Author(s):  
Andrew Crispin ◽  
Paul Schmidt ◽  
Dean Campagna ◽  
Chang Cao ◽  
Daniel Lichtenstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Metabolism ◽  
Conflicts Of Interest ◽  
K562 Cells ◽  
Luciferase Reporter ◽  
Mitochondrial Translation ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Congenital sideroblastic anemias (CSAs) are uncommon inherited diseases resulting from defects in heme biosynthesis, mitochondrial translation or mitochondrial iron-sulfur cluster (ISC) assembly. CSAs are characterized by pathological mitochondrial iron deposits in bone marrow erythroblasts. Recently, mutations in mitochondrialheat shock protein 70 (HSPA9), a critical chaperone involved in mitochondrial ISC assembly, have been reported as a cause of non-syndromic CSA. Human heat shock cognate protein 20 (HSCB), a highly conserved mitochondrial co-chaperone, is the primary binding partner of HSPA9. HSCB allows the transfer of nascent ISC to HSPA9 and stimulates its ATPase activity, promoting ISC transfer to target proteins. To identify novel genes responsible for CSA, we performed whole exome sequencing on more than 75 CSA probands and their family members. In one patient, a young woman, with pancytopenia characterized by a normocytic anemia with numerous bone marrow ringed sideroblasts, we identified two variants in HSCB : a paternally-inherited promoter variant (c.-134C>A) predicted to disrupt a conserved ETS transcription factor binding site, and a maternally-inherited frameshift (c.259dup, p.T87fs*27). A fibroblast cell-line derived from the proband showed a decrease in HSCB expression, but normal HSPA9 expression compared to healthy, unrelated controls. Impairment of ETS1-dependent transcriptional activation of the promoter variant was demonstrated in K562 cells transfected with an HSCB-luciferase reporter construct. K562 cells were also employed to determine if reduced expression of HSCB could result in impaired erythroid metabolism, maturation, or proliferation. K562 cells infected with shRNA directed against HSCB were deficient in multiple mitochondrial respiratory complexes, had abnormal iron metabolism and a defect of protein lipoylation, all consistent with defective ISC metabolism. In addition, both IRP1 and IRP2 expression were decreased and cell surface transferrin receptor 1 (TFR1) expression was enhanced, suggesting disturbed cellular iron metabolism. Nevertheless, cells lacking HSCB partially retained an ability to respond to iron chelation and iron overload. Cells lacking HSCB lose their ability to hemoglobinize in response to sodium butyrate treatment (Figure 1A). This defect was confirmed in vivo using a morpholino strategy in zebrafish, as fish lacking HSCB are also unable to hemoglobize (Fig 1B). We generated an Hscb conditional mouse to better elucidate the underlying pathophysiology of the disease. Heterozygous (Hscb+/-) animals have no discernable phenotype; however, null animals die prior to embryonic day E7.5. Thus, to avoid this lethality, we employed Vav-cre animals (Tg(Vav1-cre)1Graf) to evaluate the loss of HSCB specifically in the hematopoietic compartment. Hscbc/- Vav-cre+ pups are pale and growth retarded compared to control littermates and die at approximately p10 with severe pancytopenia. To assess the loss of HSCB specifically in the erythroid lineage, we bred conditional animals to EpoR-cre (Eportm1(EGFP/cre)Uk) mice. Hscbc/- EpoR-cre+ mice die at approximately E12.5 due to a complete failure of erythropoiesis (Figure 1C). Finally, temporally inducible, hematopoietic-specific deletion animals were generated by transplantation of fetal livers from Mx-Cre (Tg(Mx1-cre)1Cgn) positive Hscbc/- animals. After polyinosinic:polycytidylic acid (pIpC) induction, global defects of hematopoiesis were observed in Mx-Cre+ animals, leading to their death 3-weeks post-induction from profound pancytopenia. A transient siderocytosis was seen in the peripheral blood between days 6-8 post-pIpC. Flow cytometry using FSC-TER119-CD44 gating strategy confirmed the defect in erythropoiesis. Taken together, these data demonstrate that HSCB is essential for hematopoiesis; both whole animal and in vitro cell culture models recapitulate the patient's phenotype, suggesting that the two patient mutations are likely disease-causing. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Effects of Mitochondrial Ferritin Expression on Tumor Iron Metabolism and Tumor Growth in Nude Mice Xenografts.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3582-3582
Author(s):  
Guangjun Nie ◽  
Guohua Chen ◽  
Alex Sheftel ◽  
Kostas Pantopoulos ◽  
Prem Ponka
Keyword(s):  
Tumor Growth ◽  
Nude Mice ◽  
Iron Metabolism ◽  
Rna Binding ◽  
Heme Oxygenase 1 ◽  
Iron Starvation ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Tumor Xenografts ◽  
Mitochondrial Iron

Abstract Mitochondrial ferritin (MtFt) is a mitochondrial iron storage protein, whose function and regulation is largely unknown. Our previous results have shown that MtFt markedly affects intracellular iron distribution and homeostasis in mammalian cells (Blood105: 2161–2167, 2005). Using tumor xenografts, we examined the effects of expression MtFt on tumor iron metabolism and growth. H1299 parental or MtFt overexpressing cells were implanted into nude mice. As compared to control tumor xenografts, the expression of MtFt dramatically reduced the implanted tumor growth. A cytosolic iron starvation phenotype in MtFt expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) and, concomitantly, both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to a decrease in both total cellular heme content and heme oxygenase-1 levels. In addition, the expression of MtFt in tumors was associated with a decrease in aconitase activity and lower frataxin protein levels. Mitochondrial iron deposition in MtFt expressing tumors was directly observed by transmission electron microscopy. The pattern of iron accumulation in MtFt overexpressing tumor cells is remarkably similar to that observed in the mitochondria of sideroblastic anemia patients. In conclusion, our study shows that MtFt expression significantly affected tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partial defects in heme and iron-sulfur cluster syntheses. It is likely that deprivation of iron in the cytosol is the cause of the significant inhibition of xenograft tumor growth.

Deciphering Mitochondrial Iron Metabolism Using a Knockout Mouse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1995-1995
Author(s):  
Michael Huang ◽  
Erika Becker ◽  
Megan Whitnall ◽  
Yohan Suryo Rahmanto ◽  
Prem Ponka ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Uptake ◽  
Knockout Mouse ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Down Regulation ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract 1995 Poster Board I-1017 We utilized the muscle creatine kinase conditional frataxin knockout mouse to elucidate how frataxin-deficiency alters iron metabolism. This is of significance since frataxin-deficiency leads to the neuro- and cardio-degenerative disease, Friedreich's ataxia. Using cardiac tissues, we demonstrate that frataxin-deficiency leads to down-regulation of key molecules involved in three mitochondrial utilization pathways: iron-sulfur cluster (ISC) synthesis (iron-sulfur cluster scaffold protein1/2 and the cysteine desulferase, Nfs1); mitochondrial-iron storage (mitochondrial ferritin); and heme synthesis (5-aminolevulinate dehydratase, coproporphyrinogen oxidase, hydroxymethylbilane synthase, uroporphyrinogen III synthase and ferrochelatase). This marked decrease in mitochondrial-iron utilization and resultant reduced release of heme and ISC from the mitochondrion could contribute to the excess mitochondrial-iron observed. Indeed, this effect is compounded by increased iron availability for mitochondrial uptake through: (1) transferrin receptor1 up-regulation that increases iron uptake from transferrin; (2) decreased ferroportin1 expression, limiting iron export; (3) increased expression of the heme catabolism enzyme, heme oxygenase1, and down-regulation of ferritin-H and —L, both of which likely lead to increased “free iron” for mitochondrial uptake; and (4) increased expression of the mammalian exocyst protein, Sec15l1, and the mitochondrial-iron importer, mitoferrin-2 (Mfrn2), that facilitate cellular iron uptake and mitochondrial-iron influx, respectively. This study enables construction of a model explaining the cytosolic iron-deficiency and mitochondrial-iron-loading in the absence of frataxin that is important for understanding the pathogenesis of Friedreich's ataxia. Disclosures: No relevant conflicts of interest to declare.

Multiple Causes of Iron Overload In Tissues, Cells and Subcellular Compartments

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Tracey Rouault
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract SCI-27 Iron metabolism is regulated in mammals to assure that adequate iron is delivered to the hematopoietic system to support erythropoiesis. In systemic iron metabolism, regulation of both iron uptake from the diet and release from erythrophagocytosing macrophages is coordinated by action of the peptide hormone, hepcidin, which inhibits activity of the iron exporter, ferroportin. In general, high expression of hepcidin diminishes duodenal iron uptake and reduces macrophage iron release, a combination observed in the anemia of chronic disease. Low expression of hepcidin, which is synthesized by hepatocytes and influenced by transferrin receptor 2, HFE, hemojuvelin and bone morphogenetic receptors, facilitates iron uptake. Mutations affecting genes in the hepcidin pathway cause hemochromatosis, characterized by systemic iron overload that affects mainly hepatocytes and cardiac myocytes, but spares the CNS. In contrast, there are several degenerative diseases of the CNS in which neuronal iron overload is prominent and may play a causal role. The underlying pathophysiologies of neuronal brain iron accumulation syndromes remain unclear, even though several causal genes have been identified, including pantothenate kinase 2 and aceruloplasminemia. In some cases, increased iron may be inaccessible, and cells may suffer from functional iron insufficiency, as we propose for animals that lack iron regulatory protein 2. It is also possible that errors in subcellular iron metabolism can lead to mitochondrial iron overload and concomitant cytosolic iron deficiency, a combination observed in Friedreich ataxia, ISCU myopathy, and the sideroblastic anemia caused by glutaredoxin 5 deficiency. In each of these diseases, mitochondrial iron-sulfur cluster assembly is impaired, and it appears that normal regulation of mitochondrial iron homeostasis depends on intact iron-sulfur cluster assembly. Finally, in heme oxygenase 1 deficient animals, macrophages in the spleen and liver die upon erythrophagocytosis, and failure to normally metabolize heme leads to shift of heme iron to proximal tubules and macrophages of the kidney. Thus, treatment of “iron overload” must depend on the underlying causes, and removal of iron is appropriate in hemochromatosis, but more specific forms of therapy are needed for other forms of iron overload. 1. Ye, H. & Rouault, T. A. (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49, 4945–4956. 2. Zhang, A. S. & Enns, C. A. (2009). Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program 207–214. 3. Ye, H., Jeong, S. Y., Ghosh, M. C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C. & Rouault, T. A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749–1761. 4. Ghosh, M. C., Tong, W. H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M. C., Mitchell, J. B. & Rouault, T. A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028–12033. 5. Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. (2010). Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869. Disclosures: No relevant conflicts of interest to declare.

Mitochondrial iron metabolism and its role in diseases

2021 ◽  
Vol 513 ◽  
pp. 6-12
Author(s):  
Jiayin Gao ◽  
Qionglin Zhou ◽  
Di Wu ◽  
Linxi Chen
Keyword(s):  
Iron Metabolism ◽  
Mitochondrial Iron

Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia

1999 ◽  
Vol 45 (5) ◽  
pp. 673-675 ◽  
Author(s):  
Martin B. Delatycki ◽  
James Camakaris ◽  
Hilary Brooks ◽  
Tracy Evans-Whipp ◽  
David R. Thorburn ◽  
...  
Keyword(s):  
Direct Evidence ◽  
Friedreich Ataxia ◽  
Iron Accumulation ◽  
Mitochondrial Iron
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