HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

AbstractCytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.

Download Full-text

Nitric oxide and frataxin: two players contributing to maintain cellular iron homeostasis

Annals of Botany ◽

10.1093/aob/mcp147 ◽

2009 ◽

Vol 105 (5) ◽

pp. 801-810 ◽

Cited By ~ 27

Author(s):

Leonor Ramirez ◽

Eduardo Julián Zabaleta ◽

Lorenzo Lamattina

Keyword(s):

Nitric Oxide ◽

Iron Homeostasis ◽

Cellular Iron ◽

Cellular Iron Homeostasis

Download Full-text

Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: Implications for cellular iron homeostasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.96.10.5434 ◽

1999 ◽

Vol 96 (10) ◽

pp. 5434-5439 ◽

Cited By ~ 114

Author(s):

L. Salter-Cid ◽

A. Brunmark ◽

Y. Li ◽

D. Leturcq ◽

P. A. Peterson ◽

...

Keyword(s):

Transferrin Receptor ◽

Iron Homeostasis ◽

Cellular Iron ◽

Cellular Iron Homeostasis

Download Full-text

Loss of Cardiolipin Leads to Perturbation of Mitochondrial and Cellular Iron Homeostasis

Journal of Biological Chemistry ◽

10.1074/jbc.m112.428938 ◽

2012 ◽

Vol 288 (3) ◽

pp. 1696-1705 ◽

Cited By ~ 51

Author(s):

Vinay A. Patil ◽

Jennifer L. Fox ◽

Vishal M. Gohil ◽

Dennis R. Winge ◽

Miriam L. Greenberg

Keyword(s):

Iron Homeostasis ◽

Cellular Iron ◽

Cellular Iron Homeostasis

Download Full-text

Human Iron−Sulfur Cluster Assembly, Cellular Iron Homeostasis, and Disease

Biochemistry ◽

10.1021/bi1004798 ◽

2010 ◽

Vol 49 (24) ◽

pp. 4945-4956 ◽

Cited By ~ 168

Author(s):

Hong Ye ◽

Tracey A. Rouault

Keyword(s):

Iron Homeostasis ◽

Cluster Assembly ◽

Iron Sulfur Cluster ◽

Sulfur Cluster ◽

Cellular Iron ◽

Iron Sulfur ◽

Cellular Iron Homeostasis

Download Full-text

Function and crystal structure of the dimeric P-loop ATPase CFD1 coordinating an exposed [4Fe-4S] cluster for transfer to apoproteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807762115 ◽

2018 ◽

Vol 115 (39) ◽

pp. E9085-E9094 ◽

Cited By ~ 11

Author(s):

Oliver Stehling ◽

Jae-Hun Jeoung ◽

Sven A. Freibert ◽

Viktoria D. Paul ◽

Sebastian Bänfer ◽

...

Keyword(s):

Crystal Structure ◽

Iron Homeostasis ◽

De Novo ◽

Regulatory Protein ◽

Protein Translation ◽

Cluster Assembly ◽

Cellular Iron ◽

Chaetomium Thermophilum ◽

Cellular Iron Homeostasis ◽

S Proteins

Maturation of iron-sulfur (Fe-S) proteins in eukaryotes requires complex machineries in mitochondria and cytosol. Initially, Fe-S clusters are assembled on dedicated scaffold proteins and then are trafficked to target apoproteins. Within the cytosolic Fe-S protein assembly (CIA) machinery, the conserved P-loop nucleoside triphosphatase Nbp35 performs a scaffold function. In yeast, Nbp35 cooperates with the related Cfd1, which is evolutionary less conserved and is absent in plants. Here, we investigated the potential scaffold function of human CFD1 (NUBP2) in CFD1-depleted HeLa cells by measuring Fe-S enzyme activities or 55Fe incorporation into Fe-S target proteins. We show that CFD1, in complex with NBP35 (NUBP1), performs a crucial role in the maturation of all tested cytosolic and nuclear Fe-S proteins, including essential ones involved in protein translation and DNA maintenance. CFD1 also matures iron regulatory protein 1 and thus is critical for cellular iron homeostasis. To better understand the scaffold function of CFD1-NBP35, we resolved the crystal structure of Chaetomium thermophilum holo-Cfd1 (ctCfd1) at 2.6-Å resolution as a model Cfd1 protein. Importantly, two ctCfd1 monomers coordinate a bridging [4Fe-4S] cluster via two conserved cysteine residues. The surface-exposed topology of the cluster is ideally suited for both de novo assembly and facile transfer to Fe-S apoproteins mediated by other CIA factors. ctCfd1 specifically interacted with ATP, which presumably associates with a pocket near the Cfd1 dimer interface formed by the conserved Walker motif. In contrast, ctNbp35 preferentially bound GTP, implying differential regulation of the two fungal scaffold components during Fe-S cluster assembly and/or release.

Download Full-text

Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

Pharmaceuticals ◽

10.3390/ph12030125 ◽

2019 ◽

Vol 12 (3) ◽

pp. 125 ◽

Cited By ~ 2

Author(s):

Samira Lakhal-Littleton

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

Chronic Heart Failure ◽

Iron Deficiency ◽

Iron Supplementation ◽

Iron Homeostasis ◽

Iron Regulatory Proteins ◽

Cellular Iron ◽

Cellular Iron Homeostasis

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension.

Download Full-text