Nitric Oxide-Mediated Modulation of Iron Regulatory Proteins: Implication for Cellular Iron Homeostasis

2002 ◽  
Vol 29 (3) ◽  
pp. 400-410 ◽  
Author(s):  
Sangwon Kim ◽  
Prem Ponka
Keyword(s):  
Nitric Oxide ◽  
Iron Homeostasis ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2161-2167 ◽  
Author(s):  
Guangjun Nie ◽  
Alex D. Sheftel ◽  
Sangwon F. Kim ◽  
Prem Ponka
Keyword(s):  
Iron Homeostasis ◽  
Rna Binding ◽  
Binding Activity ◽  
Intracellular Iron ◽  
Free Radical Damage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Uptake ◽  
A Cell ◽  
Cellular Iron Homeostasis

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.

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

2009 ◽  
Vol 105 (5) ◽  
pp. 801-810 ◽  
Author(s):  
Leonor Ramirez ◽  
Eduardo Julián Zabaleta ◽  
Lorenzo Lamattina
Keyword(s):  
Nitric Oxide ◽  
Iron Homeostasis ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 12 (3) ◽  
pp. 125 ◽  
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.

Calcein and the Labile Iron Pool.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1546-1546
Author(s):  
Shan Soe-Lin ◽  
Joan L. Buss ◽  
Evelyn Tang ◽  
Prem Ponka
Keyword(s):  
Iron Homeostasis ◽  
Iron Chelator ◽  
Acetoxymethyl Ester ◽  
Iron Regulatory Proteins ◽  
Labile Iron Pool ◽  
Cellular Iron ◽  
Labile Iron ◽  
The Difference ◽  
Iron Pool ◽  
Cellular Iron Homeostasis

Abstract The labile iron pool is a putative cytosolic compartment of loosely bound, redox-active, chelator-accessible iron. Iron contained within this pool is thought to influence the activity of iron regulatory proteins (IRPs), which bind to iron response elements (IRE) during low iron conditions; this association blocks the translation of ferritin mRNA, and stabilizes transferrin receptor mRNA. High levels of labile iron have been shown to promote oxidative stress. As this pool has such profound effects upon cellular iron homeostasis, there has been great interest in the development of methods to measure labile iron. Calcein, a fluorescent iron chelator, has been widely used to monitor the labile iron pool. When the non-fluorescent acetoxymethyl ester moiety (calcein-AM), enters cells, it is immediately cleaved by cytosolic esterases to its cell-impermeable, fluorescent calcein form. Iron binding to calcein quenches its fluorescence, which can subsequently be recovered following the loss of its iron to a stronger chelator. The difference in fluorescence between the bound and unbound calcein forms is thought to be proportional to the labile iron pool itself. While this method has been commonly exploited, it is unknown whether calcein may over-estimate the size of the labile pool by stripping iron from sources where it may be loosely bound, or by intercepting iron during its passage from one compartment to another. Although it is believed that calcein exerts very little direct influence on cellular iron homeostasis and acts only as a passive sensor of labile iron, some recent evidence from our lab indicates that this may not be the case. We have observed that incubation with calcein results in the activation of IRP-2 and stabilization of HIF-1α, a potent physiological regulator governing the expression of genes involved in oxygen sensing and iron metabolism. Furthermore, we have found that the size of the labile iron pool as measured by calcein was proportional to the amount of calcein loaded in HeLa and K562 cell lines. These findings suggest that calcein may be able to perturb cellular iron homeostasis, and may not accurately reflect the size of the labile iron pool. While calcein may still be used for comparative purposes under identically controlled conditions, its usefulness as a quantifying agent should be regarded with caution.

Iron Regulatory Proteins in Systemic Iron Metabolism and Erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Matthias W. Hentze
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Mutant Mouse ◽  
Conflicts Of Interest ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Regulatory Systems ◽  
Biology I ◽  
Mouse Lines

Abstract Abstract SCI-22 Imbalances of iron homeostasis account for some of the most common human diseases. Pathologies can result from both iron deficiency or overload. The hepcidin/ferroportin and the IRE/IRP regulatory systems balance systemic and cellular iron metabolism, respectively, and understanding their points of intersection and crosstalk represents a major challenge in iron biology. I will discuss an emerging picture from studies with different mutant mouse lines according to which the “cellular” IRE/IRP system determines “set points” via its targets (including ferroportin and HIF2α). These are then subject to modulation via hepcidin in response to systemic cues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inflaming the Brain with Iron

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 61
Author(s):  
Pamela J. Urrutia ◽  
Daniel A. Bórquez ◽  
Marco Tulio Núñez
Keyword(s):  
Nitric Oxide ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Iron Accumulation ◽  
Cellular Iron ◽  
Bidirectional Relationship ◽  
Inflammatory Phenotype ◽  
Related Proteins ◽  
Cellular Iron Homeostasis ◽  
The Brain

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood–brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.

scholarly journals Iron Regulatory Protein 1 Outcompetes Iron Regulatory Protein 2 in Regulating Cellular Iron Homeostasis in Response to Nitric Oxide

2011 ◽  
Vol 286 (26) ◽  
pp. 22846-22854 ◽  
Author(s):  
Agnieszka Styś ◽  
Bruno Galy ◽  
Rafal R. Starzyński ◽  
Ewa Smuda ◽  
Jean-Claude Drapier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Iron Regulatory Protein ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis ◽  
Iron Regulatory Protein 1

Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

2014 ◽  
Vol 15 (12) ◽  
pp. 1125-1140 ◽  
Author(s):  
Mohsin Raza ◽  
Sankalpa Chakraborty ◽  
Monjoy Choudhury ◽  
Prahlad Ghosh ◽  
Alo Nag
Keyword(s):  
Iron Homeostasis ◽  
Iron Chelators ◽  
Therapeutic Implications ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J. Devin ◽  
T. Cañeque ◽  
Y.‐L. Lin ◽  
L. Mondoulet ◽  
J.‐L. Veyrune ◽  
...  
Keyword(s):  
B Cell ◽  
Iron Homeostasis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cellular Iron ◽  
Large B Cell Lymphoma ◽  
Cellular Iron Homeostasis ◽  
Large B Cell
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