Check out our New Publishers' Select for Free Articles

BBA - General Subjects (v.1790, #7)

Editorial Board (pp. i).

The impact of host iron homeostasis on disease by James R. Connor; Andrew Ghio (pp. 581-582).

No Title by James Connor Guest Editor (pp. 583-583).

Systemic iron status by John Beard; Okhee Han (pp. 584-588).

Iron is one of the essential micronutrients, and as such, is required for growth, development, and normal cellular functioning. In contrast to some other micronutrients such as water-soluble vitamins, there is a significant danger of toxicity if excessive amounts of iron accumulate in the body. A finely tuned feedback control system functions to limit this excessive accumulation by limiting absorption of iron. This chapter will discuss systemic and brain iron homeostasis.

Keywords: Iron deficiency; Ferritin; Ferroportin; DMT1; Iron status; Iron homeostasis

Ferritins: A family of molecules for iron storage, antioxidation and more by Paolo Arosio; Rosaria Ingrassia; Patrizia Cavadini (pp. 589-599).

Ferritins are characterized by highly conserved three-dimensional structures similar to spherical shells, designed to accommodate large amounts of iron in a safe, soluble and bioavailable form. They can have different architectures with 12 or 24 equivalent or non-equivalent subunits, all surrounding a large cavity. All ferritins readily interact with Fe(II) to induce its oxidation and deposition in the cavity in a mineral form, in a reaction that is catalyzed by a ferroxidase center. This is an anti-oxidant activity that consumes Fe(II) and peroxides, the reagents that produce toxic free radicals in the Fenton reaction. The mechanism of ferritin iron incorporation has been characterized in detail, while that of iron release and recycling has been less thoroughly studied. Generally ferritin expression is regulated by iron and by oxidative damage, and in vertebrates it has a central role in the control of cellular iron homeostasis. Ferritin is mostly cytosolic but is found also in mammalian mitochondria and nuclei, in plant plastids and is secreted in insects. In vertebrates the cytosolic ferritins are composed of H and L subunit types and their assembly in a tissues specific ratio that permits flexibility to adapt to cell needs. The H-ferritin can translocate to the nuclei in some cell types to protect DNA from iron toxicity, or can be actively secreted, accomplishing various functions. The mitochondrial ferritin is found in mammals, it has a restricted tissue distribution and it seems to protect the mitochondria from iron toxicity and oxidative damage. The various functions attributed to the cytosolic, nuclear, secretory and mitochondrial ferritins are discussed.

Keywords: Abbreviations; ARE; antioxidant responsive element; Dps; DNA-binding proteins from stressed cells; FtMt; mitochondrial ferritin; HHCS; Hereditary Hyperferritinemia Cataract Sindrome; IRE; Iron Regulatory Element; IRP1; iron responsive protein-1; IRP2; iron responsive protein-2; LIP; labile iron pool; MPTP; Methyl Phenyl tetrahydroxypiridine; RARS; refractory anemias with ringed sideroblasts; ROS; reactive oxygen species; TIM-2; T-cell immunoglubulin-domain and mucin-domain-2Iron homeostasis; Ferritin; Mitochondria; Oxidative damage; Apoptosis

Iron availability and infection by Eugene D. Weinberg (pp. 600-605).

To successfully sustain an infection, nearly all bacteria, fungi and protozoa require a continuous supply of host iron.Literature review.Mechanisms of microbial iron acquisition are determinants for the kinds of cells, tissues and hosts in which pathogens can flourish. As a corollary, hosts possess an array of iron withholding devices whereby they can suppress or abort microbial invasions.Awareness of environmental and behavioral methods that can prevent iron loading plus development of pharmaceutical agents that can block microbial access to iron may help to reduce our dependence on antibiotics.

Keywords: Biofilm iron; Iron withholding defense; Lactoferrin; Siderophore; Transferrin

Iron, the substantia nigra and related neurological disorders by Amanda M. Snyder; James R. Connor (pp. 606-614).

Iron status is higher in the substantia nigra than in other brain regions but can fluctuate as function of diet and genetics and disease. Of particular note is the compartmentalization of the iron-enrichment in this region; the pars reticulata contains higher levels of stainable iron as compared to the pars compacta. The latter area is where the dopaminergic neurons reside. How this compartmentalization impacts the interpretation of data that iron contributes to cell death as in Parkinson's disease or iron deficiency contributes to altered dopaminergic activity is unknown. Nonetheless, that iron can influence neuronal cell death and dopamine function is clear.The mechanisms by which iron may be managed in the substantia nigra, particularly in the neuromelanin cells where minimal levels of ferritin the iron storage protein have been detected are addressed. The current approaches to detect iron in the substantia nigra are also reviewed. In addition, the potential mechanisms by which iron enrichment may occur in the substantia nigra are explored.This review attempts to provide a critical evaluation of the many avenues of exploration into the role of iron in one of the most iron-enriched and clinically investigated areas of the brain, the substantia nigra.

Keywords: Parkinson's disease; Restless legs syndrome

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases by Catherine M. Cahill; Debomoy K. Lahiri; Xudong Huang; Jack T. Rogers (pp. 615-628).

Recent studies that alleles in the hemochromatosis gene may accelerate the onset of Alzheimer's disease by five years have validated interest in the model in which metals (particularly iron) accelerate disease course. Biochemical and biophysical measurements demonstrated the presence of elevated levels of neurotoxic copper zinc and iron in the brains of AD patients. Intracellular levels of APP holoprotein were shown to be modulated by iron by a mechanism that is similar to the translation control of the ferritin L- and H mRNAs by iron-responsive element (IRE) RNA stem loops in their 5′ untranslated regions (5′UTRs). More recently a putative IRE-like sequence was hypothesized present in the Parkinsons's alpha synuclein (ASYN) transcript (see [A.L. Friedlich, R.E. Tanzi, J.T. Rogers, The 5'-untranslated region of Parkinson's disease alpha-synuclein messenger RNA contains a predicted iron responsive element, Mol. Psychiatry 12 (2007) 222–223. [6]]). Together with the demonstration of metal dependent translation of APP mRNA, the involvement of metals in the plaque of AD patients and of increased iron in striatal neurons in the substantia nigra (SN) of Parkinson's disease patients have stimulated the development of metal attenuating agents and iron chelators as a major new therapeutic strategy for the treatment of these neurodegenerative diseases. In the case of AD, metal based therapeutics may ultimately prove more cost effective than the use of an amyloid vaccine as the preferred anti-amyloid therapeutic strategy to ameliorate the cognitive decline of AD patients.

Keywords: Abbreviations; APP; Amyloid Precursor Protein; P97; mellanotransferrin; PS-1; Presenillin-1; ADAM-10; A Disintegrin and Metalloprotease Domain-10; TACE-1; Tumor Necrosis Factor alpha Converting Enzyme; ORF; Open Reading Frame; ASYN; Alpha synucleinKetogenic diet; Succinic semialdehyde dehydrogenase deficiency; Mitochondria; ATP; Hippocampus

The role of iron in mitochondrial function by Sonia Levi; Ermanna Rovida (pp. 629-636).

Iron is an essential element for life, as it is a cofactor for enzymes involved in many metabolic processes, but it can also be harmful, since its excess is thought to enhance the production of reactive oxygen species and induce oxidative damage. Iron is transformed into its biologically available form in the mitochondrion by the iron–sulfur (Fe/S) cluster and heme synthesis pathways. During the past decade, substantial progress has been made in the elucidation of iron-linked mechanisms that occur in the mitochondrion, demonstrating the crucial role played by this organelle in maintaining cellular iron homeostasis.This review summarizes current knowledge of the mechanisms underlying iron trafficking in mitochondria and how it is handled inside the organelle. Relevant updates with regard to the Fe/S cluster and heme biosynthetic pathways, as well as the relationship between mitochondrial iron homeostasis impairment and related diseases, are also discussed.

Keywords: Mitochondria; Iron; Iron–sulfur cluster; Heme; Mitochondria iron overload diseases

Iron homeostasis and eye disease by Allison Loh; Majda Hadziahmetovic; Joshua L. Dunaief (pp. 637-649).

Iron is necessary for life, but excess iron can be toxic to tissues. Iron is thought to damage tissues primarily by generating oxygen free radicals through the Fenton reaction.We present an overview of the evidence supporting iron's potential contribution to a broad range of eye disease using an anatomical approach.Iron can be visualized in the cornea as iron lines in the normal aging cornea as well as in diseases like keratoconus and pterygium. In the lens, we present the evidence for the role of oxidative damage in cataractogenesis. Also, we review the evidence that iron may play a role in the pathogenesis of the retinal disease age-related macular degeneration. Although currently there is no direct link between excess iron and development of optic neuropathies, ferrous iron's ability to form highly reactive oxygen species may play a role in optic nerve pathology. Lastly, we discuss recent advances in prevention and therapeutics for eye disease with antioxidants and iron chelators.Iron homeostasis is important for ocular health.

Keywords: Iron; Retina; Cornea; Lens; Chelator; Oxidative stress

Elevated hepatic iron: A confounding factor in chronic hepatitis C by Harriet C. Isom ⁎; Emily I. McDevitt; Mi Sun Moon (pp. 650-662).

Historically, iron overload in the liver has been associated with the genetic disorders hereditary hemochromatosis and thalassemia and with unusual dietary habits. More recently, elevated hepatic iron levels also have been observed in chronic hepatitis C virus (HCV) infection. Iron overload in the liver causes many changes including induction of oxidative stress, damage to lysosomes and mitochondria, altered oxidant defense systems and stimulation of hepatocyte proliferation. Chronic HCV infection causes numerous pathogenic changes in the liver including induction of endoplasmic reticulum stress, the unfolded protein response, oxidative stress, mitochondrial dysfunction and altered growth control. Understanding the molecular and cellular changes that could occur in a liver which has elevated hepatic iron levels and in which HCV replication and gene expression are ongoing has clinical relevance and represents an area of research in need of further investigation.

Keywords: Iron overload; Hemochromatosis; Acetaminophen; Hepatitis C virus; Thalassemia; Oxidative damage

Co-factors in liver disease: The role of HFE-related hereditary hemochromatosis and iron by Daniel F. Wallace; V. Nathan Subramaniam (pp. 663-670).

The severity of liver disease and its presentation is thought to be influenced by many host factors. Prominent among these factors is the level of iron in the body. The liver plays an important role in coordinating the regulation of iron homeostasis and is involved in regulating the level of iron absorption in the duodenum and iron recycling by the macrophages. Iron homeostasis is disturbed by several metabolic and genetic disorders, including various forms of hereditary hemochromatosis. This review will focus on liver disease and how it is affected by disordered iron homeostasis, as observed in hereditary hemochromatosis and due to HFE mutations. The types of liver disease covered herein are chronic hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), end-stage liver disease, hepatocellular carcinoma (HCC) and porphyria cutanea tarda (PCT).

Keywords: Iron; Hemochromatosis; Liver; Alcohol; Hepatitis; Porphyria cutanea tarda

The role of iron in type 2 diabetes in humans by Swapnil N. Rajpathak; Jill P. Crandall; Judith Wylie-Rosett; Geoffrey C. Kabat; Thomas E. Rohan; Frank B. Hu (pp. 671-681).

The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.

Keywords: Iron; Ferritin; Type 2 diabetes; Insulin resistance

Iron metabolism in the anemia of chronic disease by Günter Weiss (pp. 682-693).

The most frequent clinical condition exemplifying the interplay between iron and immune function is the anemia of chronic disease (ACD).Based on a review of the current literature this article provides an overview of our current knowledge of iron homeostasis during inflammation, how this contributes to ACD, but also emphasizes pitfalls in diagnosing iron availability and correcting iron deficiency in this setting.A diversion of iron from the circulation into the reticuloendothelial system and the resutling iron limitation for erythropoiesis are central for the development of ACD. Acute-phase proteins, such as hepcidin, as well as pro- and anti-inflammatory cytokines affect iron acquisition and release pathways of monocytes and macrophages thereby leading to iron restriction within the RES and systemic hypoferremia. These metabolic effects are in part exerted via cytokine-mediated modulation of transcriptional/translational expression of iron metabolism genes or by inducing labile radical formation, which then regulate the posttranscriptional regulation of cellular iron homeostasis. In addition, inflammatory processes affect macrophage iron acquisition via erythrophagocytosis while hepcidin inhibits macrophage iron release via direct interaction with the central iron export protein ferroportin.Being aware of the effects of iron on cell mediated immune effector function and the central importance of the metal as a nutrient of invading pathogens, iron restriction within the RES harbors potential benefits for the host and may serve as a defense strategy of the body. Therapeutic manipulation of iron balance and transport under inflammatory conditions is thus a major challenge harboring both, putative beneficial and detrimental effects.

Keywords: Macrophage; Hepcidin; Ferroportin; Iron restriction; Infection; Cytokine

Iron overload following red blood cell transfusion and its impact on disease severity by Caroline P. Ozment; Jennifer L. Turi (pp. 694-701).

Transfusion of red blood cells can be a life-saving therapy both for patients with chronic anemias and for those who are critically ill with acute blood loss. However, transfusion has been associated with significant morbidity. Chronic transfusion results in accumulation of excess iron that surpasses the binding capacity of the major iron transport protein, transferrin. The resulting non–transferrin bound iron (NTBI) can catalyze the production of highly reactive oxygen species (ROS) leading to significant and wide spread injury to the liver, heart, and endocrine organs as well as increases in infection. Acute transfusion of red blood cells in critically ill patients likewise has significant effects including increased mortality, prolonged hospital stays, and elevated risk of nosocomial infection. These effects appear to be more profound with increasing age of stored blood. The progressive release of free iron associated with storage time suggests that morbidity following acute transfusion, like that seen in chronic transfusion, may be due in part to elevated levels of NTBI. It is clear that transfusion is necessary in many instances; however, its risks and benefits must be carefully balanced before proceeding to avoid unnecessary iron toxicity.

Keywords: Iron; Transfusion; Oxidant stress; Thalassemia; Chelation

Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents by D.R. Richardson; D.S. Kalinowski; S. Lau; P.J. Jansson; D.B. Lovejoy (pp. 702-717).

Cancer contributes to 50% of deaths worldwide and new anti-tumour therapeutics with novel mechanisms of actions are essential to develop. Metabolic inhibitors represent an important class of anti-tumour agents and for many years, agents targeting the nutrient folate were developed for the treatment of cancer. This is because of the critical need of this factor for DNA synthesis. Similarly to folate, Fe is an essential cellular nutrient that is critical for DNA synthesis. However, in contrast to folate, there has been limited effort applied to specifically design and develop Fe chelators for the treatment of cancer. Recently, investigations have led to the generation of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) group of ligands that demonstrate marked and selective anti-tumour activity in vitro and also in vivo against a wide spectrum of tumours. Indeed, administration of these compounds to mice did not induce whole body Fe-depletion or disturbances in haematological or biochemical indices due to the very low doses required. The mechanism of action of these ligands includes alterations in expression of molecules involved in cell cycle control and metastasis suppression, as well as the generation of redox-active Fe complexes. This review examines the alterations in Fe metabolism in tumour cells and the systematic development of novel aroylhydrazone and thiosemicarbazone Fe chelators for cancer treatment.

Keywords: Abbreviations; 311; 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; BpT; 2-benzoylpyridine thiosemicarbazone; CDK; cyclin-dependent kinase; CDKi; cyclin-dependent kinase inhibitor; DFO; desferrioxamine; DMT1; divalent metal ion transporter 1; DpT; di-2-pyridylketone thiosemicarbazone; Dp44mT; di-2-pyridyl ketone 4,4-dimethyl-3-thiosemicarbazone; FPN1; ferroportin1; GADD45; growth arrest and DNA damage 45; G6PDH; glucose-6-phosphate dehydrogenase; HCP1; haem carrier protein 1; HIF-1α; hypoxia inducible factor-1α; HFE; haemochromatosis gene product; HRE; hypoxia response element; IRE; iron-responsive element; IRP; iron-regulatory protein; LIP; labile iron pool; MMP; matrix metalloproteinase; Ndrg-1; N-myc downstream regulated gene-1; PKIH; di-2-pyridylketone isonicotinoyl hydrazone; PIH; pyridoxal isonicotinoyl hydrazone; Rb; retinoblastoma protein; ROS; reactive oxygen species; RR; ribonucleotide reductase; Steap3; six-transmembrane epithelial antigen of the prostate 3; Tf; transferrin; TfR1; transferrin receptor 1; UTR; untranslated region; VEGF1; vascular endothelial growth factor 1; VHL; von Hippel–Lindau; WAF1; wild-type activating fragment-1Transferrin; Pyridoxal isonicotinoyl hydrazone; Iron; Transferrin receptor; Desferrioxamine

Iron in arterial plaque: A modifiable risk factor for atherosclerosis by Jerome L. Sullivan (pp. 718-723).

It has been proposed that iron depletion protects against cardiovascular disease. There is increasing evidence that one mechanism for this protection may involve a reduction in iron levels within atherosclerotic plaque. Large increases in iron concentration are seen in human atherosclerotic lesions in comparison to levels in healthy arterial tissue. In animal models, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability. A number of factors associated with increased arterial disease or increased cardiovascular events is also associated with increased plaque iron. In rats, infusion of angiotensin II increases ferritin levels and arterial thickness which are reversed by treatment with the iron chelator deferoxamine. In humans, a polymorphism for haptoglobin associated with increased cardiovascular disease is also characterized by increased lesional iron. Heme oxygenase 1 (HO1) is an important component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms causing weaker upregulation of the enzyme are associated with increased cardiovascular disease and increased serum ferritin. Increased cardiovascular disease associated with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages. Defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload. The reviewed findings support the concept that arterial plaque iron is a modifiable risk factor for atherogenesis.

Keywords: Iron; Atherosclerosis; Macrophage; Ferritin; Hemochromatosis; Hepcidin; Haptoglobin; Heme oxygenase; Angiotensin; Inflammation; Interleukin-6

Iron transport and the kidney by Craig P. Smith; Frank Thévenod (pp. 724-730).

Over the last decade there has been an explosion in our understanding of the proteins that modulate iron homeostasis. Much research has focused on the tissues classically associated with iron absorption and metabolism, namely the duodenum, the liver and the reticulo-endothelial system. Expression profiling has highlighted that many of the components associated with iron homeostasis, are also expressed in tissues which hitherto have received relatively little attention in terms of iron research. These include, testis, lung and, the subject of this review, the kidney. The latter is of great interest because other than a source of erythropoietin, a function that is of course of utmost importance for iron homeostasis, the kidney is regarded as more or less irrelevant in terms of iron handling. However, the fact that the kidneys of our favourite subjects, namely rats, mice and humans, contain many if not all of the proteins that are central to iron balance, that in some cases are expressed in considerable amounts, implies that the kidney handles iron in some way that has demanded evolutionary conservation and therefore is likely to be of importance.This review will document the evidence of iron transporter expression in the kidney, detail data showing the expression of other proteins associated with iron homeostasis and discuss the relevance of renal iron transport to pathophysiological states. Based on these data, a hypothetical model of renal iron handling will be presented.

Keywords: Kidney; Iron; Membrane transport; DMT1; Ferroportin1; DcytB; Hapheastin

Disruption of iron homeostasis and lung disease by Andrew J. Ghio (pp. 731-739).

As a result of a direct exchange with the external environment, the lungs are exposed to both iron and agents with a capacity to disrupt the homeostasis of this metal (e.g. particles). An increased availability of catalytically reactive iron can result from these exposures and, by generating an oxidative stress, this metal can contribute to tissue injury. By importing this Fe³⁺ into cells for storage in a chemically less reactive form, the lower respiratory tract demonstrates an ability to mitigate both the oxidative stress presented by iron and its potential for tissue injury. This means that detoxification is accomplished by chemical reduction to Fe²⁺ (e.g. by duodenal cytochrome b and other ferrireductases), iron import (e.g. by divalent metal transporter 1 and other transporters), and storage in ferritin. The metal can subsequently be exported from the cell (e.g. by ferroportin 1) in a less reactive state relative to that initially imported. Iron is then transported out of the lung via the mucociliary pathway or blood and lymphatic pathways to the reticuloendothelial system for long term storage. This coordinated handling of iron in the lung appears to be disrupted in several acute diseases on the lung including infections, acute respiratory distress syndrome, transfusion-related acute lung injury, and ischemia–reperfusion. Exposures to bleomycin, dusts and fibers, and paraquat similarly alter iron homeostasis in the lung to affect an oxidative stress. Finally, iron homeostasis is disrupted in numerous chronic lung diseases including pulmonary alveolar proteinosis, transplantation, cigarette smoking, and cystic fibrosis.

Keywords: Oxidative stress; Ferritin; Divalent metal transporter 1; Transferrin; Transferrin receptor

Sections

Personal tools

BBA - General Subjects (v.1790, #7)

Sections

Personal tools

Local resources

BBA - General Subjects (v.1790, #7)