The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells

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Introduction

Virtually all living cells possess an absolute requirement for iron (Fe), and it has been suggested that reactions catalyzed by Fe may have constituted a first step in the origin of life 1, 2. Approximately 5% of the earth's crust is composed of Fe, and this great abundance coupled with the fact that the metal has two readily interconvertible redox states, has led to its evolutionary selection for an astonishing array of biological reactions. Iron exerts its function either in the form of numerous non-heme Fe-containing proteins or as the Fe-protoporphyrin complex of hemoproteins. The essential role of Fe in cell growth and replication is probably because many Fe-containing proteins catalyze key reactions involved in energy metabolism (cytochromes, mitochondrial aconitase, Fe-S proteins of the electron transport chain), respiration (hemoglobin and myoglobin), and DNA synthesis (ribonucleotide reductase). In addition, Fe-containing proteins are required for the metabolism of collagen, tyrosine and catecholamines. The observation that specific Fe chelators can markedly inhibit the proliferation of cells demonstrates the importance of Fe in cellular metabolism 3, 4, 5, 6, 7. Under most physiological conditions the Fe atom exists in its oxidized ferric state, and at neutral pH, ferric salts are hydrolyzed to form insoluble ferric hydroxide polymers. Moreover, if not appropriately shielded, Fe can readily participate in one-electron transfer reactions that can lead to the production of extremely toxic free radicals. To overcome these problems, microorganisms secrete high-affinity Fe chelating molecules known as siderophores [8], whereas higher organisms have developed Fe-binding proteins known as the transferrins (Tfs). Organisms are also equipped with highly sophisticated mechanisms that prevent the expansion of a catalytically active intracellular Fe pool, while maintaining sufficient concentrations of the metal for metabolic needs.

In the past several years numerous unexpected roles for Fe in health and disease have been identified, and the efforts of many laboratories have dramatically enhanced our understanding of the mechanisms involved in the coordination of cellular Fe uptake, utilization and storage. Specifically, we have witnessed major developments in understanding a post-transcriptional regulatory system (IRE/IRP) controlling the expression of ferritin, the transferrin receptor and erythroid δ-aminolevulinic acid synthase, proteins that are functionally related in coordinating Fe metabolism. Many recent investigations have highlighted awareness of iron's major role in free radical-mediated tissue damage, and have exposed unexpected links between the metabolism of Fe and nitrogen monoxide (NO). However, despite intensive research over the last three decades, many questions relating to the transport, utilization and intracellular handling of Fe remain unanswered. Indeed, most information related to the metabolism of Fe is confined to end products of the Fe incorporation process, such as proteins with Fe centres. On the other hand, the intracellular intermediates in the Fe uptake process are totally enigmatic and remain a fascinating subject for future investigation.

In this review we will attempt to provide a detailed overview of the molecular mechanisms that are responsible for the uptake and metabolism of Fe in normal and neoplastic cells. Since many recent reviews have concentrated on iron regulatory protein 1 (IRP1), transferrin (Tf), the transferrin receptor (TfR), and ferritin, the role of these proteins will only be briefly discussed, and the reader will be referred to more detailed literature where appropriate.

Section snippets

Iron is transported in the serum bound to transferrin

Transferrins are an important class of Fe-binding proteins that are widely distributed in the physiological fluids of vertebrates (for reviews, see Aisen [9]and Morgan [10]) and some invertebrates [11]. The transferrins are members of a family of proteins that include serum Tf, lactoferrin, ovotransferrin (also known as conalbumin), and melanotransferrin (MTf; formerly known as tumor antigen p97). Serum Tf functions as the Fe-binding molecule in the circulation, while ovotransferrin from egg

Molecular properties

The existence of a specific receptor for Tf on erythroid cells was originally proposed by Jandl and his co-workers 56, 57. However, the TfR was first purified and characterized in large quantities from human placenta 58, 59. Isolation of the receptor became possible only after it had been demonstrated that a Tf-binding component could be extracted from reticulocytes with non-ionic detergent 60, 61, 62, 63. The TfR consists of a disulfide-linked transmembrane glycoprotein homodimer having a Mr

Mechanisms of iron uptake by normal and neoplastic cells

It has become clear that both normal and neoplastic cells can obtain Fe from Tf by a variety of different mechanisms. The best characterized process of Fe uptake involves the specific binding of Tf to the TfR that is then internalized via receptor-mediated endocytosis (see Fig. 1). However, in several cell types, such as hepatocytes, melanoma cells and some other neoplastic cells, additional non-receptor-mediated mechanisms exist that may also play an important role in the uptake of Fe from Tf.

What is the pathophysiological significance of iron uptake mediated by the human melanoma-associated tumor antigen, melanotransferrin (p97)?

Melanotransferrin (MTf) or melanoma-associated antigen p97, is a Tf homologue 18, 19that was first identified on the membranes of tumor cells by using monoclonal antibodies 233, 234, 235. Two other melanoma-associated antigens, namely gp 95 [234]and gp 87 [236], are identical to MTf. Studies examining the tissue distribution of MTf have shown that this membrane-bound molecule is a tumor-associated differentiation antigen expressed in only small quantities in normal tissues, but in much larger

A low molecular weight transit iron pool

After Fe has been transported through the membrane, it enters a very poorly characterized compartment known as the intracellular transit Fe pool. Crichton [256]has aptly described this entity as “somewhat like the Loch Ness monster, only to disappear from view before its presence can be confirmed.” It has been suggested by several workers that this transit pool of Fe may be composed of low-Mr ligands such as amino acids, ascorbate, sugars, riboflavin, ATP, or other nucleotides 257, 258, 259, 260

Iron-regulatory protein 1 (IRP1)

Iron is an obligate requirement for essential metabolic processes. Too little can lead to cell death, while an excess of Fe results in cellular toxicity that is probably mediated by the generation of free radicals. Hence, sensitive control mechanisms that monitor intracellular Fe levels have developed during evolution. Within the last 10 years, understanding of these mechanisms has been greatly accelerated by the discovery of the iron regulatory protein 1 (IRP1; formerly known as IRF, IRE-BP,

Erythroid cells

There are many features that mark erythroid cell Fe metabolism, rendering it distinct from that found in other tissues and cells. As indicated by in vitro and in vivo experiments, Tf appears to be the only physiological source of Fe for erythroid cells. In vitro studies with reticulocytes have shown that although some small-Mr Fe complexes can donate Fe to reticulocytes for heme synthesis, they are less efficient than Tf-bound Fe 204, 205. Some low-Mr Fe chelates (e.g., Fe-citrate) can also

Many of the functions of nitrogen monoxide are mediated by its binding to iron

Nitrogen monoxide (NO) is a short-lived messenger molecule that plays a crucial role in the function of diverse biological processes, including vasorelaxation, regulation of blood pressure, adhesion and aggregation of platelets and neutrophils, macrophage-mediated cytotoxicity and neurotransmission 468, 469. Nitrogen monoxide is a highly reactive diatomic gas that is produced within mammalian cells by the enzyme NO synthase (NOS; for reviews, see 470, 471, 472), which catalyzes the stepwise

Unresolved problems

Cellular Fe metabolism remains a fascinating area of study because many steps in the Fe uptake process remain largely uncharacterized. For instance, little is known about the mechanisms that are involved in the transport of Fe through the cell membrane. As described in this review, there appears to be a number of Fe uptake mechanisms from Tf and small-Mr Fe complexes in mammalian cells, and whether they all use the same membrane transporter or a number of distinct transporters remains an

Summary

Iron uptake by mammalian cells is mediated by the binding of serum Tf to the TfR. Transferrin is then internalized within an endocytotic vesicle by receptor-mediated endocytosis and the Fe released from the protein by a decrease in endosomal pH. Apart from this process, several cell types also have other efficient mechanisms of Fe uptake from Tf that includes a process consistent with non-specific adsorptive pinocytosis and a mechanism that is stimulated by small-Mr Fe complexes. This latter

Notes added in proof

(1) As discussed above, the transit Fe pool is poorly characterized and further examination of this compartment is essential. Cabantchik and his colleagues 516, 517have recently introduced a fluorescent method for assessing the chelatable intracellular Fe pool. This technique is based upon the quenching of the fluorescent chelator calcein by metal ions. Used in conjunction with permeant and impermeant Fe(II) and Fe(III) chelators, these studies in K562 cells have suggested that the

Acknowledgements

This study was supported by grants from the Medical Research Council of Canada (to P.P. and D.R.R.) and a National Cancer Institute of Canada Terry Fox New Investigator Award with funds from the Terry Fox Run (to D.R.R.). D.R.R. was a Medical Research Council of Canada Scholar. Miss Kamini Milnes is thanked for helping to collate the reference list. We sincerely apologize to those colleagues whose work we did not cite.

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