The long history of iron in the Universe and in health and disease

doi:10.1016/j.bbagen.2011.08.002

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1820, Issue 3, March 2012, Pages 161-187

https://doi.org/10.1016/j.bbagen.2011.08.002 Get rights and content

Abstract

Background

Not long after the Big Bang, iron began to play a central role in the Universe and soon became mired in the tangle of biochemistry that is the prima essentia of life. Since life's addiction to iron transcends the oxygenation of the Earth's atmosphere, living things must be protected from the potentially dangerous mix of iron and oxygen. The human being possesses grams of this potentially toxic transition metal, which is shuttling through his oxygen-rich humor. Since long before the birth of modern medicine, the blood—vibrant red from a massive abundance of hemoglobin iron—has been a focus for health experts.

Scope of review

We describe the current understanding of iron metabolism, highlight the many important discoveries that accreted this knowledge, and describe the perils of dysfunctional iron handling.

General significance

Isaac Newton famously penned, “If I have seen further than others, it is by standing upon the shoulders of giants”. We hope that this review will inspire future scientists to develop intellectual pursuits by understanding the research and ideas from many remarkable thinkers of the past.

Major conclusions

The history of iron research is a long, rich story with early beginnings, and is far from being finished. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

Highlights

► Iron has been a requirement for nearly all life from the very first organisms. ► We document the history of iron metabolism in health and disease. ► Unique and specific systems for handling iron evolved to control its catalytic nature. ► The plasma protein transferrin plays a key role in iron metabolism. ► Disturbed iron homeostasis can result in catastrophic consequences for humans.

Introduction

This review is divided into four major sections. We begin by discussing the current views of iron metabolism followed by the history of iron and its homeostasis. The fourth section will present a brief history of the discovery and properties of human serum transferrin and the final major section will describe the pathophysiology of iron metabolism.

Section snippets

Overview of mammalian iron metabolism

Fig. 1 illustrates the iron cycle in humans and provides the approximate size of each iron pool. For historical interest, we have included an original version of the cycle, as determined from early ferrokinetic studies by Pollycove and Mortimer in 1961 [1] (Fig. 1, upper panel) in addition to a more recent adaptation of the former (Fig. 1, lower panel). Dietary iron enters the body primarily through duodenal enterocytes. As for the uptake of inorganic iron, these polarized cells express both

Preamble

The current cosmology tells us that the Universe was born around 13.7 billion years ago and entered its own “Iron Age” 200 million years after the Big Bang. Earth, which was formed together with the solar system some 9 billion years after the Big Bang, is estimated to be about 4.6 billion years old. Iron is the most abundant element in the planet Earth, forming much of Earth's outer and inner core, and it is the fourth most abundant element in the Earth's crust. This spinning iron at the center of

Overview

Since its discovery over six decades ago (see Section 3.2.2), human serum Tf (Tf) has been extensively studied. The natural abundance of Tf in the blood (~ 35 μM), in addition to its unique spectral properties, has long fascinated scientists. In particular the ability of Tf to bind ferric iron (Fe^+ 3) and other metals in two homologous lobes, tightly but reversibly, begs an explanation at a molecular level. As previously described [281], Tf and the two other founding family members, lactoferrin

Diseases of iron deficiency

Nearly a billion people are afflicted with iron deficiency anemia. This condition arises when there is insufficient iron available for hemoglobin formation in erythroid cells. With suboptimal heme synthesis, the red blood cells in these patients possess less red color and are smaller than normal. While these hypochromic, microcytic erythrocytes are the most striking feature of iron deficiency anemia, severe iron deficiency can affect multiple organs, as iron is ubiquitously required for many

Perspectives

What we know about iron homeostasis is likely only a small fraction of what we do not know. Table 3 lists some of the pieces of iron homeostasis that we know we do not know. The most obscure aspect of iron homeostasis is its intracellular trafficking and the enigma of how this metal encounters proteins. Hemoglobin is the only protein that has been extensively scrutinized in this regard, but even in this case our knowledge is far from complete. What we do know is that iron inserts into

Epilogue

We started this treatise with cosmological thoughts about the beginning of the Universe and our solar system, presenting the hypothesis that an early form of metabolism, driven by iron-mediated catalysis, predated genetics. Hence, it would seem appropriate to end this work by discussing a possible role of iron in the ultimate fate of the Universe. Astronomers presume that the Universe will gradually erode, provided it keeps on expanding and does not re-collapse under the pull of its own

Acknowledgements

The authors thank Dr. Evan Morgan, Dr. Mark Koury, Dr. Gil Holder, Dr. Alex Rabinovitch, and Dr. Jiří Grygar for their valuable comments. We are also grateful to two anonymous reviewers for their valuable comments. This work was supported in part by the Canadian Institutes for Health Research (PP, ADS) and a USPHS Grant R01 DK21739 (ABM).

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^☆: This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

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ReviewThe long history of iron in the Universe and in health and disease☆

Abstract

Background

Scope of review

General significance

Major conclusions

Highlights

Introduction

Section snippets

Overview of mammalian iron metabolism

Preamble

Overview

Diseases of iron deficiency

Perspectives

Epilogue

Acknowledgements

Cell

Cell

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Blood

Blood

Blood

Blood

Int. J. Biochem. Cell Biol.

Anal. Biochem.

Cell

FEBS Lett.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Cell Metab.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Exp. Hematol.

Exp. Hematol.

Biochem. Biophys. Res. Commun.

Blood

Exp. Cell Res.

Blood

Blood Cells Mol. Dis.

J. Biol. Chem.

Free Radic. Biol. Med.

Trends Pharmacol. Sci.

Cell Metab.

At. Data Nucl. Data Tables

Cell Metab.

The quantitative determination of iron kinetics and hemoglobin synthesis in human subjects

J. Clin. Invest.

Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity

Br. J. Haematol.

Ferritin iron uptake and release. Structure–function relationships

Biochem. J.

Endocytosis

Physiol. Rev.

Endocytic recycling

Nat. Rev. Mol. Cell Biol.

Pathways and mechanisms of endocytic recycling

Nat. Rev. Mol. Cell Biol.

Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment

Gastroenterology

Redox properties of human transferrin bound to its receptor

Biochemistry

Reticulocyte membrane transferrin receptors

Can. J. Biochem.

Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells

Nat. Genet.

Cloning and characterization of a mammalian proton-coupled metal-ion transporter

Nature

Existence of an erythropoietic labile iron pool in animals

Nature

Incorporation of radioiron into marrow heme

J. Lab. Clin. Med.

In vivo incorporation of 59 Fe into nonhem iron and hemoglobin of red blood cells

Acta Physiol. Scand.

An intracellular protein intermediate for hemoglobin formation

J. Clin. Invest.

Studies on the formation of ferritin in red cell precursors

J. Clin. Invest.

Studies on the partition of iron in bone marrow cells

Review
The long history of iron in the Universe and in health and disease☆