Mitochondrial Iron Metabolism: Study of mitoferrin in Drosophila melanogaster (original) (raw)
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The fate of iron in the organism and its regulatory pathways
Acta medica (Hradec Králové) / Universitas Carolina, Facultas Medica Hradec Králové, 2005
Iron is an essential element involved in many life-necessary processes. Interestingly, in mammals there is no active excretion mechanism for iron. Therefore iron kinetics has to be meticulously regulated. The most important step for regulation of iron kinetics is absorption. The absorption takes place in small intestine and it is implicated that it requires several proteins. Iron is then released from enterocytes into the circulation and delivered to the cells. Iron movement inside the cell is only partially elucidated and its traffic to mitochondia is not known. Surprisingly, the regulation of various proteins related to iron kinetics and energy metabolism at the molecular level is better described. On contrary, the complex control of iron absorption cannot be fully explicated with present knowledge.
Iron Absorption in Drosophila melanogaster
Nutrients
The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration.
Chemistry and biology of eukaryotic iron metabolism
The International Journal of Biochemistry & Cell Biology, 2001
With rare exceptions, virtually all studied organisms from Archaea to man are dependent on iron for survival. Despite the ubiquitous distribution and abundance of iron in the biosphere, iron-dependent life must contend with the paradoxical hazards of iron deficiency and iron overload, each with its serious or fatal consequences. Homeostatic mechanisms regulating the absorption, transport, storage and mobilization of cellular iron are therefore of critical importance in iron metabolism, and a rich biology and chemistry underlie all of these mechanisms. A coherent understanding of that biology and chemistry is now rapidly emerging. In this review we will emphasize discoveries of the past decade, which have brought a revolution to the understanding of the molecular events in iron metabolism. Of central importance has been the discovery of new proteins carrying out functions previously suspected but not understood or, more interestingly, unsuspected and surprising. Parallel discoveries have delineated regulatory mechanisms controlling the expression of proteins long known -the transferrin receptor and ferritin -as well as proteins new to the scene of iron metabolism and its homeostatic control. These proteins include the iron regulatory proteins , a variety of ferrireductases in yeast an mammalian cells, membrane transporters (DMT1 and ferroportin 1), a multicopper ferroxidase involved in iron export from cells (hephaestin), and regulators of mitochondrial iron balance (frataxin and MFT). Experimental models, making use of organisms from yeast through the zebrafish to rodents have asserted their power in elucidating normal iron metabolism, as well as its genetic disorders and their underlying molecular defects. Iron absorption, previously poorly understood, is now a fruitful subject for research and well on its way to detailed elucidation. The long-sought hemochromatosis gene has been found, and active research is underway to determine how its aberrant functioning results in disease that is easily controlled but lethal when untreated. A surprising connection between iron metabolism and Friedreich's ataxia has been uncovered. It is no exaggeration to say that the new understanding of iron metabolism in health and disease has been explosive, and that what is past is likely to be prologue to what is ahead.
The role of iron in mitochondrial function
Biochimica et Biophysica Acta (BBA) - General Subjects, 2009
Background: 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. General Significance: 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.
Pantopoulos:Iron Metabolism book:1999.pdf
The molecular basis for the regulation of cellular iron metabolism in metazoans has been elucidated in the last years. Iron uptake, storage and utilization are coordinately regulated at the post-transcriptional level by mRNA-protein interactions. An increasing number of mRNAs encoding primarily proteins involved in cellular iron turnover, contain iron-responsive elements (IREs), conserved stem-loop structures in their untranslated regions. IREs provide the binding site for two homologous cytoplasmic iron-regulatory proteins, IRPl and IRP2. The iron-regulated IRE/IRP interactions control mRNA translation or stability. Thus, the IRE/IRP system has emerged as a major paradigm of post-transcriptional gene regulation in higher eukaryotes. The studies on IRP1, which appears to be the most abundant iron regulatory protein, have revealed an unexpected role of iron-sulfur clusters as posttranslational regulatory sites and have highlighted the versatility of iron-sulfur chemistry as a determinant of protein function. 132 8 Regulation of iron metabolism in higher eukaryotes acute or chronic iron overload poses a major threat for cells, especially under conditions of 'oxidative stress', where the concentrations of ROS are increased. All living cells, from prokaryotes to multicellular organisms, have adapted to the need for a balanced iron supply by developing elaborate regulatory systems. The regulatory circuit which controls iron homeostasis in higher eukaryotic cells is the main topic of this chapter and will be described below.
Ferritin accumulation under iron scarcity in Drosophila iron cells
Biochimie, 2009
Ferritins are highly stable, multi-subunit protein complexes with iron-binding capacities that reach 4500 iron atoms per ferritin molecule. The strict dependence of cellular physiology on an adequate supply of iron cofactors has likely been a key driving force in the evolution of ferritins as iron storage molecules. The insect intestine has long been known to contain cells that are responsive to dietary iron levels and a specialized group of ''iron cells'' that always accumulate iron-loaded ferritin, even when no supplementary iron is added to the diet. Here, we further characterize ferritin localization in Drosophila melanogaster larvae raised under iron-enriched and iron-depleted conditions. High dietary iron intake results in ferritin accumulation in the anterior midgut, but also in garland (wreath) cells and in pericardial cells, which together filter the circulating hemolymph. Ferritin is also abundant in the brain, where levels remain unaltered following dietary iron chelation, a treatment that depletes ferritin from the aforementioned tissues. We attribute the stability of ferritin levels in the brain to the function of the blood-brain barrier that may shield this organ from systemic iron fluctuations. Most intriguingly, our dietary manipulations demonstrably iron-depleted the iron cells without a concomitant reduction in their production of ferritin. Therefore, insect iron cells may constitute an exception from the evolutionary norm with respect to iron-dependent ferritin regulation. It will be of interest to decipher both the physiological purpose served and the mechanism employed to untie ferritin regulation from cellular iron levels in this cell type.
Multicopper oxidase-1 is a ferroxidase essential for iron homeostasis in Drosophila melanogaster
Proceedings of the National Academy of Sciences, 2012
Multicopper ferroxidases catalyze the oxidation of ferrous iron to ferric iron. In yeast and algae, they participate in cellular uptake of iron; in mammals, they facilitate cellular efflux. The mechanisms of iron metabolism in insects are still poorly understood, and insect multicopper ferroxidases have not been identified. In this paper, we present evidence that Drosophila melanogaster multicopper oxidase-1 (MCO1) is a functional ferroxidase. We identified candidate iron-binding residues in the MCO1 sequence and found that purified recombinant MCO1 oxidizes ferrous iron. An association between MCO1 function and iron homeostasis was confirmed by two observations: RNAi-mediated knockdown of MCO1 resulted in decreased iron accumulation in midguts and whole insects, and weak knockdown increased the longevity of flies fed a toxic concentration of iron. Strong knockdown of MCO1 resulted in pupal lethality, indicating that MCO1 is an essential gene. Immunohistochemistry experiments demonstrated that MCO1 is located on the basal surfaces of the digestive system and Malpighian tubules. We propose that MCO1 oxidizes ferrous iron in the hemolymph and that the resulting ferric iron is bound by transferrin or melanotransferrin, leading to iron storage, iron withholding from pathogens, regulation of oxidative stress, and/or epithelial maturation. These proposed functions are distinct from those of other known ferroxidases. Given that MCO1 orthologues are present in all insect genomes analyzed to date, this discovery is an important step toward understanding iron metabolism in insects.
Regulation of cellular iron metabolism
Iron is an essential but potentially hazardous biometal. Mammalian cells require sufficient amounts of iron to satisfy metabolic needs or to accomplish specialized functions. Iron is delivered to tissues by circulating transferrin, a transporter that captures iron released into the plasma mainly from intestinal enterocytes or reticuloendothelial macrophages. The binding of iron-laden transferrin to the cell-surface transferrin receptor 1 results in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of haem or iron–sulfur clusters, which are integral parts of several metalloproteins, and excess iron is stored and detoxified in cytosolic ferritin. Iron metabolism is controlled at different levels and by diverse mechanisms. The present review summarizes basic concepts of iron transport, use and storage and focuses on the IRE (iron-responsive element)/IRP (iron-regulatory protein) system, a well known post-transcriptional regulatory circuit that not only maintains iron homoeostasis in various cell types, but also contributes to systemic iron balance.
Proceedings of the National Academy of Sciences, 2010
The mitochondrion is well known for its key role in energy transduction. However, it is less well appreciated that it is also a focal point of iron metabolism. Iron is needed not only for heme and iron sulfur cluster (ISC)-containing proteins involved in electron transport and oxidative phosphorylation, but also for a wide variety of cytoplasmic and nuclear functions, including DNA synthesis. The mitochondrial pathways involved in the generation of both heme and ISCs have been characterized to some extent. However, little is known concerning the regulation of iron uptake by the mitochondrion and how this is coordinated with iron metabolism in the cytosol and other organelles (e.g., lysosomes). In this article, we discuss the burgeoning field of mitochondrial iron metabolism and trafficking that has recently been stimulated by the discovery of proteins involved in mitochondrial iron storage (mitochondrial ferritin) and transport (mitoferrin-1 and -2). In addition, recent work examining mitochondrial diseases (e.g., Friedreich's ataxia) has established that communication exists between iron metabolism in the mitochondrion and the cytosol. This finding has revealed the ability of the mitochondrion to modulate whole-cell ironprocessing to satisfy its own requirements for the crucial processes of heme and ISC synthesis. Knowledge of mitochondrial ironprocessing pathways and the interaction between organelles and the cytosol could revolutionize the investigation of iron metabolism.