Iron is a crucial regulator of cell function, but its role in human macrophage immunometabolism is only partially understood. More recently discovered was the significant amino acid sequence identity between mitochondrial aconitase and the iron regulatory factor or iron responsive element binding protein irebp. One major regulatory mechanism of cellular iron metabolism involves two. Ferritin, ealas, sdhb of drosophila, and mammalian mitochondrial aconitase are translationally regulated. Crystal structure of human iron regulatory protein 1 as cytosolic. Iron alters glutamate secretion by regulating cytosolic. Recent years have witnessed a renewed interest in this strategy because of availability of. Iron deficiency decreases mitochondrial aconitase abundance and.
There are two isoenzymes of aconitase aco mitochondrial maco and cytosolic caco ones. In typical mammalian cell metabolism, maconitase is not a regulatory, ratelimiting enzyme. Iron depletion promotes cluster disassembly, conversion of c aconitase to irebp, and repression of ferritin, m aconitase, and ealas synthesis, while stimulating tfr expression. Iron metabolism is controlled at different levels and by diverse. Acute iron deprivation reprograms human macrophage metabolism. It functions also as the cytoplasmic isoform of aconitase. Sfxn4 knockdown reduces the stability and activity of cellular fes proteins, affects iron metabolism by influencing the cytosolic aconitase irp1 switch, redistributes iron from the cytosol to. Aconitase contains a nonredox 4fe4s prosthetic group in which one of the iron ions, fe. The sequences bound include the rabbit ferritin ire and irelike sequences in the b. The iron cluster itself is coordinated by several cystine residues, without which the efficacy of the enzyme drops tenfold.
Iron regulatory proteins irps4 and the proteins whose synthesis they regulate form a homeostatic network that allows mammals to make use of the essential properties of iron while reducing its potentially toxic effects. Consequently, the steadystate citrateisocitrate ratio of most cells is generally maintained at about 111, which is established by the aconitase equilibrium reaction, 88 citrate 4 cisaconitate 8 isocitrate. Iron metabolism williams hematology, 9e accessmedicine. Aconitase is an iron sulfur protein that is involved in the first step of the tricarboxylic acid tca cycle, and oxidative inactivation of its iron sulfur cluster by superoxide leads to iron toxicity and peroxide production. Iron deficiency decreases mitochondrial aconitase abundance. Aconitase is an essential enzyme in the citric acid cycle and iron regulatory protein 1 interacts with messenger rna to control the levels of iron inside cells. To gain insight into the regulation of intracellular iron homeostasis in adipose tissue, we investigated the role of iron regulatory protein 1cytosolic aconitase 1 aco1.
Moreover, disruption of the yfh1 gene resulted in multiple fe. Aconitase and mitochondrial ironsulphur protein deficiency. Because little iron is lost from the body under normal circumstances, the iron content of the body is controlled by modulating dietary iron absorption. This reorganized form of c aconitase is called iron regulatory protein 1 irp1, and has a completely different functional role than c aconitase. Regulation of cellular iron metabolism portland press. The iron cluster itself is coordinated by several cystine residues, without which the. Pdf sulfolobus aconitase, a regulator of iron metabolism. Mitochondrial and cytosolic aconitases catalyze the interconversion of citrate and isocitrate, and aconitase activities are affected by iron levels, oxidative stress and by the status of the fe. Enzyme activities and iron metabolism in copper and iron deficiencies.
Homeostatic regulation of mammalian iron metabolism. Pdf the aconitase of sulfolobus solfataricus, a hyperthermophilic crenarchaeon, was cloned and heterologously expressed in escherichia coli. Oxidation of aconitase by rosrns results in loss of labile iron, inactivating the enzyme and switching the function to regulation of iron metabolism as iron regulatory protein 1 irp1. This has led to the realization that irebp is an alternative form of cytosolic not of mitochondrial aconitase that is devoid of its cubane fes cluster.
In the present study, iron increased caconitase activity, and this increase was associated with an increase in glutamate secretion. Cytosolic aconitase activity sustains adipogenic capacity of adipose. Argonne cancer research hospital, operated by the university of chicago for the united states atomic energy commission, and the department of medicine, the university of chicago, chicago, ill. Iron is essential for oxidationreducinvolved in energy metabolism mitochondrial aconitase. Iron absorption increases in the presence of iron deficiency and it decreases when there is iron overload. Aconitases are ironsulfur proteins which catalyze the reversible isomerization of citrate and isocitrate via cisaconitate.
Aco1 gene expression and activity increased in parallel to expression of. Selective inhibition of the citratetoisocitrate reaction of. Iron is an essential metal that finetunes the innate immune response by regulating macrophage function, but an integrative view of transcriptional and metabolic responses to iron perturbation in macrophages is lacking. Metabolic regulation of citrate and iron by aconitases. Diseases that are directly or indirectly related to iron metabolism represent major health problems.
Roles of aconitase in growth, metabolism, and morphological. However, the iron sulfur cluster cannot assemble under iron starved conditions, in which case the cytosolic enzyme undergoes a dramatic conformational change. Iron metabolism is regulated in cells to ensure that iron supplies are adequate and nontoxic. It is also a transition metal that can readily donate and accept electrons to participate in oxidationreduction reactions that are essential for a number of fundamental. Crystal structure of human iron regulatory protein 1 as cytosolic aconitase. Assembly and disassembly of fes clusters is a key process not only in regulating the enzymatic activity of mitochondrial aconitase in the citric acid cycle, but also. In contrast with the majority of iron sulfur proteins that function as electron carriers, the iron sulfur cluster of aconitase reacts directly with an enzyme substrate. Pdf cytosolic aconitase activity sustains adipogenic. Sulfolobus aconitase, a regulator of iron metabolism. Bacillus subtilis aconitase is an rnabinding protein pnas. Three cysteine cys residues have been shown to be ligands of the fe 4 s 4.
Understanding why the cell coregulates cytosolic citrate metabolism with iron metabolism will require reexamination of the consequences of changes in caco activity. Here, we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses. Aconitase and mitochondrial fes protein deficiency in friedreich ataxia. The conversion of citrate to isocitrate by caconitase is the. Iron regulatory proteins, iron responsive elements and iron. The expression of iron metabolism is regulated primarily by posttranscriptional mechanisms. Pdf aconitase and mitochondrial fes protein deficiency. The aconitase function of iron regulatory protein 1. Journal of biological chemistry 1999, 274 31, 2162521630. Ironregulatory protein 1 irp1 is a dualfunction protein with mutually exclusive roles as a posttranscriptional regulator of animalcell iron metabolism or as the cytosolic isoform of the iron sulfur enzyme aconitase cacon. While in mitochondria aconitase is part of the citric acid cycle, in the cytosol aconitase is a transregulatory factor that controls iron homeostasis at a posttranscriptional level. Mitochondrial aconitase macon is the tricarboxylic acid tca cycle enzyme that converts citrate to isocitrate. Aconitase couples metabolic regulation to mitochondrial dna.
Dec 23, 2019 sfxn4 knockdown reduces the stability and activity of cellular fes proteins, affects iron metabolism by influencing the cytosolic aconitaseirp1 switch, redistributes iron from the cytosol to. Alper sarikaya, aconitase 3 the cluster will relax to three iron ions if there is an iron deficiency6,7. Irondependent turnover of irp1caconitase in kidney cells. Iron is essential for oxidationreduc involved in energy metabolism mitochondrial aconitase tion catalysis and bioenergetics, but.
The bifunctional iron regulatory protein irp1 potentially regulates iron trafficking and participates in citrate metabolism as a cytosolic c aconitase. Aco1, or irp1, is a bifunctional protein that functions as an iron responsive element irebinding protein involved in the control of iron metabolism by binding mrna to repress translation or degradation. Aconitases are iron sulfur proteins that require a 4fe4s cluster for their. Ire binding activity was affected by the availability of iron both. In contrast to irp1, irp2 has only the ire binding activity and is regulated by iron through protein degradation via the proteasome pathway 1, 1416. The kidney plays an important role in iron homeostasis and actively reabsorbs citrate. Sideroflexin 4 affects fes cluster biogenesis, iron.
Iron and citrate are essential for the metabolism of most organisms, and regulation of iron and citrate biology at both the cellular and systemic levels is critical for normal physiology and survival. Aconitase, an iron sulphur protein involved in iron homeostasis, was found to be deficient as well. Human cytoplasmic aconitase iron regulatory protein 1 is converted into its 3fe4s form by hydrogen peroxide in vitro but is not activated for iron responsive element binding. The aconitase protein of bacillus subtilis was able to bind specifically to sequences resembling the iron response elements ires found in eukaryotic mrnas. Aconitase, an ironsulphur protein involved in iron homeostasis, was found to be deficient as well. Jun 16, 2008 friedreich ataxia is a neurological disease originating from an iron sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected. Review article aconitase posttranslational modification.
Pdf aconitase and mitochondrial fes protein deficiency in. Aconitase and mitochondrial fes protein deficiency in friedreich ataxia article pdf available in nature genetics 172. Aconitase, an enzyme possessing an iron sulfur cluster that is sensitive to oxidation, is involved in the. Acna and acnb in escherichia coli, citb 1, the only aconitase of bacillus subtilis, and bifunctional eukaryotic aconitases iron regulatory proteins 33 contain an iron sulfur center that senses low iron concentrations and oxidative stress. Article pdf available in biochemical society transactions 304. Review article aconitase posttranslational modification as a. They were discovered and studied by different researchers, who gave them names that described their two very different functions. The integrity of this iron sulfur center is essential for aconitase enzymatic activity. Iron metabolism cellular iron metabolism prem ponka lady davis institute for medical research, jewish general hospital and departments of physiology and medicine, mcgill university, montreal, quebec, canada cellular iron metabolism. Iron deficiency decreases mitochondrial aconitase abundance and citrate concentration without affecting tricarboxylic acid cycle capacity. As a mean to counteract disease progression, it has been suggested to chelate free mitochondrial iron.
Conservation of aconitase residues revealed by multiple sequence analysis. The tfr is regulated at the level of mrna stability. Pdf metabolic regulation of citrate and iron by aconitases. Iron is stored within cells inside ferritin and circulates in plasma bound to transferrin. Iron is required for key cellular functions, and there is a strong link between iron metabolism and important metabolic processes, such as cell growth, apoptosis and inflammation. Aconitase contains an iron sulfur center 4fe4s in which 3 of the 4 mol of iron are coordinated with three cysteines, cys 382, cys 445, and cys 448. Much effort has focused on the role of irp1 in posttranscriptional gene regulation and in factors. Two aconitase isozymes are present in mammalian cells.
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