Alternative titles; symbols
HGNC Approved Gene Symbol: ACO1
Cytogenetic location: 9p21.1 Genomic coordinates (GRCh38): 9:32,384,643-32,454,769 (from NCBI)
Soluble aconitase is a bifunctional protein with mutually exclusive functions as an iron-responsive element (IRE)-binding protein involved in the control of iron metabolism or as the cytoplasmic isoform of aconitase. Aconitases are iron-sulfur proteins that require a 4Fe-4S cluster for their enzymatic activity, in which they catalyze conversion of citrate to isocitrate (EC 4.2.1.3) (Eisenstein, 2000).
Rouault et al. (1990) used RNA affinity chromatography and 2-dimensional gel electrophoresis to isolate IREBP for protein sequencing. They used an oligonucleotide probe derived from the peptide sequence to isolate a cDNA encoding a protein of 87 kD. The corresponding mRNA of about 3.6 kb was found in a variety of cell types.
Aconitase-1 functions as a cytoplasmic IRE-binding protein (IREBP). IREs are translational regulatory sequences in the 5-prime UTR of ferritin (see 134790) mRNA and in the 3-prime UTR of transferrin receptor mRNA (190010). The cytoplasmic IREBP interacts with the IREs of these mRNAs. The iron status of the cell determines the ability of IREBP to bind to an IRE through reversible oxidation-reduction of sulfhydryl groups that are critical for the high-affinity RNA-protein interaction. Thus, IREBP plays a central role in cellular iron homeostasis by regulating ferritin mRNA translation and TFRC mRNA stability (Hentze et al., 1989).
Eisenstein (2000) reviewed of the role of the iron regulatory proteins, IRP1 and IRP2 (147582), and the molecular control of mammalian iron metabolism.
Meyron-Holtz et al. (2004) found that IRP2-null cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiologic tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiologic oxygen tensions.
Condo et al. (2010) demonstrated that the extramitochondrial form of frataxin (FXN; 606829) directly interacted with IRP1 through the 'iron-sulfur switch' mechanism. Cytosolic aconitase defect and consequent IRP1 activation occurring in Friedreich ataxia cells were reversed by the action of extramitochondrial frataxin.
Stehling et al. (2013) found that the CIA1 (CIAO1; 604333)-CIA2A (CIAO2A; 618382) cytosolic Fe/S assembly complex supported the specific maturation of IRP1 and stabilized IRP2, thereby linking the Fe/S assembly process to cellular iron regulation.
Crystal Structure
IRP1 binds IREs in mRNAs, to repress translation or degradation, or binds an iron-sulfur cluster, to become a cytosolic aconitase enzyme. Walden et al. (2006) determined the crystal structure of IRP1 bound to ferritin H (134770) IRE to 2.8-angstrom resolution. The IRP1:ferritin H IRE complex showed an open protein conformation compared with that of cytosolic aconitase. The extended, L-shaped IRP1 molecule embraced the IRE stem loop through interactions at 2 sites separated by about 30 angstroms, each involving about a dozen protein:RNA bonds. Walden et al. (2006) concluded that extensive conformational changes related to binding the IRE or an iron-sulfur cluster explain the alternate functions of IRP1 as an mRNA regulator or enzyme.
In studies of man-Chinese hamster somatic cell hybrids, Westerveld et al. (1975) showed that human gal-1-p uridyl transferase (GALT; 606999) and aconitase are syntenic.
Povey et al. (1976) assigned the ACO1 gene to chromosome 9. ACO1 and GALT are on chromosome 9p in man and on chromosome 4 in the mouse (Nadeau and Eicher, 1982). The location in the mouse was predicted from the human linkage. The smallest region of overlap for ACO1 was estimated to be 9p22-p13 (Robson and Meera Khan, 1982).
Because of the possibility that idiopathic hemochromatosis, which is the result of a mutant gene that maps to 6p21, is due to mutation in IREBP, Hentze et al. (1989) attempted to map the IREBP gene. Since the gene had not been cloned, and since they did not have specific antibodies for the protein, they mapped the gene in human/rodent hybrid cells by taking advantage of the different mobilities of the human and rodent IRE/IREBP complexes on nondenaturing polyacrylamide gels. Using a panel of 34 different hybrid cell lines, they assigned the IREBP gene to human chromosome 9. Southern hybridization analysis of rodent-human somatic hybrid cell lines by Rouault et al. (1990) corroborated the assignment of IREBP to chromosome 9. A high frequency RFLP was also identified.
By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Irebp gene to mouse chromosome 4.
Schmitt and Ritter (1974) found electrophoretic variants of the soluble form of aconitate hydratase in human placenta. No mitochondrial variants were found.
Slaughter et al. (1975) reported an electrophoretic survey that demonstrated 7 alleles at the ACONS locus. Among the populations studied, Nigerians showed polymorphism for ACONS.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Aconitase-1 and aconitase-2 (ACO2; 100850) are isozymes present in the cytosol and mitochondria, respectively. Other pairs of cytosolic and mitochondrial isozymes are ALDH1 (100640) and ALDH2 (100650), GOT1 (138180) and GOT2 (138150), IDH1 (147700) and IDH2 (147650), MDH1 (154200) and MDH2 (154100), SOD1 (147450) and SOD2 (147460), and TK1 (188300) and TK2 (188250). In all these cases, the 2 isozymes of different subcellular localization, although similar in structure and function, are encoded by genes on different chromosomes, i.e., are nonsyntenic. The presumption is that in each case both originated from a common ancestral gene in a primordial genome, but that whereas the cytosolic isozyme is encoded by a gene that is a direct descendant from a nuclear progenitor gene, the mitochondrial isozyme, although now encoded by a nuclear gene, is descended from a gene in the bacterium-like progenitor of the mitochondrion. When this primitive organism took up intracellular existence, most of its genes were transferred to the nuclear genome and since they inserted more or less at random into the nuclear genome, it was to be expected that the cytosolic and mitochondrial forms of the enzyme would end up being encoded by genes on different chromosomes. That mitochondrial DNA can be inserted into the nuclear genome is indicated by work such as that of Shay and Werbin (1992) who characterized in detail 2 instances of mitochondrial DNA fragments that had been inserted into the nucleus of HeLa cells. In one of these cases, the mitochondrial sequence encoding cytochrome c oxidase subunit III was contiguous with and 5-prime of exons 2 and 3 of the MYC oncogene (190080) and the chimeric gene was transcribed. Shay and Werbin (1992) discussed possible mechanisms for the transfer of mitochondrial DNA into the nucleus.
Ghosh et al. (2013) found that Irp1 -/- mice fed a low-iron diet died early of abdominal hemorrhages. Irp1 -/- mice developed polycythemia with enhanced extramedullary hematopoiesis, high serum Epo (133170), and elevated renal Hif2-alpha (EPAS1; 603349) expression. Irp1 -/- mice also developed pulmonary hypertension associated with high expression of Hif2-alpha in pulmonary endothelial cells and transcriptional activation of endothelin-1 (EDN1; 131240).
Independently, Anderson et al. (2013) found that Irp1 -/- mice developed polycythemia and extramedullary erythropoiesis with enhanced serum Epo and erythroid gene expression in spleen. Polycythemia in Irp1 -/- mice was linked to increased Hif2-alpha activity in duodenum, leading to increased transcription of the iron transport genes Dcytb (CYBRD1; 605745), Dmt1 (SLC11A2; 600523), and ferroportin (SLC40A1; 604653), as well as other Hif2-alpha target genes, in duodenum. Transcription of Hif2-alpha was substantially derepressed in Irp1 -/- kidney, leading to increased renal Epo and inappropriately elevated serum Epo levels.
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