Identification of a conserved and functional iron-responsive element in the 5'-untranslated region of mammalian mitochondrial aconitase

Iron responsive elements (IREs) are RNA stem-loop motifs found in genes of iron metabolism. When cells are iron depleted, iron regulatory proteins (IRPs) bind to IREs in the transcripts of ferritin, transferrin receptor, and erythroid amino-levulinic acid synthetase. Binding of IRPs to IRE motifs near the 5' end of the transcript results in attenuation of translation while binding to IREs in the 3'-untranslated region of the transferrin receptor results in protection from endonucleolytic cleavage. Iron deprivation results in activation of IRE binding activity, whereas iron replete cells lose IRE binding activation. Here, we report the identification of a conserved IRE in the 5'-untranslated region of the transcript of the citric acid cycle enzyme mitochondrial aconitase from four different mammalian species. The IRE in the transcript of mitochondrial aconitase can mediate in vitro translational repression of mitochondrial aconitase by IRPs. Furthermore, levels of mitochondrial aconitase are decreased in mice maintained on a low iron diet, whereas levels of mRNA remain unchanged. The decrease in levels of mitochondrial aconitase is likely due to activation of IRP binding and consequent attenuation of translation. Thus, expression of the iron-sulfur protein mitochondrial aconitase and function of the citric acid cycle may be regulated by iron levels in cells.