Differential translational control of 5′ IRE-containing mRNA in response to dietary iron deficiency and acute iron overload†

Iron regulatory proteins (IRPs) are iron-responsive RNA binding proteins that dictate changes in cellular iron metabolism in animal cells by controlling the fate of mRNAs containing iron responsive elements (IREs). IRPs have broader physiological roles as some targeted mRNAs encode proteins with functions beyond iron metabolism suggesting hierarchical regulation of IRP-targeted mRNAs. We observe that the translational regulation of IRP-targeted mRNAs encoding iron storage (L- and H-ferritins) and export (ferroportin) proteins have different set-points of iron responsiveness compared to that for the TCA cycle enzyme mitochondrial aconitase. The ferritins and ferroportin mRNA were largely translationally repressed in the liver of rats fed a normal diet whereas mitochondrial aconitase mRNA is primarily polysome bound. Consequently, acute iron overload increases polysome association of H- and L-ferritin and ferroportin mRNAs while mitochondrial aconitase mRNA showed little stimulation. Conversely, mitochondrial aconitase mRNA is most responsive in iron deficiency. These differences in regulation were associated with a faster off-rate of IRP1 for the IRE of mitochondrial aconitase in comparison to that of L-ferritin. Thus, hierarchical control of mRNA translation by IRPs involves selective control of cellular functions acting at different states of cellular iron status and that are critical for adaptations to iron deficiency or prevention of iron toxicity.