Post-Transcriptional Regulation of Iron Metabolism

Regulation of iron metabolism is a fundamental process with profound medical implications. Cell growth and erythropoiesis are most critically affected by iron deficiency, while iron overload predominantly causes hepatic and degenerative disease. The underlying molecular control mechanisms are becoming increasingly well understood. Cellular iron uptake via the transferrin receptor and intracellular storage within a molecule consisting of 24 ferritin H- and L subunits is posttranscriptionally regulated through iron-responsive elements (IREs) contained in the untranslated regions of the respective mRNAs. IREs are also found in the messages encoding a rate-limiting enzyme for erythroid heme synthesis, 5-aminolevulinate synthase (eALAS), as well as mitochondrial aconitase, a Krebs’ cycle enzyme of critical importance for cellular metabolic activity. These IRE-containing mRNAs are regulated by binding of a cytoplasmic protein, iron regulatory protein (IRP-1). IRP-1 binding reduces the translation rates of ferritin, eALAS and aconitase mRNAs and indirectly increases the synthesis of transferrin receptors by stabilising the mRNA against degradation. IRP-1 binding to IREs is regulated by multiple cellular signals: first by cellular iron levels, second by nitric oxide (NO), and third by oxidative stress (in the form of hydrogen peroxide, H2O2). Iron deficiency, NO and H2O2 independently activate IRE binding by inducing the posttranslational conversion of 4Fe-4S IRP-1 to, apparently, apoIRP-1.