Regulation of iron homeostasis by microRNAs

Abstract

Iron homeostasis is maintained at the cellular and systemic levels to assure adequate iron supply while preventing iron overload. The identification of genes mutated in patients with iron-related disorders or animal models with imbalances of iron homeostasis gave insight into the molecular mechanisms underlying processes critical for balancing iron levels, such as iron uptake, storage, export, and monitoring of available iron. MicroRNAs control genes involved in some of these processes adding an additional level of complexity to the regulation of iron metabolism. This review summarizes recent advances how miRNAs regulate iron homeostasis.

Fig. 1

microRNA-mediated control of cellular iron metabolism. A The ubiquitously expressed transferrin receptor-1 (TfR1) controls cellular uptake of iron-bound transferrin (Tf, iron indicated by red dots). B The Tf-iron-TfR1 complex is taken up into the cell via endocytosis and the iron is released from the endosome by the nonIRE isoform of Divalent Metal Transporter 1 (DMT1). C In the cytoplasm iron is incorporated within the cellular labile iron pool (LIP), is stored and detoxified by ferritin or D is utilized by mitochondria for heme synthesis and Fe–S cluster biogenesis. E Heme is critical for the processing of miRNA primary transcripts (pri-miRNAs) and binds to the microprocessor complex composed of DGCR8 and DROSHA. F miRNA precursors (pre-miRNA) are exported to the cytoplasm where they are processed to form single stranded miRNAs that are bound by the RISC. The miRISC will target MREs within the 3′ UTR of genes to repress their translation or to trigger mRNA degradation. Several miRNAs control genes involved in maintaining cellular iron homeostasis, whereby miR-320 post-transcriptionally controls TfR1 expression, Let-7d targets the DMT1-nonIRE isoform, and miR-200b regulates the expression of ferritin

Fig. 2

Systemic iron homeostasis is controlled by miR-122. A Levels of iron-bound transferrin (Tf) are monitored by Transferrin Receptor 1 (TfR1) and proteins mutated in different subtypes of hereditary hemochromatosis, the MHC class I-like protein HFE, Transferrin Receptor 2 (TfR2) and the co-receptor for bone morphogenetic proteins (BMPs), Hemojuvelin (HJV). B, C High levels of iron-bound transferrin and BMP6 activate BMP/SMAD signaling and stimulate Hepcidin transcription. D Increased systemic Hepcidin levels inhibit iron release from macrophages and duodenal enterocytes, which will (E) decrease the amount of iron-bound transferrin. F Likewise, HFE and HJV are required to activate the expression of miR-122, while miR-122 specifically represses the HFE and HJV mRNA. Experimental depletion of miR-122 increases HFE and HJV expression, which stimulates hepcidin transcription and triggers systemic iron deficiency. The proposed feedback mechanism will fine tune Hepcidin expression to satisfy systemic iron demands