Molecular coordination of iron homeostasis by microRNA

Abstract

Iron is an essential nutrient critical for oxygen transport, DNA synthesis, ATP generation, and cellular proliferation. At the molecular level, insufficient iron elicits a cascade of cellular events aimed at conserving iron for the maintenance of these life-preserving functions, but tissue-specific responses and metabolic adaptations to iron deficiency (ID) are not fully understood. Recently, small regulatory RNA molecules called microRNA (or miRNA) have been identified as an important mechanism for regulating various cellular processes. Therefore we sought to determine if the expression pattern of miRNA changes in response to dietary ID and to examine the potential regulatory capacity of miRNA in the adaptive response to ID. To do this, we first characterized the expression of miRNA in the livers of iron-sufficient and iron-deficient animals using next-generation sequencing technology. Results compiled from three different bioinformatics approaches indicate that ~10 miRNA are differentially expressed in the livers of ID rats. Further bioinformatics analyses suggested that at least two of these miRNA, miR-210 and miR-181d, had predicted targets directly involved in either the maintenance of iron homeostasis or the metabolic adaptation to iron deficiency. We then used reporter assays to validate the putative miRNA targets including the miR-210 target, cytoglobin, and the miR-181d targets, carnitine palmitoyltransferase 1B and mitoferrin 1. These findings have provided insight into the metabolic adaptation to ID and have demonstrated how miRNA contribute to the molecular coordination of iron homeostasis in a physiologic model of dietary ID.