Cellular and mitochondrial iron homeostasis in vertebrates

Abstract

Iron plays an essential role in cellular metabolism and biological processes. However, due to its intrinsic redox activity, free iron is a potentially toxic molecule in cellular biochemistry. Thus, organisms have developed sophisticated ways to import, sequester, and utilize iron. The transferrin cycle is a well-studied iron uptake pathway that is important for most vertebrate cells. Circulating iron can also be imported into cells by mechanisms that are independent of transferrin. Once imported into erythroid cells, iron is predominantly consumed by the mitochondria for the biosynthesis of heme and iron sulfur clusters. This review focuses on canonical transferrin-mediated and the newly discovered, non-transferrin mediated iron uptake pathways, as well as, mitochondrial iron homeostasis in higher eukaryotes. This article is part of a Special Issue entitled: Cell Biology of Metals.

Fig. 1

Iron uptake through transferrin cycle. Diferric Tf binds TfR on the plasma membrane. The Tf-TfR complex is internalized through clathrin-dependent endocytosis. Acidification of endosomes by proton-ATPase lowers the affinity of Tf to ferric iron, which is subsequently released into the lumen. The released ferric iron is reduced by Steaps and exported out of endosomes by divalent metal transporter DMT1. The transient receptor potential mucolipin TRPML1 and the zinc transporter ZRT/IRT-like protein Zip14 may also be involved in endosomal iron release. Within acidic environment, apotransferrin remains bound to TfR. The complex is recycled to the cell surface, where Tf dissociates from TfR. The trafficking molecule Sec15L1 is required for the efficient recycling of Tf-TfR. Details of the basic trafficking machinery such as clathrin, adaptor, and Rab proteins are not shown in the Figure.

Fig. 2

Mitochondrial iron import. The iron imported through Tf-TfR cycle can be readily utilized by mitochondria. Cytosolic ferritin may also provide iron for mitochondria. Tf iron is released into endosomes, whereas ferritin is degraded in either proteasomes or lysosomes. Iron is delivered to mitochondrial outer membrane through unknown mechanisms. Mitoferrin (Mfrn) imports iron into the mitochondria, where iron is either utilized for the synthesis of heme and Fe-S clusters, or stored in mitochondrial ferritin (MtF). Fe-S clusters may regulate erythroid heme synthesis through modulating the activity of iron regulatory protein 1 and the expression of δ-aminolevulinate synthase 2.