Zebrafish in the sea of mineral (iron, zinc, and copper) metabolism

Abstract

Iron, copper, zinc, and eight other minerals are classified as essential trace elements because they present in minute in vivo quantities and are essential for life. Because either excess or insufficient levels of trace elements can be detrimental to life (causing human diseases such as iron-deficiency anemia, hemochromatosis, Menkes syndrome and Wilson's disease), the endogenous levels of trace minerals must be tightly regulated. Many studies have demonstrated the existence of systems that maintain trace element homeostasis, and these systems are highly conserved in multiple species ranging from yeast to mice. As a model for studying trace mineral metabolism, the zebrafish is indispensable to researchers. Several large-scale mutagenesis screens have been performed in zebrafish, and these screens led to the identification of a series of metal transporters and the generation of several mutagenesis lines, providing an in-depth functional analysis at the system level. Moreover, because of their developmental advantages, zebrafish have also been used in mineral metabolism-related chemical screens and toxicology studies. Here, we systematically review the major findings of trace element homeostasis studies using the zebrafish model, with a focus on iron, zinc, copper, selenium, manganese, and iodine. We also provide a homology analysis of trace mineral transporters in fish, mice and humans. Finally, we discuss the evidence that zebrafish is an ideal experimental tool for uncovering novel mechanisms of trace mineral metabolism and for improving approaches to treat mineral imbalance-related diseases.

Keywords: copper; iron; metabolism; minerals; trace elements; zebrafish; zinc.

Figure 1

Generalized overview of iron metabolism in vertebrate cells. Dietary iron is absorbed by enterocytes through the concerted activity of the reductase DCYTB and the transporter DMT1. Iron is then oxidized by HEPH and exits the enterocytes through the iron exporter FPN1. Iron is transferred as a complex with Transferrin (TF) in the bloodstream and is delivered to target cells that express Transferrin receptors (TFRs) on their plasma membrane. TF-Iron-TFR complexes are then endocytosed. In the endosome, iron is released from TF by STEAP3 and then transported out of the endosome through DMT1. The cytoplasmic iron then enters the labile iron pool and is delivered by MFRN and siderophores to the mitochondria to be used for the synthesis of heme and Fe-S clusters. Excess iron is stored in Ferritin. Iron leaves the cell through FPN1, the plasma expression of which is negatively regulated by Hepcidin. Proteins for which zebrafish knockout and/or knockdown models are available are written in red.

Figure 2

Generalized overview of zinc metabolism in vertebrate cells. Zinc Transporters (ZnTs) downregulate intracellular zinc levels by exporting zinc through the plasma membrane (ZnT1, ZnT2, and ZnT4) or by transporting zinc into various intracellular compartments, including lysosomes (ZnT2), the Golgi apparatus (ZnT5-7), mammary gland vesicles (ZnT2 and ZnT4), insulin granules (ZnT8), and synaptic vesicles (ZnT3). In addition, ZnT9 can translocate to the nucleus, where it regulates target gene transcription. Zrt- and Irt-like proteins (ZIPs) upregulate cytoplasmic zinc levels by importing extracellular zinc (ZIP1–6, ZIP8, ZIP10, and ZIP14) and release zinc from intracellular vesicles (ZIP1 and ZIP13), lysosomes (ZIP3 and ZIP8), the Golgi apparatus (ZIP7, ZIP9, and ZIP13) and the nucleus (ZIP7). Proteins for which zebrafish knockout/knockdown models are available are written in red.

Figure 3

Generalized overview of copper metabolism in vertebrate cells. Extracellular copper enters the cell through the high-affinity CTR1 receptor. The CTR2 receptor primarily mediates the release of copper from intracellular vesicles, but is also expressed in low levels in the plasma membrane. Intracellular copper is bound by a variety of copper chaperones and transported to various proteins in the following intracellular sites: COX17 delivers copper to CCO in the mitochondria; CCS delivers copper to cytosolic SOD1; and ATOX1 delivers copper to copper-ATPases in the Golgi apparatus. Copper is secreted from the basolateral and apical sides via ATP7A-mediatedand ATP7B-mediated exocytosis, respectively. Proteins for which zebrafish knockout/knockdown models are available are written in red.