Animal Models of Normal and Disturbed Iron and Copper Metabolism

Abstract

Research on the interplay between iron and copper metabolism in humans began to flourish in the mid-20th century, and diseases associated with dysregulated homeostasis of these essential trace minerals are common even today. Iron deficiency is the most frequent cause of anemia worldwide, leading to significant morbidity, particularly in developing countries. Iron overload is also quite common, usually being the result of genetic mutations which lead to inappropriate expression of the iron-regulatory hormone hepcidin. Perturbations of copper homeostasis in humans have also been described, including rare genetic conditions which lead to severe copper deficiency (Menkes disease) or copper overload (Wilson disease). Historically, the common laboratory rat (Rattus norvegicus) was the most frequently utilized species to model human physiology and pathophysiology. Recently, however, the development of genetic-engineering technology combined with the worldwide availability of numerous genetically homogenous (i.e., inbred) mouse strains shifted most research on iron and copper metabolism to laboratory mice. This created new opportunities to understand the function of individual genes in the context of a living animal, but thoughtful consideration of whether mice are the most appropriate models of human pathophysiology was not necessarily involved. Given this background, this review is intended to provide a guide for future research on iron- and copper-related disorders in humans. Generation of complementary experimental models in rats, swine, and other mammals is now facile given the advent of newer genetic technologies, thus providing the opportunity to accelerate the identification of pathogenic mechanisms and expedite the development of new treatments to mitigate these important human disorders.

Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications

“…Newly recognized mitochondrial (including renal mitochondria) acquisition of iron via OMM DMT1 needs to be set the broader context of systemic and cellular iron homeostasis ( Hentze et al, 2010 ; Garrick, 2016 ; Wang et al, 2019 ; Yanatori and Kishi, 2019 ). Systemic iron metabolism in humans begins with uptake of iron from the diet in the duodenal lumen where it presents as Fe 3+ ( Figure 3 , left).…”

“…di-ferric Tf binding to TfR1, apo-Tf released by it, endocytosis -making an endosome to go through the Tf-cycle (see text), an endosomal reductase, an ATPase, DMT1, cytosolic ferritin, mitochondrial components, and metabolism including Mfrn1 = erythroid mitoferrin, FXN – frataxin, ETC and Fe-S plus Heme synthesis and hemoglobin formation. Adapted and redrawn from Wang et al (2019) with permission from Oxford University Press on behalf of the American Society for Nutrition.…”

“…With no regulated means for iron depletion, excellent renal recovery (see below) and competent recycling, the onus is on the duodenum (and recovery systems) to prevent systemic iron overload and to withhold iron during inflammation. How hepcidin, a master regulatory peptide, accomplishes these goals is well covered in reviews ( Hentze et al, 2010 ; Wang et al, 2019 ; Camaschella et al, 2020 ).…”

Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

“…Our second model, hepcidin KO mice, a genetic model of iron overload, is representative of iron overload caused by hepcidin deficiency in human hemochromatosis. Other differences between murine and human iron homeostasis include proportionally greater dietary iron absorption as well as iron losses in mice than in humans, but also greater resistance of mice to iron-induced tissue toxicity 54 . In our study, both genetic and dietary maternal iron loading resulted in higher placental iron and embryo iron stores.…”

Antianemic action of the iron (IV) clathrochelate complexes

“…Although anemia is a symptomatic complex which accompanies many pathological processes in the young, it is necessary to allocate precisely nutritional anemia (Bonkovsky & Herbert, 1991;Camaschella, 2013;Knight & Dilger, 2018), which causes significant economic losses on farms. This is a clinical hematological syndrome, which is as result of the shortage of iron, cuprum, cobalt, zinc, vitamins C and B 12 , which are essential for sustaining their organism (Walter et al, 1997;Svoboda et al, 2008;Wang et al, 2019). In conclusion it causes violations of the synthesis of hemoglobin and a decrease in the number of erythrocytes (Ganz, 2013;Leyshon et al, 2016;Shero et al, 2019).…”