Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins

Abstract

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack expression of one or both Irps, and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1−/−Irp2−/−) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1−/− mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2−/− mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1−/− mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1−/− mice, and will discuss the phenotypes observed for Irp2−/− mice in detail with a particular emphasis on the neurological problems of these mice.

Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts

“…S11A and S12B). Hif2α stabilization seems more complex because it can be regulated both by iron, similar to Hif1α, and directly by Irps (15,25), probably mainly by Irp1 (14). Interestingly, the Irp1 levels were reduced in Irp2 −/− cells ( Fig.…”

Mitochondrial iron overload: causes and consequences

“…In the cytosolic compartment of cells, it is well known that cytosolic iron levels are highly regulated by iron regulatory proteins (IRP1 and IRP2) (reviewed in [16]. These proteins sense cytosolic iron levels and bind to mRNA transcripts of important iron metabolism proteins, including ferritin, an iron storage heteropolymer, and transferrin receptor 1 (TFRC), an important iron uptake protein.…”

Iron, Aging, and Neurodegeneration

“…NBIA diseases also include neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration, and a number of inherited diseases [43,47,48]. The incidence of NBIA disease continues to increase and clearly shows the importance of understanding iron metabolism and its potential link to neuronal loss.…”