Control of Systemic Iron Homeostasis by the 3’ Iron‐Responsive Element of Divalent Metal Transporter 1 in Mice

Tybl, Elisabeth; Gunshin, Hiromi; Gupta, Sanjay; Barrientos, Tomasa; Bonadonna, Michael; Nos, Ferran Celma; Palais, Gaël; Karim, Zoubida; Sánchez, Mayka; Andrews, Nancy C.; Galy, Bruno

doi:10.1097/hs9.0000000000000459

Cited by 13 publications

(14 citation statements)

References 15 publications

(41 reference statements)

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“…SLC11A2 in the Caco-2 cultured cell line), and genes with IRE-like elements deviating from the canonical IRE sequence. Interestingly, Tybl et al [82] found that the 3' IRE in SLC11A2 (DMT1) appears to influence transcript abundance in a developmentspecific manner in mice, by promoting transcript expression during postnatal growth and suppressing expression in adulthood. Together with our findings, this demonstrates that the regulation of IRE genes is more complex than commonly appreciated.…”

Section: Discussionmentioning

confidence: 99%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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Background: Iron trafficking and accumulation has been associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3' IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3' IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

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Section: Discussionmentioning

confidence: 99%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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“…Under conditions of iron deficiency, the IRE in the target mRNA can be recognized and bound by IRPs, but the consequence of IRP binding depends on the position of the IRE on the mRNA of the target genes. If the IRE is in the 5untranslated region (UTR) of the target mRNA, the binding of IRPs may inhibit the translation of the genes, including L-and H-ferritin and FPN1; if the IRE is in the 3 -UTR, the binding of IRPs may stabilize the mRNA, such as that of transferrin receptor 1 (TfR1) (Casey et al, 1988;Müllner et al, 1989) and divalent metal transporter 1 (DMT1) (Tybl et al, 2020). When cellular iron is sufficient, IRP1 binds to a (4Fe-4S) cluster and, therefore, gains aconitase activity and loses the ability to bind IRE, whereas IRP2 is removed by iron and oxygen-mediated proteasome degradation (Salahudeen et al, 2009;Vashisht et al, 2009) to avoid the excessive iron uptake and to promptly store excess intracellular iron and/or export excess iron.…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2

Shen

et al. 2021

Front. Neurosci.

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Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression; inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction; and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated in vivo and play a similar role in neurological disorder of Irp2–/– mice. In this study, we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2–/– mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) was reversed. Our results indicate that Irp2 depletion-induced Hif2α is, in vivo, in charge of the switch between OXPHOS and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.

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“…Since DMT1 activity is dependent to acidic pH, we assume that an increase in iron intake due to increase DMT1 activity by diet-induced acid load must be retro-controlled by the local IRE/IRP system. Indeed, iron regulatory protein IRP1 appears to be active in the intestinal compartment [36] and the 3 -UTR region of DMT1-mRNA contains at least one IRE element, which was recently shown to be active [37,38]. The IRE/IRP system also acts on the expression of the FPN by blunting its translation after binding to the 5 -UTR-IRE of the mRNA [37].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Acidosis and Iron Metabolism: Data from In Vivo Studies

et al. 2022

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Iron absorption requires an acidic environment that is generated by the activity of the proton pump gastric H(+)/K(+)ATPase (ATP4), expressed in gastric parietal cells. However, hepcidin, the iron regulatory peptide that inhibits iron absorption, unexpectedly upregulates ATP4 and increases gastric acidity. Thus, a concept of link between acidosis and alterations in iron metabolism, needs to be explored. We investigated this aspect in-vivo using experimental models of NH4Cl-induced acidosis and of an iron-rich diet. Under acidosis, gastric ATP4 was augmented. Serum hepcidin was induced and its mRNA level was increased in the liver but not in the stomach, a tissue where hepcidin is also expressed. mRNA and protein levels of intestinal DMT1(Divalent Metal Transporter 1) and ferroportin were downregulated. Serum iron level and transferrin saturation remained unchanged, but serum ferritin was significantly increased. Under iron-rich diet, the protein expression of ATP4A was increased and serum, hepatic and gastric hepcidin were all induced. Taken together, these results provide evidence of in-vivo relationship between iron metabolism and acidosis. For clinical importance, we speculate that metabolic acidosis may contribute in part to the pathologic elevation of serum hepcidin levels seen in patients with chronic kidney disease. The regulation of ATP4 by iron metabolism may also be of interest for patients with hemochromatosis.

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Control of Systemic Iron Homeostasis by the 3’ Iron‐Responsive Element of Divalent Metal Transporter 1 in Mice

Abstract: Supplemental Digital Content is available in the text

Cited by 13 publications

References 15 publications

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Protective Effects of Hif2 Inhibitor PT-2385 on a Neurological Disorder Induced by Deficiency of Irp2

Crosstalk between Acidosis and Iron Metabolism: Data from In Vivo Studies

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