Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2α and Altered Expression of Iron Absorption Genes in Mice

Matak, Pavle; Zumerle, Sara; Mastrogiannaki, Maria; Balkhi, Souleiman El; Delga, Stéphanie; Mathieu, Jacques; Canonne‐Hergaux, François; Poupon, Joël; Sharp, Paul; Vaulont, Sophie; Peyssonnaux, Carole

doi:10.1371/journal.pone.0059538

Cited by 51 publications

(38 citation statements)

References 48 publications

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“…The BBM ferrireductase CYBRD1 can reduce iron and copper (117), demonstrating a potential point of intersection. Moreover, Matak et al (71) recently reported that CYBRD1 was induced in the intestinal epithelium of copper-deprived mice. The proposed mechanism related to intestinal hypoxia resulting from copper-deficiency anemia and a concomitant increase in CYBRD1 gene transcription mediated by the hypoxia-inducible transcription factor HIF2α.…”

Section: Iron-copper Interactions In Intestinementioning

confidence: 99%

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Molecular Mediators Governing Iron-Copper Interactions

Güleç

Collins²

2014

Annu. Rev. Nutr.

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Given their similar physiochemical properties, it is a logical postulate that iron and copper metabolism are intertwined. Indeed, iron-copper interactions were first documented over a century ago, but the homeostatic effects of one on the other has not been elucidated at a molecular level to date. Recent experimental work has, however, begun to provide mechanistic insight into how copper influences iron metabolism. During iron deficiency, elevated copper levels are observed in the intestinal mucosa, liver, and blood. Copper accumulation and/or redistribution within enterocytes may influence iron transport, and high hepatic copper may enhance biosynthesis of a circulating ferroxidase, which potentiates iron release from stores. Moreover, emerging evidence has documented direct effects of copper on the expression and activity of the iron-regulatory hormone hepcidin. This review summarizes current experimental work in this field, with a focus on molecular aspects of iron-copper interplay and how these interactions relate to various disease states.

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Section: Iron-copper Interactions In Intestinementioning

confidence: 99%

“…Whether its expression or activity is altered by variations in copper status has been investigated. Copper deficiency in mice was shown to increase FPN1 mRNA expression, possibly by a transcriptional mechanism involving HIF2α (71). Another recent study, however, provided contradictory results (90).…”

Section: Iron-copper Interactions In Intestinementioning

confidence: 99%

Molecular Mediators Governing Iron-Copper Interactions

Güleç

Collins²

2014

Annu. Rev. Nutr.

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“…For the long isoform, there was uniform protein distribution throughout the cytoplasm and appreciable localization in the vicinity of the plasma membrane; in contrast, the protein encoded by the short isoform was largely perinuclear ( Figure 3B). Given the quantitative limitations of immunocytochemistry, we performed biochemical localizations studies, in which we fractionated cells in high sucrose buffer as previously described, 26 purified membrane fractions, and performed immunoblotting either with the Myc tag or with an antibody against Na þ /Kþ ATPase, a membrane marker (Abcam ab7671; 1:10,000 dilution). In this experiment, we observed a striking difference in the relative ratios of long and short protein isoforms in the membrane ( Figure 3C), a result consistent with the observed immunocytochemical distributions.…”

Section: Renal Defectsmentioning

confidence: 99%

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Ta‐Shma

Khan

Vivante

et al. 2017

The American Journal of Human Genetics

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Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.Whole-exome and whole-genome sequencing (WES and WGS, respectively) have accelerated the expansion of the repertoire of human loci underscoring Mendelian phenotypes to account for~3,000 human genes (15%).1 Nonetheless, the diagnostic yield remains <50%, 2-4 suggesting that the majority of disease-causing lesions are yet to be identified and that a significant fraction of this genetic burden is likely to be contributed by ultra-rare or private mutations. To contribute to the saturation of the morbid human genome as a means of improving both diagnostic value and mechanistic insight, we undertook the systematic sequencing of families affected by suspected genetic disorders, with an emphasis on congenital syndromic traits. Here, we report the genetic and functional dissection of affected individuals with a genetically undiagnosed syndrome characterized by cardiac, CNS, renal, and digit abnormalities in two unrelated consanguineous pedigrees. We show that the likely molecular cause, homozygous truncating mutations in TMEM260, affect the functions of one of the two established isoforms transcribed from this locus, thereby demonstrating the necessity of the long isoform for the development of multiple tissues. We consulted family 1, a con...

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“…However, models of intestinal iron overload coupled with systemic anemia indicate that elevated iron levels do not have a pronounced effect on HIF-2 per se and that systemic anemia/hypoxia is the predominant regulator of HIF-2. 74 It would be interesting to examine these hypotheses more specifically in mice with inducible deletion of Irp1 or Irp2 in the intestinal epithelium. Further studies addressing these questions may provide evidence for nonredundant roles of IRPs in the duodenum and their importance in integrating systemic physiological signals in vivo.…”

Section: Posttranscriptional Regulation By the Irps: A New Irp1/hif-2mentioning

confidence: 99%

The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

Mastrogiannaki

Matak

Peyssonnaux

2013

Blood

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115

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Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the past decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that hypoxia inducible factor-2 (HIF-2a) regulates the expression of key genes that contribute to iron absorption. Here we review the current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2-based therapeutic strategies in iron-related pathological conditions. (Blood. 2013;122(6):885-892) Introduction Iron (Fe) is an essential nutrient required in many cellular biosynthetic and metabolic processes such as heme and sulfur-iron cluster biosynthesis, oxygen transport, mitochondrial respiration, and DNA replication. 1 The body of a healthy human male contains ;4 g of total iron, which is in a dynamic equilibrium between different tissues: 1 g is predominantly stored in hepatocytes, whereas 65% to 80% of total iron traffics in a closed circuit in which erythrophagocytosis of senescent red blood cells by reticuloendothelial macrophages in the spleen enables iron to be returned to the bone marrow for incorporation into new erythrocytes. Approximately 1 mg of dietary iron is absorbed daily at the proximal duodenum, a process that is essential in order to replace daily losses due to limited blood losses, desquamation, and so forth.2 Excess iron accumulation and the resulting production of reactive oxygen species through the Fenton/ Haber Weiss reaction are involved in the pathogenesis of ironoverload-related diseases including hereditary hemochromatosis (HH) and b-thalassemia.Iron absorption is increased during iron deficiency and decreased upon iron loading.2 This inverse relationship depends on a network of signals, which reflect systemic body iron requirements and the interaction of these signals with the enterocyte iron sensing and transport machinery. Iron homeostasis is regulated systemically by the hormone hepcidin, a 25-aminoacid peptide produced mainly by the hepatocytes. Hepcidin expression is increased by iron loading and inflammatory signals and is attenuated by iron deficiency, anemia, increased erythropoietic activity, and hypoxia.3 Hepcidin inhibits iron absorption and iron recycling by binding to the only known iron exporter, ferroportin (FPN). 4 Recent advances in the understanding of the regulation of hepcidin expression and the mechanism of hepcidin action have been detailed elsewhere. Here, we review current knowledge regarding the roles of hypoxia inducible factor-2 (HIF-2) and iron regulatory proteins 1 (IRP1) and 2 (IRP2) in the molecular circuitry that regulates iron absorption by enterocytes. We als...

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Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2α and Altered Expression of Iron Absorption Genes in Mice

Cited by 51 publications

References 48 publications

Molecular Mediators Governing Iron-Copper Interactions

Molecular Mediators Governing Iron-Copper Interactions

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

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