Lack of the bone morphogenetic protein BMP6 induces massive iron overload

Meynard, Delphine; Kautz, Léon; Darnaud, Valérie; Canonne‐Hergaux, François; Coppin, Hélène; Roth, Marie‐Paule

doi:10.1038/ng.320

Cited by 530 publications

(507 citation statements)

References 26 publications

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“…The lack of significant cardiac dysfunction in our Hamp −/− mice and in other reported mouse models of impaired hepcidin production (29)(30)(31) is in contrast with the clinical characteristics of juvenile hemochromatosis, in which patients develop severe cardiomyopathy (5). This contrast points to possible differences between human and murine cardiomyocytes in iron entry, export, storage, or detoxification pathways.…”

Section: Discussionmentioning

confidence: 59%

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Lakhal‐Littleton

Wolna

Carr

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

182

181

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Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.

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Section: Discussionmentioning

confidence: 59%

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Lakhal‐Littleton

Wolna

Carr

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

182

181

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“…2). BMP6 and BMP2 stimulate hepcidin mRNA production by hepatocytes, and the absence of either BMP results in iron overload caused by inadequate hepcidin production (33)(34)(35)(36), suggesting that BMP2 and BMP6 may also function as a heterodimer. BMP signaling in hepatocytes and the control of basal and iron-stimulated hepcidin expression (37,38) are carried out by heteromeric BMP receptors combining type 1 activin receptor-like kinase (ALK) 2 or ALK3 with type 2 BMP receptors BMPR2 or activin A receptor type 2A (ActR2a).…”

Section: Hepcidin Regulation By Iron Is Mediated By the Bmp Pathwaymentioning

confidence: 99%

Iron homeostasis: An anthropocentric perspective

Coffey

Ganz

2017

Journal of Biological Chemistry

159

167

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The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation.

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“…Furthermore, the ligand BMP-6 is essential for appropriate HJV-mediated hepcidin expression (27,28), and serine/threonine type I (predominately ALK3 (29)) and type II (ActRIIA and BMPRII (30)) receptors are required for transmission of this signal. Stimulation of these receptors leads to phosphorylation of SMAD1/5/8 transcription factors.…”

Section: Regulation Of Hepcidin Through the Bone Morphogenetic Proteimentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

137

105

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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Lack of the bone morphogenetic protein BMP6 induces massive iron overload

Cited by 530 publications

References 26 publications

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

Iron homeostasis: An anthropocentric perspective

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

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