Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice

Viatte, Lydie; Lesbordes-Brion, Jeanne-Claire; Lou, Dan-Qing; Bennoun, Myriam; Nicolas, Gaël; Kahn, Axel; Canonne‐Hergaux, François; Vaulont, Sophie

doi:10.1182/blood-2004-12-4608

Cited by 103 publications

(104 citation statements)

References 22 publications

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“…Hepcidin negatively controls the plasma iron pool, by binding and internalizing the iron exporter ferroportin on cells that release iron to the circulation, as duodenal enterocytes, macrophages and hepatocytes (Donovan, et al, 2005;Nemeth, et al, 2004). Consistently, hepcidindeficient mice (Nicolas, et al, 2001;Viatte, et al, 2005) and humans with hepcidin mutations (Roetto, et al, 2003) develop severe iron overload. Conversely, mice with increased transgenic expression of hepcidin in the liver manifest severe iron deficiency anemia (Nicolas, et al, 2002).…”

Section: Introductionmentioning

confidence: 83%

Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA)

Falco¹,

Totaro²,

Nai

et al. 2010

Hum. Mutat.

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Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. In this paper we describe 12 IRIDA patients belonging to 7 unrelated families and identify 10 (9 novel) TMPRSS6 mutations spread along the gene sequence: 5 missense, 1 non sense and 4 frameshift. The frameshift and non sense mutations are predict to result in truncated protein lacking the catalytic domain. The causal role of missense mutations (Y141C, I212T, R271Q, S304L and C510S) is demonstrated by in silico analysis, their absence in 100 control chromosomes and the high conservation of the involved residues. The C510S mutation in the LDLRA domain in silico model causes an intra-molecular structural imbalance that impairs matriptase-2 activation. We also assessed the in vitro effect on hepcidin promoter and the proteolytic activity of I212T and R271Q variants demonstrating a reduced inhibitory effect for the former mutation, but surprisingly a normal function for R271Q which appears a silent mutation in vitro. Based on mRNA expression studies I212T could also decrease the total amount of protein produced, likely interfering with mRNA stability. Collectively, our results extend the pattern of TMPRSS6 mutations associated with IRIDA and propose a model of causality for some of the novel missense mutation. ©2010Wiley-Liss, Inc.

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Section: Introductionmentioning

confidence: 83%

Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA)

Falco¹,

Totaro²,

Nai

et al. 2010

Hum. Mutat.

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“…The reduction in ferroportin and its ability to export iron probably contributes to the MPTP-induced accumulation of iron observed in previous MPTP studies. Given that ferroportin is intricately regulated by hepcidin (27), the stabilization of HIF␣ by DHB, even in the presence of MPTP, could promote iron export and prevent neurodegeneration associated with MPTP. Similar to previous studies, divalent metal transporter-1 was observed to be up-regulated by MPTP (59) and this increase was sustained even in the presence of DHB (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of cytosolic HIF␣, hepcidin is down-regulated and prevented from binding to and internalizing FPT (26,27), thereby increasing the levels of the iron exporter. MPTP treatment alone was observed to result in a decrease of ferroportin levels within the SN (Fig.…”

Section: Phd Inhibition By Dhb Prevents Mptp-induced Losses In Sn Levmentioning

confidence: 99%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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“…Knockouts of hepcidin in mice produce a model of hereditary hemochromatosis with severe multiorgan iron overload (6). Conversely, transgenic mice that overexpress hepcidin die at birth as a result of a severe iron deficiency anemia (7).…”

Section: Biologic Actions Of Hepcidinmentioning

confidence: 99%

Hepcidin for Clinicians

Young¹,

Zaritsky

2009

Clinical Journal of the American Society of Nephrology

102

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Despite the use of erythropoiesis-stimulating agents (ESAs), the anemia of chronic kidney disease (CKD) can be resistant to therapy. Both absolute and functional iron deficiency along with inflammation can contribute to ESA resistance and can be difficult to identify with current-day markers of iron storage. Hepcidin, a small peptide produced by the liver, is a recently discovered key regulator of iron homeostasis. Via regulation of ferroportin, hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes. Because of its renal elimination and regulation by inflammation, it is possible that progressive renal insufficiency leads to altered hepcidin metabolism, subsequently affecting enteric absorption of iron and the availability of iron stores. Thus, hepcidin likely plays a major role in the anemia of CKD as well as ESA resistance. This article discusses the biologic actions and regulation of hepcidin along with reviewing studies of hepcidin in CKD.

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Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice

Cited by 103 publications

References 22 publications

Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA)

Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA)

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Hepcidin for Clinicians

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