Cp/Heph mutant mice have iron‐induced neurodegeneration diminished by deferiprone

Zhao, Lingling; Hadziahmetovic, Majda; Wang, Chenguang; Xu, Xueying; Song, Ying; Jinnah, Hyder A.; Wodzinska, Jolanta; Iacovelli, Jared; Wolkow, Natalie; Krajacic, Predrag; Weissberger, Alyssa Cwanger; Connelly, John T.; Spino, Michael; Lee, Michael K.; Connor, James R.; Harris, Z. Leah; Dunaief, Joshua L.

doi:10.1111/jnc.13292

Cited by 35 publications

(21 citation statements)

References 54 publications

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“…Hephaestin and CP are two well‐known MCFs which are in charge of the iron efflux from the intestine and liver, respectively. However, there is increasing evidence that these two MCFs are also coexpressed in many tissues, such as retina, kidney, and brain . Due to the similar function of these two MCFs, the phenotype of iron accumulation in these tissues could only be observed when both MCFs are KO.…”

Section: Discussionmentioning

confidence: 99%

Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes

et al. 2018

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Little is known about the iron efflux mechanism in adipocytes. Here, we used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout (KO) mice and Heph/Cp double-KO mice to investigate the roles of multicopper ferroxidases (MCFs) in this process. We show that both HEPH and CP are expressed in subcutaneous adipose tissue. Ablation of either MCF leads to a compensatory increase in the other, which contributes to the balance of iron status. However, ablation of both MCFs together induces severe iron deposition in adipocytes which is associated with decreased adiponectin and leptin mRNA expression. Furthermore, Heph/Cp KO mice display disordered carbohydrate metabolism characterized as type 2 diabetes. Together, these results demonstrate the protective roles of HEPH and CP in preventing iron overload in adipocytes.

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Section: Discussionmentioning

confidence: 99%

Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes

et al. 2018

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“…Heph -/- Cp -/- mice, but not Heph int/int Cp -/- mice, died prematurely, typically between 20 and 30 weeks of age, of unknown cause. Mice carrying the sla mutation in HEPH on a CP knockout background ( Heph sla/sla Cp -/- ) have also been reported to have an iron loading phenotype similar to Heph -/- Cp -/- mice, and developed neurologic abnormalities (including weakness and gait changes), and died prematurely 14, 2522, 26, 27…”

Section: Discussionmentioning

confidence: 99%

Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin

Fuqua

Frazer

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsMulticopper ferroxidases (MCFs) facilitate intestinal iron absorption and systemic iron recycling, likely by a mechanism involving the oxidization of Fe2+ from the iron exporter ferroportin 1 for delivery to the circulating Fe3+ carrier transferrin. Hephaestin (HEPH), the only MCF known to be expressed in enterocytes, aids in the basolateral transfer of dietary iron to the blood. Mice lacking HEPH in the whole body (Heph-/-) or intestine alone (Hephint/int) exhibit defects in dietary iron absorption but still survive and grow. Circulating ceruloplasmin (CP) is the only other known MCF likely to interact with enterocytes. Our aim was to assess the effects of combined deletion of HEPH and CP on intestinal iron absorption and homeostasis in mice.MethodsMice lacking both HEPH and CP (Heph-/-Cp-/-) and mice with whole-body knockout of CP and intestine-specific deletion of HEPH (Hephint/intCp-/-) were generated and phenotyped.ResultsHeph-/-Cp-/- mice were severely anemic and had low serum iron, but they exhibited marked iron loading in duodenal enterocytes, the liver, heart, pancreas, and other tissues. Hephint/intCp-/- mice were moderately anemic (similar to Cp-/- mice) but were iron loaded only in the duodenum and liver, as in Hephint/int and Cp-/- mice, respectively. Both double knockout models absorbed iron in radiolabeled intestinal iron absorption studies, but the iron was inappropriately distributed, with an abnormally high percentage retained in the liver.ConclusionsThese studies indicate that HEPH and CP, and likely MCFs in general, are not essential for intestinal iron absorption but are required for proper systemic iron distribution. They also point to important extra-intestinal roles for HEPH in maintaining whole-body iron homeostasis.

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“…Heph/CP double KO has also been found to induce iron accumulation in the brain, oxidative damage, and learning and memory defects in mice (Zheng et al, ). Compared to single mutants, iron accumulation in the cerebellum, substantia nigra and hippocampus was accelerated in Heph/CP‐KO mice (Zhao et al, ). Treatment with the oral iron chelator deferiprone reduced brain iron levels, protected against neuron loss, and extended lifespan in these mice (Zhao et al, ).…”

Section: Iron Transport Within the Brainmentioning

confidence: 99%

“…Compared to single mutants, iron accumulation in the cerebellum, substantia nigra and hippocampus was accelerated in Heph/CP‐KO mice (Zhao et al, ). Treatment with the oral iron chelator deferiprone reduced brain iron levels, protected against neuron loss, and extended lifespan in these mice (Zhao et al, ). These findings imply that the absent or decreased expression of these iron exporters may be associated with neurodegenerative diseases of unclear etiology that exhibit increased iron levels in the brain.…”

Section: Iron Transport Within the Brainmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

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Cp/Heph mutant mice have iron‐induced neurodegeneration diminished by deferiprone

Cited by 35 publications

References 54 publications

Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes

Ablation of hephaestin and ceruloplasmin results in iron accumulation in adipocytes and type 2 diabetes

Severe Iron Metabolism Defects in Mice With Double Knockout of the Multicopper Ferroxidases Hephaestin and Ceruloplasmin

Brain iron transport

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