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ABSTRACT: Divalent metal-ion transporter-1 (DMT1) is required for iron uptake by the intestine and developing erythroid cells. DMT1 is also present in the liver, where it has been implicated in the uptake of transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI), which appears in the plasma during iron overload. To test the hypothesis that DMT1 is required for hepatic iron uptake, we examined mice with the Dmt1 gene selectively inactivated in hepatocytes (Dmt1(liv/liv) ). We found that Dmt1(liv/liv) mice and controls (Dmt1(flox/flox) ) did not differ in terms of hepatic iron concentrations or other parameters of iron status. To determine if hepatocyte DMT1 is required for hepatic iron accumulation, we crossed Dmt1(liv/liv) mice with Hfe(-/-) and hypotransferrinemic (Trf(hpx/hpx) ) mice that develop hepatic iron overload. Double-mutant Hfe(-/-) ;Dmt1(liv/liv) and Trf(hpx/hpx) ;Dmt1(liv/liv) mice were found to accumulate similar amounts of hepatic iron as did their respective controls. To directly assess the role of DMT1 in NTBI and TBI uptake, we injected (59) Fe-labeled ferric citrate (for NTBI) or (59) Fe-transferrin into the plasma of Dmt1(liv/liv) and Dmt1(flox/flox) mice and measured the uptake of (59) Fe by the liver. Dmt1(liv/liv) mice displayed no impairment of hepatic NTBI uptake, but TBI uptake was 40% lower. Hepatic levels of transferrin receptors 1 and 2 and ZIP14 (ZRT/IRT-like protein 14), which may also participate in iron uptake, were unaffected in Dmt1(liv/liv) mice. Additionally, liver iron levels were unaffected in Dmt1(liv/liv) mice fed an iron-deficient diet. Conclusion: Hepatocyte DMT1 is dispensable for hepatic iron accumulation and NTBI uptake. Although hepatocyte DMT1 is partially required for hepatic TBI uptake, hepatic iron levels were unaffected in Dmt1(liv/liv) mice, suggesting that this pathway is a minor contributor to the iron economy of the liver. (HEPATOLOGY 2013.).
Hepatology 03/2013; · 11.66 Impact Factor
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ABSTRACT: ZIP8 (SLC39A8) belongs to the ZIP family of metal-ion transporters. Among the ZIP proteins, ZIP8 is most closely related to ZIP14, which can transport iron, zinc, manganese, and cadmium. Here we investigated the iron transport ability of ZIP8, its subcellular localization, pH dependence, and regulation by iron. Transfection of HEK 293T cells with ZIP8 cDNA enhanced the uptake of (59)Fe and (65)Zn by 200 and 40%, respectively, compared with controls. Excess iron inhibited the uptake of zinc and vice versa. In RNA-injected Xenopus oocytes, ZIP8-mediated (55)Fe(2+) transport was saturable (K(0.5) of ∼0.7 μm) and inhibited by zinc. ZIP8 also mediated the uptake of (109)Cd(2+), (57)Co(2+), (65)Zn(2+) > (54)Mn(2+), but not (64)Cu (I or II). By using immunofluorescence analysis, we found that ZIP8 expressed in HEK 293T cells localized to the plasma membrane and partially in early endosomes. Iron loading increased total and cell-surface levels of ZIP8 in H4IIE rat hepatoma cells. We also determined by using site-directed mutagenesis that asparagine residues 40, 88, and 96 of rat ZIP8 are glycosylated and that N-glycosylation is not required for iron or zinc transport. Analysis of 20 different human tissues revealed abundant ZIP8 expression in lung and placenta and showed that its expression profile differs markedly from ZIP14, suggesting nonredundant functions. Suppression of endogenous ZIP8 expression in BeWo cells, a placental cell line, reduced iron uptake by ∼40%, suggesting that ZIP8 participates in placental iron transport. Collectively, these data identify ZIP8 as an iron transport protein that may function in iron metabolism.
Journal of Biological Chemistry 08/2012; 287(41):34032-43. · 4.77 Impact Factor
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ABSTRACT: Zinc, iron, and manganese are essential trace elements that serve as catalytic or structural components of larger molecules that are indispensable for life. The three metal ions possess similar chemical properties and have been shown to compete for uptake in a variety of tissues, suggesting that they share common transport proteins. Two likely candidates are the recently identified transmembrane proteins ZIP14 and ZIP8, which have been shown to mediate the cellular uptake of a number of divalent metal ions including zinc, iron, manganese, and cadmium. Although knockout and transgenic mouse models are beginning to define the physiologic roles of ZIP14 and ZIP8 in the handling of zinc and cadmium, their roles in the metabolism of iron and manganese remain to be defined. Here we review similarities and differences in ZIP14 and ZIP8 in terms of structure, metal transport, tissue distribution, subcellular localization, and regulation. We also discuss potential roles of these proteins in the metabolism of zinc, iron, manganese, and cadmium as well as recent associations with human diseases.
Biology of Metals 02/2012; 25(4):643-55. · 3.17 Impact Factor
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ABSTRACT: Aging is associated with disturbances in iron metabolism and storage. During the last decade, remarkable progress has been made toward understanding their cellular and molecular mechanisms in aging and age-associated diseases using both cultured cells and animal models. The field has moved beyond descriptive studies to potential intervention studies focusing on iron chelation and removal. However, some findings remain controversial and inconsistent. This review summarizes important features of iron dyshomeostasis in aging research with a particular emphasis on current knowledge of the mechanisms underlying age-associated disorders in rodent models.
International Journal of Molecular Sciences 01/2012; 13(2):2368-86. · 2.60 Impact Factor
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ABSTRACT: In the present study, we investigated the effects of 7 and 14 days of re-loading following 14-day muscle unweighting (hindlimb suspension, HS) on iron transport, non-heme iron levels and oxidative damage in the gastrocnemius muscle of young (6 months) and old (32 months) male Fischer 344×Brown Norway rats. Our results demonstrated that old rats had lower muscle mass, higher levels of total non-heme iron and oxidative damage in skeletal muscle in comparison with young rats. Non-heme iron concentrations and total non-heme iron amounts were 3.4- and 2.3-fold higher in aged rats as compared with their young counterparts, respectively. Seven and 14 days of re-loading was associated with higher muscle weights in young animals as compared with age-matched HS rats, but there was no difference in muscle weights among aged HS, 7 and 14 days of re-loading rats, indicating that aged rats may have a lower adaptability to muscle disuse and a lower capacity to recover from muscle atrophy. Protein levels of cellular iron transporters, such as divalent metal transport-1 (DMT1), transferrin receptor-1 (TfR1), Zip14, and ferroportin (FPN), and their mRNA abundance were determined. TfR1 protein and mRNA levels were significantly lower in aged muscle. Seven and 14 days of re-loading were associated with higher TfR1 mRNA and protein levels in young animals in comparison with their age-matched HS counterparts, but there was no difference between cohorts in aged animals, suggesting adaptive responses in the old to cope with iron deregulation. The extremely low expression of FPN in skeletal muscle might lead to inefficient iron export in the presence of iron overload and play a critical role in age-related iron accumulation in skeletal muscle. Moreover, oxidative stress was much greater in the muscles of the older animals measured as 4-hydroxy-2-nonhenal (HNE)-modified proteins and 8-oxo-7,8-dihydroguanosine levels. These markers remained fairly constant with either HS or re-loading in young rats. In old rats, HNE-modified proteins and 8-oxo-7,8-dihydroguanosine levels were markedly higher in HS and were lower after 7 days of recovery. However, no difference was observed following 14 days of recovery between control and re-loading animals. In conclusion, advanced age is associated with disruption of muscle iron metabolism which is further perturbed by disuse and persists over a longer time period.
Experimental gerontology 11/2011; 47(1):100-8. · 3.34 Impact Factor
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ABSTRACT: The mammalian ZIP (Zrt-, Irt-like Protein) family of transmembrane transport proteins consists of 14 members that share considerable homology. ZIP proteins have been shown to mediate the cellular uptake of the essential trace elements zinc, iron, and manganese. The aim of the present study was to determine the effect of dietary iron deficiency and overload on the expression of all 14 ZIP transporters in the liver, the main site of iron storage. Weanling male rats (n = 6/group) were fed iron-deficient (FeD), iron-adequate (FeA), or iron-overloaded (FeO) diets in two independent feeding studies. In study 1, diets were based on the TestDiet 5755 formulation and contained iron at 9 ppm (FeD), 215 ppm (FeA), and 27,974 ppm (3% FeO). In study 2, diets were based on the AIN-93G formulation and contained iron at 9 ppm Fe (FeD), 50 ppm Fe (FeA), or 18916 ppm (2% FeO). After 3 weeks, the FeD diets depleted liver non-heme iron stores and induced anemia, whereas FeO diets resulted in hepatic iron overload. Quantitative RT-PCR revealed that ZIP5 mRNA levels were 3- and 8-fold higher in 2% FeO and 3% FeO livers, respectively, compared with FeA controls. In both studies, a consistent downregulation of ZIP6, ZIP7, and ZIP10 was also observed in FeO liver relative to FeA controls. Studies in H4IIE hepatoma cells further documented that iron loading affects the expression of these ZIP transporters. Overall, our data suggest that ZIP5, ZIP6, ZIP7, and ZIP10 are regulated by iron, indicating that they may play a role in hepatic iron/metal homeostasis during iron deficiency and overload.
Biology of Metals 08/2011; 25(1):115-24. · 3.17 Impact Factor
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ABSTRACT: Recent studies have shown that overexpression of the transmembrane protein Zrt- and Irt-like protein 14 (Zip14) stimulates the cellular uptake of zinc and nontransferrin-bound iron (NTBI). Here, we directly tested the hypothesis that Zip14 transports free zinc, iron, and other metal ions by using the Xenopus laevis oocyte heterologous expression system, and use of this approach also allowed us to characterize the functional properties of Zip14. Expression of mouse Zip14 in RNA-injected oocytes stimulated the uptake of (55)Fe in the presence of l-ascorbate but not nitrilotriacetic acid, indicating that Zip14 is an iron transporter specific for ferrous ion (Fe(2+)) over ferric ion (Fe(3+)). Zip14-mediated (55)Fe(2+) uptake was saturable (K(0.5) ≈ 2 μM), temperature-dependent (apparent activation energy, E(a) = 15 kcal/mol), pH-sensitive, Ca(2+)-dependent, and inhibited by Co(2+), Mn(2+), and Zn(2+). HCO(3)(-) stimulated (55)Fe(2+) transport. These properties are in close agreement with those of NTBI uptake in the perfused rat liver and in isolated hepatocytes reported in the literature. Zip14 also mediated the uptake of (109)Cd(2+), (54)Mn(2+), and (65)Zn(2+) but not (64)Cu (I or II). (65)Zn(2+) uptake also was saturable (K(0.5) ≈ 2 μM) but, notably, the metal-ion inhibition profile and Ca(2+) dependence of Zn(2+) transport differed from those of Fe(2+) transport, and we propose a model to account for these observations. Our data reveal that Zip14 is a complex, broad-scope metal-ion transporter. Whereas zinc appears to be a preferred substrate under normal conditions, we found that Zip14 is capable of mediating cellular uptake of NTBI characteristic of iron-overload conditions.
AJP Cell Physiology 06/2011; 301(4):C862-71. · 3.54 Impact Factor
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ABSTRACT: ZIP14 is a transmembrane metal ion transporter that is abundantly expressed in the liver, heart, and pancreas. Previous studies of HEK 293 cells and the hepatocyte cell lines AML12 and HepG2 established that ZIP14 mediates the uptake of non-transferrin-bound iron, a form of iron that appears in the plasma during pathologic iron overload. In this study we investigated the role of ZIP14 in the cellular assimilation of iron from transferrin, the circulating plasma protein that normally delivers iron to cells by receptor-mediated endocytosis. We also determined the subcellular localization of ZIP14 in HepG2 cells. We found that overexpression of ZIP14 in HEK 293T cells increased the assimilation of iron from transferrin without increasing levels of transferrin receptor 1 or the uptake of transferrin. To allow for highly specific and sensitive detection of endogenous ZIP14 in HepG2 cells, we used a targeted knock-in approach to generate a cell line expressing a FLAG-tagged ZIP14 allele. Confocal microscopic analysis of these cells detected ZIP14 at the plasma membrane and in endosomes containing internalized transferrin. HepG2 cells in which endogenous ZIP14 was suppressed by siRNA assimilated 50% less iron from transferrin compared with controls. The uptake of transferrin, however, was unaffected. We also found that ZIP14 can mediate the transport of iron at pH 6.5, the pH at which iron dissociates from transferrin within the endosome. These results suggest that endosomal ZIP14 participates in the cellular assimilation of iron from transferrin, thus identifying a potentially new role for ZIP14 in iron metabolism.
Journal of Biological Chemistry 10/2010; 285(42):32141-50. · 4.77 Impact Factor
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Mitchell D Knutson
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ABSTRACT: The human body cannot actively excrete excess iron. As a consequence, iron absorption must be strictly regulated to ensure adequate iron uptake and prevent toxic iron accumulation. Iron absorption is controlled chiefly by hepcidin, the iron-regulatory hormone. Produced by the liver and secreted into the circulation, hepcidin regulates iron metabolism by inhibiting iron release from cells, including duodenal enterocytes, which mediate the absorption of dietary iron. Hepcidin production increases in response to iron loading and decreases in iron deficiency. Such regulation of hepcidin expression serves to modulate iron absorption to meet body iron demand. This review discusses the proteins that orchestrate hepatic hepcidin production and iron absorption by the intestine. Emphasis is placed on the proteins that directly sense iron and how they coordinate and fine-tune the molecular, cellular, and physiologic responses to iron deficiency and overload.
Annual Review of Nutrition 08/2010; 30:149-71. · 9.45 Impact Factor
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ABSTRACT: Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities.
Nutrition Reviews 03/2010; 68(3):133-47. · 4.47 Impact Factor
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ABSTRACT: The transmembrane protein ferroportin (Fpn) is essential for iron efflux from the liver, spleen, and duodenum. Fpn is regulated predominantly by the circulating iron regulatory hormone hepcidin, which binds to cell surface Fpn, initiating its degradation. Accordingly, when hepcidin concentrations decrease, Fpn levels increase. A previous study found that Fpn levels were not elevated in copper-deficient (CuD) mice that had anemia, a condition normally associated with dramatic reductions in hepcidin. Lack of change in Fpn levels may be because CuD mice do not display reduced concentrations of plasma iron (holotransferrin), a modulator of hepcidin expression. Here, we examined Fpn protein levels and hepcidin expression in CuD rats, which exhibit reduced plasma iron concentrations along with anemia. We also examined hepcidin expression in anemic CuD mice with normal plasma iron levels. We found that CuD rats had higher liver and spleen Fpn levels and markedly lower hepatic hepcidin mRNA expression than did copper-adequate (CuA) rats. In contrast, hepcidin levels did not differ between CuD and CuA mice. To examine potential mediators of the reduced hepcidin expression in CuD rats, we measured levels of hepatic transferrin receptor 2 (TfR2), a putative iron sensor that links holotransferrin to hepcidin production, and transcript abundance of bone morphogenic protein 6 (BMP6), a key endogenous positive regulator of hepcidin production. Diminished hepcidin expression in CuD rats was associated with lower levels of TfR2, but not BMP6. Our data suggest that holotransferrin and TfR2, rather than anemia or BMP6, are signals for hepcidin synthesis during copper deficiency.
Journal of Nutrition 02/2010; 140(4):723-30. · 3.92 Impact Factor
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Mitchell D Knutson
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ABSTRACT: Matriptase-2 is a recently identified membrane-bound, cell-surface serine protease expressed primarily in liver. Mutations in matriptase-2 in mice and humans cause iron-deficiency anemia that responds poorly to iron therapy. The poor response results from an inability to decrease hepcidin production during iron deficiency. Cell culture studies reveal that matriptase-2 inhibits hepcidin induction by cleaving membrane hemojuvelin, a potent activator of hepcidin transcription. As a novel suppressor of hepcidin expression, matriptase-2 emerges as a possible candidate for therapeutic interventions aimed at treating disorders of iron metabolism.
Nutrition Reviews 06/2009; 67(5):284-8. · 4.47 Impact Factor
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ABSTRACT: The transmembrane protein ferroportin is highly expressed in tissue macrophages, where it mediates iron export into the bloodstream. Although ferroportin expression can be controlled post-transcriptionally through a 5' iron-responsive element in its mRNA, various studies have documented increased ferroportin mRNA levels in response to iron, suggesting transcriptional regulation. We studied the effect of iron loading on levels of macrophage ferroportin mRNA, as well as heterogeneous nuclear RNA (hnRNA), the immediate product of ferroportin gene transcription. J774 cells, a mouse macrophage cell line, were incubated for 0, 3, 6, 9, 12, and 24 h in medium supplemented or not with 200 mumol/L iron. Quantitative RT-PCR was used to measure steady-state levels of ferroportin mRNA and hnRNA. Ferroportin mRNA levels increased by 12 h after iron treatment, reaching 6 times the control levels after 24 h. Changes in ferroportin mRNA levels were paralleled by similar changes in the levels of ferroportin hnRNA. Time course studies of ferroportin mRNA and hnRNA abundance after incubating cells with the transcriptional inhibitor actinomycin D revealed that ferroportin mRNA has a half-life of approximately 4 h and that iron loading does not stabilize ferroportin mRNA or hnRNA. Collectively, these data are consistent with the hypothesis that iron increases macrophage ferroportin mRNA levels by inducing transcription of the ferroportin gene.
Journal of Nutrition 02/2009; 139(3):434-8. · 3.92 Impact Factor
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ABSTRACT: The discovery of hepcidin as a key regulator of iron homeostasis has advanced our current knowledge of this field. Liver-derived hepcidin peptide is secreted in response to iron and inflammation and interacts with the iron export protein ferroportin. This review summarizes recent advances discussed at the Symposium. A particular focus is on molecular interactions between hepcidin and ferroportin, the regulation of hepcidin expression by iron and inflammation, and emerging methods to measure serum hepcidin in human populations.
Journal of Nutrition 12/2008; 138(11):2284-8. · 3.92 Impact Factor
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ABSTRACT: During the aging process, an accumulation of non-heme iron disrupts cellular homeostasis and contributes to the mitochondrial dysfunction typical of various neuromuscular degenerative diseases. Few studies have investigated the effects of iron accumulation on mitochondrial integrity and function in skeletal muscle and liver tissue. Thus, we isolated liver mitochondria (LM), as well as quadriceps-derived subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), from male Fischer 344 x Brown Norway rats at 8, 18, 29 and 37 months of age. Non-heme iron content in SSM, IFM and LM was significantly higher with age, reaching a maximum at 37 months of age. The mitochondrial permeability transition pore (mPTP) was more susceptible to the opening in aged mitochondria containing high levels of iron (i.e. SSM and LM) compared to IFM. Furthermore, mitochondrial RNA oxidation increased significantly with age in SSM and LM, but not in IFM. Levels of mitochondrial RNA oxidation in SSM and LM correlated positively with levels of mitochondrial iron, whereas a significant negative correlation was observed between the maximum Ca(2+) amounts needed to induce mPTP opening and iron contents in SSM, IFM and LM. Overall, our data suggest that age-dependent accumulation of mitochondrial iron may increase mitochondrial dysfunction and oxidative damage,thereby enhancing the susceptibility to apoptosis.
Aging cell 11/2008; 7(5):706-16. · 7.55 Impact Factor
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ABSTRACT: Studies show that the plant polyphenol resveratrol can extend the life span of yeast, worms, flies, and fish. It also mitigates the metabolic dysfunction of mice fed high-fat diets. Resveratrol appears to mediate these effects partly by activating SIRT1, a deacetylase enzyme that regulates the activity of several transcriptional factors and enzymes responsive to nutrient availability. However, few foods contain resveratrol and humans metabolize it extensively, resulting in very low systemic bioavailability. Substantial research effort now focuses on identifying and testing more bioavailable and potent activators of SIRT1 for use as pharmacologic interventions in aging and age-related disorders.
Nutrition Reviews 11/2008; 66(10):591-6. · 4.47 Impact Factor
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ABSTRACT: Lack of functional hereditary hemochromatosis protein, HFE, causes iron overload predominantly in hepatocytes, the major site of HFE expression in the liver. In this study, we investigated the role of HFE in the regulation of both transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI) uptake in HepG2 cells, a human hepatoma cell line. Expression of HFE decreased both TBI and NTBI uptake. It also resulted in a decrease in the protein levels of Zip14 with no evident change in the mRNA level of Zip14. Zip14 (Slc39a14) is a metal transporter that mediates NTBI into cells (Liuzzi, J. P., Aydemir, F., Nam, H., Knutson, M. D., and Cousins, R. J. (2006) Proc. Natl. Acad. Sci. U. S. A. 103, 13612-13617). Knockdown of Zip14 with siRNA abolished the effect of HFE on NTBI uptake. To determine if HFE had a similar effect on Zip14 in another cell line, HeLa cells expressing HFE under the tetracycline-repressible promoter were transfected with Zip14. As in HepG2 cells, HFE expression inhibited NTBI uptake by approximately 50% and decreased Zip14 protein levels. Further analysis of protein turnover indicated that the half-life of Zip14 is lower in cells that express HFE. These results suggest that HFE decreases the stability of Zip14 and therefore reduces the iron loading in HepG2 cells.
Journal of Biological Chemistry 08/2008; 283(31):21462-8. · 4.77 Impact Factor
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ABSTRACT: Muscle atrophy with aging or disuse is associated with deregulated iron homeostasis and increased oxidative stress likely inflicting damage to nucleic acids. Therefore, we investigated RNA and DNA oxidation, and iron homeostasis in gastrocnemius muscles. Disuse atrophy was induced in 6- and 32-month old male Fischer 344/Brown Norway rats by 14 days of hind limb suspension (HS). We show that RNA, but not DNA, oxidative damage increased 85% with age and 36% with HS in aged muscle. Additionally, non-heme iron levels increased 233% with aging and 83% with HS at old age, while staining for free iron was strongest in the smallest fibers. Simultaneously, the mRNA abundance of transferrin receptor-1 decreased by 80% with age and 48% with HS for young animals, while that of the hepcidin regulator hemojuvelin decreased 37% with age, but increased about 44% with disuse, indicating a dysregulation of iron homeostasis favoring increased intracellular free iron in atrophied muscles. RNA and DNA concentrations increased with age and were negatively correlated with muscle mass, whereas protein concentrations decreased with aging, indicating a preferential loss of protein compared to nucleic acids. Furthermore, xanthine oxidase activity increased with age, but not with HS, while mRNA abundance of the Y box-binding protein-1, which has been suggested to bind oxidized RNA, did not change with age or HS. These results suggest that RNA oxidation, possibly mediated by increased non-heme iron, might contribute to muscle atrophy due to disuse particularly in aged muscle.
Experimental Gerontology 07/2008; 43(6):563-70. · 3.74 Impact Factor
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ABSTRACT: Identification of biological mediators in sarcopenia is pertinent to the development of targeted interventions to alleviate this condition. Iron is recognized as a potent pro-oxidant and a catalyst for the formation of reactive oxygen species in biological systems. It is well accepted that iron accumulates with senescence in several organs, but little is known about iron accumulation in muscle and how it may affect muscle function. In addition, it is unclear if interventions which reduced age-related loss of muscle quality, such as calorie restriction, impact iron accumulation. We investigated non-heme iron concentration, oxidative stress to nucleic acids in gastrocnemius muscle and key indices of sarcopenia (muscle mass and grip strength) in male Fischer 344 X Brown Norway rats fed ad libitum (AL) or a calorie restricted diet (60% of ad libitum food intake starting at 4 months of age) at 8, 18, 29 and 37 months of age. Total non-heme iron levels in the gastrocnemius muscle of AL rats increased progressively with age. Between 29 and 37 months of age, the non-heme iron concentration increased by approximately 200% in AL-fed rats. Most importantly, the levels of oxidized RNA in gastrocnemius muscle of AL rats were significantly increased as well. The striking age-associated increase in non-heme iron and oxidized RNA levels and decrease in sarcopenia indices were all attenuated in the calorie restriction (CR) rats. These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects.
PLoS ONE 02/2008; 3(8):e2865. · 4.09 Impact Factor
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Mitchell D Knutson
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ABSTRACT: Erythroid cells of the bone marrow, the most avid consumers of iron in the body, acquire ferric (Fe3+) iron exclusively via the transferrin cycling pathway. A long-standing fundamental molecular question of how ferric iron is handled in this pathway has been recently resolved by the identification of Steap3 (sixtransmembrane epithelial antigen of the prostate 3) as an endosomal ferrireductase needed for efficient utilization of transferrin-delivered iron. Further characterization of Steap3 and other Steap proteins reveals a possible greater role of Steap proteins in iron and copper metabolism.
Nutrition Reviews 08/2007; 65(7):335-40. · 4.47 Impact Factor
