Ferroxidase Activity Of Ceruloplasmin Research Articles

Criteria for Early Identification of Aceruloplasminemia

A 52-year-old Japanese woman being treated for type 1 diabetes showed forgetfulness and microcytic anemia with a high serum ferritin concentration. Serum and brain radiological examinations revealed aceruloplasminemia, which was confirmed by genetic testing. Aceruloplasminemia is characterized by the triad of retinal degeneration, diabetes mellitus, and adult-onset disorder of the extrapyramidal system. Though physicians should treat such patients earlier, it is difficult to diagnose the disease before the presentation of neurological symptoms. Despite the presence of microcytic anemia, aceruloplasminemia patients usually have a high serum ferritin concentration due to the complete absence of ceruloplasmin ferroxidase activity. Thus, physicians should consider aceruloplasminemia when diabetic patients present with microcytic anemia and a high serum ferritin concentration.

Effect of Lactoferrin on Consequences of Acute Experimental Hemorrhagic Anemia in Rats

The effect of human lactoferrin on the arrest of experimental hemorrhagic anemia consequences was studied in rats. After six blood losses (days 1-4 and 7-8 of the experiment), the rats developed acute anemia: hemoglobin concentration decreased to 59% of the initial level, serum iron level decreased 3-fold. Intraperitoneal injections of lactoferrin (10 mg/day) for 4 days starting from day 7 led to an increase in hemoglobin level to 109% and of serum iron to 125% on day 14. In controls, hemoglobin level on day 14 was 70% and iron content 49% of the initial level. Ferroxidase activity of ceruloplasmin in blood serum decreased after 5 blood losses returned to normal only in rats receiving lactoferrin. The results indicate that lactoferrin modified ceruloplasmin activity in vivo, promoting normalization of iron metabolism.

NO Way to Relax

The roles of nitric oxide (NO) in the heart have been studied intensely ever since the first report nearly 2 decades ago showing that endogenous NO modulates cardiac myocyte function.1 All 3 NO synthase (NOS) isoforms have been found in mammalian heart tissues (see reviews in Massion et al2 and Belge et al3). A complex array of myocyte and nonmyocyte cells in the heart express NOS isoforms, and the local generation of NO2,3 and reactive oxygen species (ROS)4 may exert both autocrine and paracrine effects on cellular function. Not only is the endothelial isoform of NOS (eNOS, or NOS3) robustly expressed in the endothelial cells of the cardiac vasculature, but eNOS is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin-3 in T tubules in plasmalemmal caveolae.5 The neuronal NOS (nNOS, or NOS1) is also expressed in cardiac myocytes, where the enzyme appears to be localized in the sarcoplasmic reticulum and modulates phospholamban phosphorylation.6 Although both eNOS and nNOS appear to be physiologically expressed in cardiac tissues, the inflammation-related NOS isoform (iNOS, or NOS2) only appears in the heart after immunoactivation; iNOS may modulate the decline in myocardial function seen in sepsis.7 There have been innumerable studies of the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself.2 The cardiac phenotypes of NOS “knockout” mouse models have been characterized extensively, and mice lacking 1, 2, or all 3 NOS isoforms have been generated and characterized.8 In addition, the roles of NOS substrates, cofactors, and allosteric modulators have been explored exhaustively in diverse cardiac model systems. Emerging from this broad range of experimental evidence is an increasingly clear view that NO and NOS are key determinants of cardiac function. Yet the molecular mechanisms and …

Usefulness of ferroxidase activity of ceruloplasmin in the diagnosis of Wilson’s disease

Serum ceruloplasmin is one of the most commonly used screening tests for Wilson's disease. However immunological assays for ceruloplasmin are not recommended for diagnosis and management of Wilson's disease through calculation of free copper index. Enzymatic methods using non-physiological substrates have toxicity and stability problems, making them difficult to automate. Ferroxidase assays may be a satisfactory alternative for measuring serum ceruloplasmin. The o-dianisidine hydrochloride manual method for estimation of serum ceruloplasmin enzyme activity was compared with an automated method using the ferroxidase activity of ceruloplasmin in measurement in a double blind study in 91 consecutive patients screened for Wilson's disease. The o-dianisidine and ferroxidase methods both successfully identified 7 patients with Wilson's disease. Values for these 7 patients in the o-dianisidine and ferroxidase methods were median 5.0 (range 0-16.0 U/L) and median 45.0 (range 4-166 U/L) respectively. There were 7 other positive values (<62 U/L) with the o-diansidine method and 2 (<200 U/L) with the ferroxidase method, where WD was not confirmed. ROC curves for both methods showed area under the curve of 0.998 for o-dianisidine and 0.997 for ferroxidase. Using literature cut off values of 62 U/L and 200 U/L respectively both methods had 100% sensitivity and specificity was 91.7% (o-dianisidine) and 97.6% (ferroxidase). For the o-dianisidine assay, specificity was improved to 98.8% using a cut off of 22.5 U/L. In the 84 persons (46 adults and 38 children) in whom the diagnosis of Wilson's disease was not established, the mean value for ceruloplasmin activity by the o-dianisidine and ferroxidase methods was 124.7 ± 48.7 U/L and 571.4 ± 168.1 U/L respectively. There were no significant differences between sex or age of patients (p > 0.29). In a subsequent evaluation with 372 specimens, the Pearson correlation coefficient between the assays was 0.908, p < 0.01, slope 4.06, intercept 265.8, with the manual assay as the x-axis. The ferroxidase assay is a suitable replacement for the o-dianisidine assay in detecting patients with Wilson's disease.

Raspberry seed extract effect on the ferroxidase activity of ceruloplasmin isolated from plasma

In this study, the effect of the raspberry seed extract (RSE) on the ferroxidase activity of ceruloplasmin (Cp) isolated from healthy male subject serum was analyzed. The ferroxidase activity of Cp was determined by spectrophotometry using Fe(II) – histidine complex and ferrozine as a chromogenic reagent. The ferroxidase activity of ceruloplasmin was demonstrated in dose-dependent way within the range 22–66 μg/ml. The effect of RSE on Fe(II) concentration, measured as the decrease of Fe(II) concentration in samples and expressed as ΔFe(II), was found to be a dose-dependent within the range 1.20–51.56 μg dm/ml. The ferroxidase activity of Cp was influenced by the RSE within its studied range. However, the addition of the highest concentration of RSE (51.56 μg dm/ml) to the sample containing the highest level of Cp (66 μg/ml) did not affect its ferroxidase activity. It may be suggested that the competition for Fe(II) as the substrate limits the effect of RSE on Cp activity and causes no further changes in Fe(II) elimination.

Copper Availability Contributes to Iron Perturbations in Human Nonalcoholic Fatty Liver Disease

Iron perturbations are frequently observed in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate a potential association of copper status with disturbances of iron homeostasis in NAFLD. We retrospectively studied 140 NAFLD patients and 25 control subjects. Biochemical and hepatic iron and copper parameters were analyzed. Hepatic expression of iron regulatory molecules was investigated in liver biopsy specimens by reverse-transcription polymerase chain reaction and Western blot analysis. NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020). Lower serum concentrations of the copper-dependent ferroxidase ceruloplasmin (21.7 +/- 4.1 vs 30.4 +/- 6.4 mg/dL; P < .001) and decreased liver ferroportin (FP-1; P = .009) messenger RNA expression were found in these patients compared with NAFLD patients with high liver or serum copper concentrations. Accordingly, in rats, a reduced dietary copper intake was paralleled by a decreased hepatic FP-1 protein expression. A significant proportion of NAFLD patients should be considered copper deficient. Our results indicate that copper status is linked to iron homeostasis in NAFLD, suggesting that low copper bioavailability causes increased hepatic iron stores via decreased FP-1 expression and ceruloplasmin ferroxidase activity thus blocking liver iron export in copper-deficient subjects.

Plasma Hormones, ceruloplasmin Ferroxidase Activity and Total Antioxidant Status (Tas) Concentration in Regularly Menstruating Women of Reproductive Age with Ovulatory and Anovulatory Menstrual Cycles

Plasma Hormones, ceruloplasmin Ferroxidase Activity and Total Antioxidant Status (Tas) Concentration in Regularly Menstruating Women of Reproductive Age with Ovulatory and Anovulatory Menstrual Cycles

Ceruloplasmin, Copper, Selenium, Iron, Zinc, and Manganese Levels in Normal and Sulfite Oxidase Deficient Rat Plasma: Effects of Sulfite Exposure

A noticeable effect of sulfite treatment was observed on the plasma ceruloplasmin ferroxidase activity of rats with normal sulfite oxidase activity when compared to normal controls. The plasma levels of selenium, iron, and zinc were unaffected by sulfite in normal and sulfite oxidase (SOX)-deficient rats. While plasma level of Mn was decreasing, plasma Cu level increased in SOX-deficient rats. Treating SOX-deficient groups with sulfite did not alter plasma level of Mn but made plasma level of Cu back to its normal level. This is the first evidence that Cu and Mn status were affected in experimental sulfite oxidase deficiency induced by low molybdenum diet with tungsten addition deserving further research to determine the underlying mechanisms of these observations in experimental sulfite oxidase deficiency.

The iron-o-dianisidine/xylenol orange assay in comparative oxidative stress assessment. Some possible shortcomings

We recently published in this journal an article entitled ‘‘Plasma oxidative stress biomarkers, nitric oxide and heat shock protein 70 in trained elite soccer players’’ (Banfi et al. 2005) but our results with the d-ROMs test (Diacron International, Grosseto, Italy) were believed invalid by Harma et al. (2006), who reported the findings of a previous paper of Erel (2005) comparing the above test with the new iron-o-dianisidine/xylenol orange assay. In this article we provide the following evidence strongly indicating that the above authors made some relevant errors in the assessment of the d-ROMs test validity. Firstly, the relationships between d-ROMs test and ferroxidase activity are neither new nor an original finding. Indeed, Alberti et al. (2000), just in the study leading to the definitive validation of the d-ROMs test by electron paramagnetic resonance (EPR) spectrometry, reported that the contribution of ceruloplasmin ferroxidase activity to the typical change of absorbance at 505 nm (DA505/min) in such a test (see below), although not negligible, appeared relatively small. This is because in the d-ROMs test the serum sample is 100-fold diluted. Moreover, Alberti et al. (2000) demonstrated that an amount of sodium azide equivalent to the maximum expected concentration of ceruloplasmin in the serum (i.e. 4.0 lM) causes only an approximately 7% decrease of the DA505/min value. This may explain the reported correlation between d-ROMs test results and ferroxidase activity (Erel 2005). Of course, the above correlation does not mean that d-ROMs test measures only and exactly the serum ferroxidase activity. Indeed, a 70% of the DA505/min value is still detectable even with a five-to-ten fold excess of the azide in the test (Alberti et al. 2000). Furthermore, the found correlation between ferroxidase activity and d-ROMs test (Erel 2005) is not a general rule. For instance, in hemodyalised patients d-ROMs test value was shown to be increased (Gerardi et al. 2002) while the ferroxidase activity of ceruloplasmin was reduced (Roxborough et al. 2000). In this respect, if right that d-ROMs test measures only the ferroxidase activity, Erel (2005) failed to demonstrate and/or explain how an increased ceruloplasmin activity may justify the experimental/clinical findings, which have been reported to be associated to an increased result of d-ROMs test. On the other hand, even granting, for the sake of an argument, that the above relation is the rule, this is not consistent with the recently recognised controversial role of ferroxidase (Shukla et al. 2006). About the lack of response of d-ROMs test during copper-induced lipoprotein autoxidation, apart from the questionable significance of this experimental approach, this finding may be explained by the fact that d-ROMs test is significantly inhibited by the adding of chelants (Alberti et al. 2000) which sequester the iron thus, inhibiting the Fenton’s reaction. Indeed, Erel (2005), in the autoxidation tests used a citrate buffer to obtain lowdensity lipoprotein and ethylendiamine tetra acetate (EDTA) to prevent further oxidation during the eating. This reply refers to the Letter to the Editors, at http://dx.doi.org/ 10.007/s00421-006-0202.

Decreased Hephaestin Activity in the Intestine of Copper-Deficient Mice Causes Systemic Iron Deficiency

Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (approximately 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (approximately 60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to approximately 40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.

Functional relevance of ceruloplasmin mutations in Parkinson's Disease

Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.

Production and Characterization of Monoclonal Antibodies against Human Ceruloplasmin

Ceruloplasmin (CP) is the major plasma antioxidant and copper transport protein. Monoclonal antibodies (mAbs) against human CP were produced and characterized. A total of five hybridoma cell lines were established (CP2, CP10, CP20, CP25, CP30). From the epitope mapping analysis, two subgroups of mAbs recognize different peptide fragments were identified. When the purified CP was incubated with the mAbs, the ferroxidase activity of CP was inhibited up to a maximum 57 %. Immunoblotting with various tissue homogenates indicated that all the mAbs specifically recognize a single protein band of 130 kDa. They also appear to be extensively cross-reactive among different mammalian including human and avian sources. These results demonstrated that only one type of immunologically similar CP is present in all of the mammalian tissues including human. The CP mAbs could be of great benefit to design the diagnostic kit for CP-related diseases such as Wilson's disease.

The relationship between haptoglobin polymorphism and serum ceruloplasmin ferroxidase activity.

The antioxidative potential of haptoglobin is type dependent; Hp2-2 has much lower antioxidative capacity than Hp1-1 or Hp2-1. It is therefore possible that other antioxidants may compensate for decreased antioxidative capacity in Hp2-2 individuals. Haptoglobin polymorphism was correlated with ceruloplasmin ferroxidase activity in a sample population of unrelated black Jordanians. Hp2-1 was the predominant type, occurring at a frequency of 0.518 and Hp2 was the common allele, occurring at a frequency of 0.6455; no Hp0-0 individuals were observed in the sample population. In general, haptoglobin concentration was highest among Hp1 homozygotes and lowest among Hp2 homozygotes, while ceruloplasmin ferroxidase activity was highest among Hp2 homozygotes and lowest among Hp1 homozygotes. Furthermore, ceruloplasmin ferroxidase activity was higher at haptoglobin concentrations >85 mg/dl compared with that at haptoglobin concentrations of 30-85 mg/dl, which was also higher than at haptoglobin concentrations <30 mg/dl, irrespective of haptoglobin type. These results suggest that ceruloplasmin ferroxidase activity is both haptoglobin type and concentration dependent.

Aceruloplasminemia, an iron metabolic disorder.

Aceruloplasminemia is an inherited disorder of iron metabolism caused by the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of adult-onset neurologic disease, retinal degeneration and diabetes mellitus. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. Severe iron overload and extensive neuronal loss were observed in the basal ganglia, while iron deposition and neuronal cell loss were trivial in the frontal cortices. The cerebellar cortex showed marked loss of Purkinje cells. Iron deposition was more prominent in the astrocytes than in the neurons. Excess iron functions as a potent catalyst of biologic oxidation. Astrocytic deformity and globular structures are characteristic features in aceruloplasminemia brains. The globular structures in the astrocytes were seen in proportion to the degree of iron deposition and reacted positively to anti-4-hydroxynonenal, one of the indicators of lipid peroxidation, and anti-ubiquitin antibodies, but not to anti-alpha-synuclein antibody. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemia brains through lipid peroxidation. Ceruloplasmin may play an essential role in neuronal survival in the central nervous system.

Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems.

Reactive oxygen species and oxidative stress are involved in quinolinic acid (QUIN)-induced neurotoxicity. QUIN, a N-methyl-D-aspartate receptor (NMDAr) agonist and prooxidant molecule, produces NMDAr overactivation, excitotoxic events, and direct reactive oxygen species formation. Copper is an essential metal exhibiting both modulatory effects on neuronal excitatory activity and antioxidant properties. To investigate whether this metal is able to counteract the neurotoxic and oxidative actions of QUIN, we administered copper (as CuSO(4)) intraperitoneally to rats (2.5, 5.0, 7.5, and 10.0 mg/kg) 30 min before the striatal infusion of 1 microliter of QUIN (240 nmol). A 5.0 mg/kg CuSO(4) dose significantly increased the copper content in the striatum, reduced the neurotoxicity measured both as circling behavior and striatal gamma-aminobutyric acid (GABA) depletion, and blocked the oxidative injury evaluated as striatal lipid peroxidation (LP). In addition, copper reduced the QUIN-induced decreased striatal activity of Cu,Zn-dependent superoxide dismutase, and increased the ferroxidase activity of ceruloplasmin in cerebrospinal fluid from QUIN-treated rats. However, copper also produced significant increases of plasma lactate dehydrogenase activity and mortality at the highest doses employed (7.5 and 10.0 mg/kg). These results show that at low doses, copper exerts a protective effect on in vivo QUIN neurotoxicity.

Copper deficiency increases iron absorption in the rat.

Release of iron from enterocytes and hepatocytes is thought to require the copper-dependent ferroxidase activity of hephaestin (Hp) and ceruloplasmin (Cp), respectively. In swine, copper deficiency (CD) impairs iron absorption, but whether this occurs in rats is unclear. By feeding a diet deficient in copper, CD was produced, as evidenced by the loss of copper-dependent plasma ferroxidase I activity, and in enterocytes, CD reduced copper levels and copper-dependent oxidase activity. Hematocrit was reduced, and liver iron was doubled. CD reduced duodenal mucosal iron and ferritin, whereas CD increased iron absorption. Duodenal mucosal DMT1-IRE and ferroportin1 expression remained constant with CD. When absorption in CD rats was compared with that seen normally and in iron-deficient anemic animals, strong correlations were found among mucosal iron, ferritin, and iron absorption, suggesting that the level of iron absorption was appropriate given that the erythroid and stores stimulators of iron absorption are opposed in CD. Because CD reduced the activity of Cp, as evidenced by copper-dependent plasma ferroxidase I activity and hepatocyte iron accumulation, but iron absorption increased, it is unlikely that the ferroxidase activity of Hp is important and suggests another function for this protein in the export of iron from the enterocyte during iron absorption. Also, the copper-dependent ferroxidase activity of Cp does not appear important for iron efflux from macrophages, because Kupffer cells of the liver and nonheme iron levels of the spleen were normal during copper deficiency, suggesting another role for Cp in these cells.

Recent advances in cellular iron metabolism

AbstractIron is essential for oxidation–reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport, and storage (ferritin) of iron in a soluble nontoxic form have evolved. The delivery of iron to most cells occurs after the binding of transferrin to transferrin receptors on the cell membrane. The transferrin receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification. Iron is then transported through the endosomal membrane by the Fe2+ transporter Nramp2/DMT1. Importantly, the identical transporter is involved in the absorption of inorganic iron in the duodenum, a process that is facilitated by the ferric reductase, Dcytb, which provides Fe2+ for Nramp2/DMT1. Organisms and cells have limited ability to excrete excess iron and only some specialized cells evolved active mechanisms to export iron. Iron release from these “donor cells” (primarily enterocytes and macrophages that recycle hemoglobin iron) is mediated by ferroportin 1. The ferroxidase activity of copper‐containing proteins, hephaestin and ceruloplasmin, facilitates the movement of iron across the membranes of enterocytes and macrophages, respectively. Cells are also equipped with a regulatory system that controls iron levels in the labile pool. Levels of iron modulate the capacity of iron regulatory proteins to bind to the iron responsive elements present in the untranslated regions of mRNAs for several proteins involved in iron metabolism (e.g., ferritin, transferrin receptor, Nramp2); these associations, or lack of them, in turn control the expression of these proteins. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. J. Trace Elem. Exp. Med. 16:201–217, 2003. © 2003 Wiley‐Liss, Inc.

Aceruloplasminemia, an inherited disorder of iron metabolism.

Ceruloplasmin, a multi-copper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron. Aceruloplasminemia is an inherited disorder of iron metabolism due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurological disease, which include ataxia, involuntary movements, and dementia. These symptoms reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Twenty-one mutations in the ceruloplasmin gene have been reported in 24 families worldwide. In Japan, the incidence was estimated to be approximately one per 2,000,000 in the case of non-consanguineous marriages. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with increased levels of lipid peroxidation in the serum, cerebrospinal fluid, and erythrocyte membranes. The levels of malondialdehyde and 4-hydroxynonenals, indicators of lipid peroxidation, were also elevated in the basal ganglia and cerebral cortex. Positron emission tomography showed diminished brain metabolism of glucose and oxygen. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximate 45% and 42%, respectively, for complexes I and IV. These findings suggest that iron-mediated free radicals causes neuronal cell damage through lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains.

Increased Lipid Peroxidation and Mitochondrial Dysfunction in Aceruloplasminemia Brains

ABSTRACT Aceruloplasminemia is characterized by iron accumulation in the brain as well as in visceral organs, due to the absence of ceruloplasmin ferroxidase activity. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. An increased iron concentration was associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed brain glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50 and 43%, respectively, for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62 and 65%. These findings suggest that iron-mediated free radicals may contribute to neuronal cell damage through increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.

The copper-iron connection: Hereditary aceruloplasminemia

Hereditary aceruloplasminemia is an autosomal recessive disorder of iron homeostasis due to loss-of-function mutations in the ceruloplasmin gene. Affected individuals may present in adulthood with evidence of hepatic iron overload, diabetes, peripheral retinal degeneration, dystonia, dementia, or dysarthria. Laboratory studies demonstrate microcytic anemia, elevated serum ferritin, and a complete absence of serum ceruloplasmin ferroxidase activity. Consistent with the observed neurologic findings, magnetic resonance imaging reveals iron accumulation within the basal ganglia. Histologic studies detect abundant iron in hepatocytes, reticuloendothelial cells of the liver and spleen, β cells of the pancreas, and astrocytes and neurons throughout the central nervous system. Characterization of this disorder reveals an essential role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and provides new insights into the mechanisms of human iron metabolism. Semin Hematol 39:282-289. Copyright 2002, Elsevier Science (USA). All rights reserved.