Serum ferritin: Does it differ from tissue ferritin?

Linder, Maria C.; Schaffer, Kenneth J.; Hazegh‐Azam, Maryam; Zhou, Cecilia Y.J.; Tran, Tue N.; Nagel, Glenn M.

doi:10.1111/j.1440-1746.1996.tb00030.x

Cited by 139 publications

(185 citation statements)

References 10 publications

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“…1). This observation may be related to the function of liver for storing excess copper, which may allow for a larger window of copper concentrations (48). Aside from the elevated copper content in the G37R, G93A, and WT livers, total tissue copper levels were generally independent of SOD1 mutant expression levels and remained consistent in the spinal cords and brains across the different types of mice (Fig.…”

Section: Overall Copper and Zinc Concentrations From Brain Spinal Comentioning

confidence: 87%

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Lelie

Liba

Bourassa

et al. 2011

Journal of Biological Chemistry

114

138

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Mutations in the metalloenzyme copper-zinc superoxide dismutase (SOD1) cause one form of familial amyotrophic lateral sclerosis (ALS), and metals are suspected to play a pivotal role in ALS pathology. To learn more about metals in ALS, we determined the metallation states of human wild-type or mutant (G37R, G93A, and H46R/H48Q) SOD1 proteins from SOD1-ALS transgenic mice spinal cords. SOD1 was gently extracted from spinal cord and separated into insoluble (aggregated) and soluble (supernatant) fractions, and then metallation states were determined by HPLC inductively coupled plasma MS. Insoluble SOD1-rich fractions were not enriched in copper and zinc. However, the soluble mutant and WT SOD1s were highly metallated except for the metal-bindingregion mutant H46R/H48Q, which did not bind any copper. Due to the stability conferred by high metallation of G37R and G93A, it is unlikely that these soluble SOD1s are prone to aggregation in vivo, supporting the hypothesis that immature nascent SOD1 is the substrate for aggregation. We also investigated the effect of SOD1 overexpression and disease on metal homeostasis in spinal cord cross-sections of SOD1-ALS mice using synchrotron-based x-ray fluorescence microscopy. In each mouse genotype, except for the H46R/H48Q mouse, we found a redistribution of copper between gray and white matters correlated to areas of high SOD1. Interestingly, a diseasespecific increase of zinc was observed in the white matter for all mutant SOD1 mice. Together these data provide a picture of copper and zinc in the cell as well as highlight the importance of these metals in understanding SOD1-ALS pathology.First described in 1869 by French neurologist Jean-Martin Charcot (1), amyotrophic lateral sclerosis (ALS) 4 is defined by the progressive demise of lower and upper motor neurons leading to the degeneration of muscle tissue and eventual paralysis (2). Familial ALS was linked in 1993 to mutations in the gene that encodes the metalloenzyme copper-zinc, superoxide dismutase (SOD1) (3), and since that time more than 140 different disease-causing mutations have been identified (4). Before the discovery linking SOD1 and ALS, epidemiological studies on ALS suggested that exposure to metallic trace elements was a significant factor among many other environmental factors such as viruses, strenuous exercise, and excitotoxic chemicals that may have a role in ALS etiology (4 -6). Studies on exposure to and tissue accumulation of metallic elements in ALS patients show a correlative yet unspecified role for many metals including copper and zinc in SOD1-related ALS (7-19). Over the years, a number of hypotheses relating metal toxicity to ALS have been proposed. For example, abnormal accumulations of redox-active metal ions such as iron or copper in ALS patients were generally believed to be detrimental due to their ability to mediate oxidative damage through participation in reactions that lead to formation of reactive oxygen species. A more specific hypothesis linking metallation levels of mutant SOD1 to...

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Section: Overall Copper and Zinc Concentrations From Brain Spinal Comentioning

confidence: 87%

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Lelie

Liba

Bourassa

et al. 2011

Journal of Biological Chemistry

114

138

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“…Until recently, ceruloplasmin had been widely regarded as the copper delivery protein (14), as 95% of copper in the circulation is complexed with this protein. However, the role of ceruloplasmin in copper uptake has been confounded by the description of aceruloplasminemic patients who suffer no copper imbalance (15,16).…”

mentioning

confidence: 99%

The copper transporter CTR1 provides an essential function in mammalian embryonic development

Kuo

Zhou

Cosco

et al. 2001

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

333

261

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Copper serves as an essential cofactor for a variety of proteins in all living organisms. Previously, we described a human gene (CTR1;SLC31A1) that encodes a high-affinity copper-uptake protein and hypothesized that this protein is required for copper delivery to mammalian cells. Here, we test this hypothesis by inactivating the Ctr1 gene in mice by targeted mutagenesis. We observe early embryonic lethality in homozygous mutant embryos and a deficiency in copper uptake in the brains of heterozygous animals. Ctr1 ؊/؊ embryos can be recovered at E8.5 but are severely developmentally retarded and morphologically abnormal. Histological analysis reveals discontinuities and variable thickness in the basement membrane of the embryonic region and an imperfect Reichert's membrane, features that are likely due to lack of activity in the collagen cross-linking cupro-enzyme lysyl oxidase. A collapsed embryonic cavity, the absence of an allantois, retarded mesodermal migration, and increased cell death are also apparent. In the brains of heterozygous adult mice, which at 16 months are phenotypically normal, copper is reduced to approximately half compared with control littermates, implicating CTR1 as the required port for copper entry into at least this organ. A study of the spatial and temporal expression pattern of Ctr1 during mouse development and adulthood further shows that CTR1 is ubiquitously transcribed with highest expression observed in the specialized epithelia of the choroid plexus and renal tubules and in connective tissues of the eye, ovary, and testes. We conclude that CTR1 is the primary avenue for copper uptake in mammalian cells.

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“…Copper ions are required for at least three key enzymes in Saccharomyces cerevisiae. The cuproenzymes include the cytosolic superoxide dismutase Sod1, 1 the plasma membrane ferroxidase Fet3, and the mitochondrial inner membrane enzyme cytochrome c oxidase (CcO). The copper quota of the yeast S. cerevisiae is about 5 ϫ 10 5 atoms per cell (3,4).…”

mentioning

confidence: 99%

Yeast Contain a Non-proteinaceous Pool of Copper in the Mitochondrial Matrix

Cobine

Ojeda

Rigby

et al. 2004

Journal of Biological Chemistry

202

199

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The yeast mitochondrion is shown to contain a pool of copper that is distinct from that associated with the two known mitochondrial cuproenzymes, superoxide dismutase (Sod1) and cytochrome c oxidase (CcO) and the copper-binding CcO assembly proteins Cox11, Cox17, and Sco1. Only a small fraction of mitochondrial copper is associated with these cuproproteins. The bulk of the remainder is localized within the matrix as a soluble, anionic, low molecular weight complex. The identity of the matrix copper ligand is unknown, but the bulk of the matrix copper fraction is not protein-bound. The mitochondrial copper pool is dynamic, responding to changes in the cytosolic copper level. The addition of copper salts to the growth medium leads to an increase in mitochondrial copper, yet the expansion of this matrix pool does not induce any respiration defects. The matrix copper pool is accessible to a heterologous cuproenzyme. Co-localization of human Sod1 and the metallochaperone CCS within the mitochondrial matrix results in suppression of growth defects of sod2⌬ cells. However, in the absence of CCS within the matrix, the activation of human Sod1 can be achieved by the addition of copper salts to the growth medium.Copper is an essential cell nutrient acting as a cofactor in nearly 20 enzymes (1). However, excess accumulation of copper ions results in toxicity. Evidence for the effectiveness of copper ions as a toxin comes from its historic use as a fungicide, molluscide, and algicide. Homeostatic mechanisms exist in cells to regulate the cellular concentration of copper ions, thus maintaining copper balance and minimizing deleterious effects. Cells appear to maintain a quota for essential metal ions; this quota is primarily the quantity necessary to metallate the various copper proteins (2, 3). Copper ions are required for at least three key enzymes in Saccharomyces cerevisiae. The cuproenzymes include the cytosolic superoxide dismutase Sod1, 1 the plasma membrane ferroxidase Fet3, and the mitochondrial inner membrane enzyme cytochrome c oxidase (CcO). The copper quota of the yeast S. cerevisiae is about 5 ϫ 10 5 atoms per cell (3, 4).It is unclear what fraction of the 5 ϫ 10 5 copper atoms per cell is from copper in Sod1, Fet3, and CcO. Expression of these copper-binding proteins varies with growth conditions, suggesting that the copper may be distributed differently depending on growth conditions. Clearly, a significant fraction of the cellular copper is associated with Sod1; however, not all Sod1 molecules are metallated (4, 5). Fet3 requires four copper ions for activity, but levels of this protein are dependent on iron status of the medium (6). CcO levels vary depending on whether the cells are grown by fermentation or respiration. In addition, a varying quantity of cellular copper exists bound to two metallothioneins, Cup1 and Crs5 (7,8). Expression of CUP1 and CRS5 is regulated by copper levels through the copper-responsive transcription factor Ace1 (9, 10). An increase in the free Cu(I) ion pool activates Ace1 throu...

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Serum ferritin: Does it differ from tissue ferritin?

Cited by 139 publications

References 10 publications

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

Copper and Zinc Metallation Status of Copper-Zinc Superoxide Dismutase from Amyotrophic Lateral Sclerosis Transgenic Mice

The copper transporter CTR1 provides an essential function in mammalian embryonic development

Yeast Contain a Non-proteinaceous Pool of Copper in the Mitochondrial Matrix

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