Recent advances in the understanding of the role of zinc in ocular tissues.

Metallomics View Article Online

Published on 07 November 2013. Downloaded by University of Chicago on 30/10/2014 21:49:55.

CRITICAL REVIEW

Cite this: Metallomics, 2014, 6, 189

View Journal | View Issue

Recent advances in the understanding of the role of zinc in ocular tissues Marta Ugarte*a and Neville N. Osborneb Zinc levels are high in ocular tissues and the distribution is non-uniform. Zinc is particularly concentrated in the corneal epithelium and posterior stroma. Zinc is the most abundant trace metal in the retina. Bound-zinc is particularly located in the inner nuclear layer, (e.g. forming part of the structure of zinc finger transcription factors), while loosely-bound zinc is prominent in the retinal pigment epithelium and photoreceptor layers. Loosely-bound zinc ions in the photoreceptors might play a role in the phototransduction cascade and rhodopsin regeneration. Loosely-bound zinc is also found in presynaptic vesicles of photoreceptor cells in the outer plexiform and inner plexiform layers and can be synaptically released to affect both ionotropic and

Received 4th October 2013, Accepted 6th November 2013

metabotropic receptors and also ion channels to modulate neurotransmission. The correct amount of

DOI: 10.1039/c3mt00291h

trafficking/storage proteins (i.e. metallothionein). The retinal homeostasis of zinc is dysregulated in systemic zinc depletion, aging and diseases such as age-related macular degeneration. Manipulation of

www.rsc.org/metallomics

retinal zinc metabolism in these situations might improve visual function.

loosely-bound zinc ions is maintained by regulating the function of zinc transporters, sensors and

Introduction Among ocular tissues, zinc levels are high and unevenly distributed in the multi-layered neuroretina, retinal pigment epithelium a

Moorfields Eye Hospital, City Road EC1V 2PD, London, UK. E-mail: [email protected] b ńdez-Vega, Fundacioń de Investigacioń Oftalmolo´gica, Instituto Oftalmolo´gico Ferna ńdez-Vega s/n 33012, Oviedo, Asturias, Spain Avda. Dres. Ferna

Marta Ugarte studied Medicine at the Basque Country University in Spain and then a DPhil degree at the University of Oxford under the supervision of Professor Osborne. Training in ophthalmology following in hospitals in London and Manchester, where she was a clinical lecturer. She is presently a medical retina fellow at Moorfields Eye Hospital in London. She has constantly remained interested in the subject of her DPhil studies, Marta Ugarte which was in trying to understand the role of zinc in the healthy and unhealthy retina and in particular whether dyshomeostasis of zinc contributes significantly in the pathogenesis of age-related macular degeneration, as this may lead to a novel way to treat the disease.

This journal is © The Royal Society of Chemistry 2014

(RPE)1–7 (Fig. 1) and cornea7 (Fig. 2). Although zinc is present in all retinal cells, it appears to be particularly concentrated in photoreceptors. Zinc amounts are significant across the corneal epithelium and posterior stroma. Zinc, as an essential part of zinc-finger DNA binding proteins, participates in the transcriptional regulation of hundreds of binding elements8,9 and in relation to the retina it influences the expression of numerous zinc-binding proteins. Induction of metallothionein (MT) synthesis can cause a decrease in peroxide levels.10 Zinc is also an

Neville Osborne obtained PhD and DSc degrees at London and St Andrews Universities in the UK. After spending six years at a Max Planck Institute in Germany he returned to the UK to take up a position at Oxford University where he taught medical students and lead a large research group for many years. Professor Osborne now spends a significant part of his time at the Fundacioń de Investigacioń Neville N. Osborne Oftalmolo´gica in Oviedo. His long time research interest relates to retinal neuronal death in ocular diseases and neuroprotection.

Metallomics, 2014, 6, 189--200 | 189

View Article Online


Critical Review

Metallomics

Fig. 1 The retina, the light-sensitive layer at the back of the eye (A), is formed of functionally different layers with cells (B). The retinal pigment epithelium (RPE) is loosely attached to the highly organised neuroretina, which consists of two synaptic layers, the outer (OPL) and inner (IPL) plexiform layers, intercalated between three cellular layers: (1) the outer nuclear layer (ONL), where the perikarya of the photoreceptors are located; (2) the inner nuclear layer (INL), where the bodies of the horizontal (red), bipolar (blue), amacrine (yellow), and interplexiform cells are found, and (3) the ganglion cell layer (GCL) with ganglion cell bodies. In the OPL the processes of the photoreceptors, bipolar, horizontal and interplexiform layers interact. In the IPL, the processes of 4 neuronal classes interact: bipolar, amacrine, ganglion and interplexiform cells. In addition to neurones, the neuroretina also possesses glial cells. The most prominent type being the Mu ¨ller cell (grey). This elongated cell contains its body usually in the middle of the INL and extends from the outer limiting membrane (OLM) to the inner limiting membrane. At the level of the OLM, Mu ¨ller cells are fused to the photoreceptors inner segments (RIS), which are very rich in cellular organelles (i.e. mitochondria, Golgi apparatus and endoplasmic reticulum). The RIS are connected to the photosensitive outer segments of the photoreceptors (ROS). (C) Frozen rat retinal section stained with DAPI to identify layers containing cell nuclei (RPE, ONL, INL. GCL). (D) False colour overlay maps of the distributions of phosphorus (red), potassium (blue) and sulphur (green) highlighted anatomical landmarks and allowed delineation of the boundaries of each retinal layer, (E) zinc distribution map (2 4 mm resolution) of 30 mm-thick freeze-dried cryosections of rat retina were obtained with synchrotron X-ray fluorescence microscopy at the I18 beamline Diamond Light Source (www.diamond.ac.uk). Zinc was mainly localised in the RIS/OLM, OPL and INL. Scale bar, 20 mm (modified from Ugarte et al. 20124).

antioxidant reducing superoxide formation by inhibiting NADPH oxidase11 and inhibits re-uptake mechanisms H+ 12 by altering voltage-gated membrane proton channels.13 The ability of zinc to inhibit oxidation appears to be concentration dependent, as high levels of zinc are toxic to the retina/RPE.3,14,15 Thus, zinc appears to have a host of different functions either directly or by indirectly altering enzyme/proteins. The purpose of this overview is to summarise some of the most recent studies related to the role of zinc in retinal dysfunction caused by systemic zinc deficiency. Significantly, zinc concentrations in the retina have been suggested to be affected in age-related macular degeneration (AMD).16 However, conclusive data related to the efficacy of zinc intake in order to prevent or treat age-related macular degeneration and retinal ischemia, simply does not exist. Moreover, inconclusive information exists on the role of loosely-bound zinc to act as a second messenger and be involved in cell–cell and neuronal–glial interactions. Fig. 2 Structure of rat cornea (A–C) and heat map (D) (false colour image) showing the distribution of endogenous zinc. Red colours represent areas of high concentration, while blue shades represent areas of low concentration. (B) Diagram showing different corneal structures. (C) Corneal section stained with DAPI showing cell nuclei. Scale bar, 50 mm (modified from Ugarte, Grime and Osborne7).

190 | Metallomics, 2014, 6, 189--200

Retinal zinc concentration and localisation Normal development, homeostasis and repair following injury depend upon appropriate levels of zinc and other elements


View Article Online


Metallomics

such as calcium, magnesium, copper and iron.17,18 Zinc is the second most abundant metal in the human body (total 2.5 g)16 after iron (total 3.5 g),19 but it is the most common in the retina4 implying a very important role in this tissue. Zinc is present in the body in the form of a bivalent cation, Zn(II), through donation of electrons from its outer orbitals. Zn(II), unlike other transition metals [e.g. Mn(II), Fe(II), Co(II), Ni(II), Cu(II)], contains a filled d orbital (d10) and does not participate in redox reactions but functions as a Lewis acid to accept a pair of electrons. This lack of redox activity makes Zn(II) an ideal metal cofactor for reactions that require redox-stable ions, such as proteolysis and hydration of CO2.20 The great majority of zinc binds tightly to ligands rich in sulphur (e.g. cysteine), nitrogen (e.g. histidine) and oxygen (e.g. glutamate, aspartate) by accepting pairs of electrons in its unfilled outer orbital. However, approximately 10% of total zinc is thought to exist as loosely bound zinc.21 Zinc’s biochemical properties explain the mechanisms by which it exerts its diverse biological functions (i.e. catalytic, structural, regulatory). Erie et al.22 measured total zinc at a concentration of 292.1 98.5 mg g1 dry weight (dw) in human retinal pigment epithelium (RPE)/choroid and 123.1 62.2 mg g1 dry weight in the neuroretina using inductively coupled plasma mass spectrometry (ICP-MS). Their values approximate those found in other mammals. Thus, for example, with the colorimetric dithizone method, the concentration of zinc in the RPE/choroid was estimated to be 466 mg g1 dw in pigmented rabbits,23 86.2 mg g1 dw in albino rabbits24 and 75.8 7.4 mg g1 dw in albino rats with ICP-MS.5 With the same technique, the absolute amount of zinc in albino rats has been measured as 66 12.6 mg per neuroretina4 and the concentration 32 4.7 (ref. 4) to 72 mg g1 dw.5 Proton induced X ray emission (PIXE) and synchrotron X ray fluorescence have shown that the distribution of zinc in the multi-layered retina is non-uniform.4 The highest levels are found in the outer plexiform layer (OPL) (91.3 25.12 mg g1 dw) and inner nuclear layer (INL) (103.8 16.22 mg g1 dw), 1.37 and 1.55 greater than the average retinal level (66.8 2.62 mg g1 dw), respectively. The presence of a high concentration of zinc in these layers,1,3,4,24–27 is likely to be related to their particular physiology and demand for specific metal-dependent functions. In the RPE, zinc is found bound to melanin (in melanosomes),28–30 MT31 and retinol dehydrogenase (at the catalytic site of the enzyme).32 In the photoreceptor inner segment (RIS)/outer limiting membrane (OLM) layer, loosely bound zinc is within Golgi apparatus, endoplasmic reticulum in the myoid part of the RIS and in Muller cell end feet.1 In the plexiform layers, loosely-bound zinc ions are found within synaptic vesicles together with glutamate.1 In the outer nuclear layer (ONL), zinc is localised in the nucleus1 likely being part of DNAbinding proteins (e.g. zinc finger transcription factors) in a loosely-bound form in dark-adapted retina and more tightly bound in light-adapted.3 No evidence appears to exist in relation to the quantification of loosely-bound zinc in the normal mammalian retina. Studies on brain tissue have reported transient increases of Zn(II) ranging from sub mM33 to 1–100 mM34–36 at the synaptic cleft


Critical Review

with neuronal depolarisation. Similar concentrations could be found in the retinal synaptic layers (i.e. OPL, IPL). This needs further investigation.

Retinal functions of zinc Zinc’s biological functions are usually associated with proteins.37–39 Zinc is required for the function of more than 300 proteins.18 Sixty percent of zinc-binding proteins in the human proteome are primarily enzymes and proteins involved in ion transport. The remaining 40% are transcription factors.18 Bound zinc can participate directly in chemical catalysis of enzymes or maintain the structure and stability of proteins. In addition, increasing evidence suggests a regulatory role of loosely-bound zinc ions,38–40 influencing the activity of several protein targets (Table 1), including phosphatases, phosphodiesterases, caspases, kinases, membrane receptors and channels. This has led to the idea that zinc ions might be a second messenger regulating various cellular signals (similar to what has previously been shown for calcium cAMP, cGMP). Zinc appears to be essential for optimal retinal cell metabolism. Depletion of intracellular zinc induces caspase-dependent apoptosis of cultured retinal cells.41–43 Zinc is a key player for multiple functions of general cell metabolism (e.g. mitochondrial function,44,45 gene expression,46–49 antioxidant defense,50,51 DNA repair mechanisms,52 cell proliferation,53 cell differentiation,53 apoptosis54), as well as retinal development53,55–58 and specific retinal functions (e.g. phototransduction, rhodopsin recovery, neurotransmission).59–77 A brief list of some of the most recent zinc finger transcription factors found to play a role in the retina can be seen in Table 2. Although zinc is present in all retinal cells it appears to be concentrated in photoreceptor rod segments, the ONL and in photoreceptor cell synaptic region (i.e. outer plexiform layer, OPL)3,4 (Fig. 1). Zinc could participate in: (1) the conversion of light stimulation into an electrical signal (i.e. phototransduction) in the ROS, (2) intracellular signals within the photoreceptors (e.g. rhodopsin deactivation and/or regeneration) and/or (3) communication between photoreceptors and other retinal neurones and ¨ller) cells (Fig. 3). Phototransduction, the process by glial (Mu which light stimulation is converted into an electrical signal, takes place in the photoreceptors (Fig. 3). Absorption of a photon by the photopigment, rhodopsin, in photoreceptor cell disc membranes, is coupled with the closure of cation channels in the plasma membrane of the ROS and photoreceptor cell hyperpolarisation. Rhodopsin consists of an apo-protein, opsin, attached to the chromophore, 11-cis-retinaldehyde, derived from vitamin A. The absorption of light by rhodopsin ultimately causes the conversion of 11-cis-retinal to all-trans-retinal (photoreaction) (which is rapidly reduced to all-trans-retinol) and a conformational change of rhodopsin that leads to the phototransduction cascade. In the absence of light, cation channels in the ROS that conduct an inward current, carried largely by Na+ and Ca2+, are opened by intracellular cGMP. In the presence of light, these channels are closed by a three-step process: (1) light is absorbed

Metallomics, 2014, 6, 189--200 | 191

View Article Online

Critical Review


Table 1

Metallomics

Proteins whose activity is influenced by loosely-bound Zn(II)

Zn(II)-binding proteins

Zinc effect

Biological function

Protein tyrosine phosphatase b

Inhibition

Aconitase (tricarboxylic acid cycle)

Inhibition

Activation of receptor tyrosine kinases Reduced ATP production

Alpha-ketoglutarate dehydrogenase (tricarboxylic acid cycle) Phosphofructokinase (glycolysis)

Inhibition

Reduced ATP production

Inhibition


Inhibition


Glyceraldehyde 3-phosphate dehydrogenase (glycolysis) Isocitrate dehydrogenase-NAD+ dependent (glycolysis) Cytochromes bc complex (electron transport chain)

Inhibition


Inhibition


Succinate dehydrogenase

Inhibition


Cytochrome c oxidase (electron transport chain)

Inhibition


Protein kinase C

Stimulation

NADPH oxidase subunits

Facilitates translocation to membrane

Immediate early gene egr-1

Induction

Enhances the expression of the enzyme NADPH oxidase Stimulate the activation of poly (SDP-ribose) polymerase (PARP) RAS/ERK/MAPK signalling pathway

Extracellular signal-regulated kinase (ERK) 1, 2

Activation

Phosphatidylinositol 3-kinase

Stimulation

Caspase AMPA receptors on horizontal cells membrane

Activation Potentiation/inhibition (depending on local concentration) Blockade

Voltage-gated calcium channels on photoreceptor terminals membrane

Hemigap junctions on horizontal cells membrane Glycine receptors on AII amacrine cells membrane GABA A on transient amacrine cells membrane GABA on L-type horizontal cells membrane GABA on cone terminal membrane

Table 2

Inhibition Potentiation/inhibition (depending on local concentration) Inhibition Inhibition Inhibition

RAS/ERK/MAPK signalling pathway Impaired mitochondrial trafficking Apoptosis Neuromodulation

Ref. Angiogenesis

164

Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Mitochondrial dysfunction Generation of ROS

165 and 166 166

170

Generation of ROS

171

Mitochondrial dysfunction Change in gene expression Mitochondrial dysfunction Mitochondrial dysfunction

172

Reduces photoreceptor glutamate release. Suppresses the radial dark current of photoreceptors. Reduction of a-wave amplitude. Reduces b-wave amplitude. Neuromodulation

Cone signal reduction Reduce negative feedback from L horizontal cells to cones

167 168 166 169, 170 166 166

172 173 174 142 91 77

62 72 70 67 75

Zinc finger transcription factors with known function in the mammalian retina

Zinc finger transcription factors

Retinal function

Ref.

Zic1, 2, 3 ZNF644 Zinc finger protein 408 Splat family Yin Yang 1 KLF15

Proliferation and differentiation of retinal progenitor cells Retinal development Retinal vasculogenesis Photoreceptor development Retinal cell differentiation Repression of photoreceptor-specific gene expression in the inner retina

53 175 176 177 81 47

by and activates rhodopsin, (2) the activated rhodopsin stimulates the G-protein transducin, which in turn activates the cGMP phosphodiesterase, the enzyme that catalyses the breakdown of cGMP to 5 0 -GMP; (3) as the cGMP concentration is lowered, the channels close, reducing the inward current and

192 | Metallomics, 2014, 6, 189--200

causing photoreceptor hyperpolarisation. Rhodopsin either undergoes additional rounds of transducin activation or is phosphorylated by rhodopsin kinase. Phosphorylated rhodopsin complexes with arrestin and is regenerated by conjugation of opsin with 11-cis-retinal. Reisomerization of the 11-cis-retinal


View Article Online


Metallomics

Critical Review

Fig. 3 Schematic representation of the proposed roles of zinc in the retina. The photopigment, rhodopsin (Rho), possesses seven zinc coordination motifs, which mediate dose-dependent changes in rhodopsin stability and function in the physiological range. The enzyme 3 0 ,5 0 -cGMP phosphodiesterase (PDE), which catalyzes the hydrolysis of cGMP and leads to closure of the cGMP-gated channel and blockade of the dark influx of extracellular cations (Na+ and Ca2+) into the outer segments (OS), requires zinc for the stability of its structure and catalytic functions. Zinc binding increases the affinity for rod outer segment membrane of recoverin (Recov), the protein which is involved in deactivation of rhodopsin after light stimulation. Zinc is necessary for the function of the RPE enzyme, retinol dehydrogenase (RD).

from the all-trans retinol occurs in the adjacent RPE by the zincdependent metalloenzyme, retinol dehydrogenase, which requires catalytic Zn(II) at the active site of the enzyme, where it participates directly in the catalytic mechanism interacting with the retinol substrate undergoing dehydrogenation (Fig. 3).78 Among other effects within the retina,24,27,55,60,62,79–82 zinc influences the function of rhodopsin,83–86 recoverin,87 phosphodiesterase88 and arrestin.89 Rhodopsin binds 7 zinc atoms per dimer, three in each monomer and the 7th in the area of contact between both monomers. Localisation of zinc binding sites at the dimer interface of rhodopsin suggests that zinc modulates the intermolecule interactions between adjacent rhodopsin molecules that in turn modulate intermolecular interactions to enhance the stability and function of their receptor thermal stability (required for regeneration of rhodopsin). Two zinc-binding sites located in the intradiscal loop are low affinity and zinc binding destabilizes rhodopsin. The high-affinity binding sites are in the transmembrane domain and are essential in rhodopsin folding, 11-cisretinal binding and chromophore-receptor interaction stability. What is more, loosely-bound Zn(II) by acting directly on rhodopsin increases its phosphorylation (required for rhodopsin regeneration). Zinc binding to calcium-loaded recoverin, the protein involved in deactivation of rhodopsin after light stimulation, reduces its thermal stability and increases its affinity for the ROS membrane.


The enzyme 3 0 ,5 0 -cGMP phosphodiesterase requires zinc for the stability of its structure and catalytic functions.88 Loosely-bound zinc is localized to the presynaptic vesicles of photoreceptor cells in the OPL, as well as in the inner plexiform layer (IPL).1,3,4,68,69 Zn(II) is released into the synaptic cleft with neuronal depolarisation and modulates both ionotropic and metabotropic post-synaptic receptors through zinc-specific allosteric binding sites.63,64,66,69,74 For example, zinc inhibits GABA receptors,70,76,90 reducing their inhibitory action. The effect of zinc on excitatory glutamate receptors is complex. Not only can zinc act as an inhibitory neuromodulator of glutamate release,3,63,69 but it has biphasic and cell type-specific regulation of both NMDA and AMPA/kainate glutamate receptors.73,91 Additionally, zinc can potentiate glycine-mediated currents67 and regulate voltage-gated calcium channels, as well as potassium,65 sodium, and chloride channels.72,75 In addition to the pool of vesicular loosely-bound zinc, there is evidence for an additional intracellular pool of loosely-bound zinc in the photoreceptor RIS that can be released to the extracellular space with photoreceptor activity. Redenti et al.64,66 stained extracellular loosely-bound zinc with a membrane impermeable probe, Newport Green, and showed accumulation extracellularly upon exposure of retinal slices to K+. While this work did not definitively determine the source of this pool of released

Metallomics, 2014, 6, 189--200 | 193

View Article Online

Critical Review

Metallomics


loosely-bound zinc, Golgi and mitochondrial pools of zinc from the RIS could contribute loosely-bound zinc. Protein-bound zinc could also potentially be released to form a looselybound zinc pool upon light stimulation. We propose that the change in the coordination environment of rhodopsin-bound zinc upon exposure to light could result in a release of Zn(II) in the ROS and flow to the inner segments via the cytoplasm. This needs further investigation.

Retinal zinc homeostasis Despite the essential role of zinc in cell metabolism, high levels of loosely-bound zinc promote neuronal and RPE cell death through effects on excitotoxicity, oxidative stress and disruption of energy generation.14,15,45,46,92–98 The cellular zinc buffering capacity determines the threshold between physiological and pathophysiological action of zinc ions. The correct amount of zinc ions is maintained by regulating the expression and function of transporters, sensor and trafficking/storage proteins (MTs, semenogelins).38,39,95,99,100 Zinc crosses cellular membranes through transporters of the ZIP [Zrt- and Irt-like proteins (SLC39A)] and ZnT [solute-linked carrier 30 (SLC30A)] families.20,101–105 ZIP proteins promote zinc transport from the extracellular fluid or from intracellular vesicles into the cytoplasm along a concentration gradient. ZIP1, ZIP2, ZIP3, ZIP4, ZIP12, ZnT3, ZnT6 and ZnT7 have all been identified in human RPE cells in culture (Table 3).103,105 The basolaterally localised ZIP2 and ZIP4 have been shown to participate actively in zinc uptake in vitro105 and could mediate transport from choroidal blood into the retina in vivo. ZnT3106 and ZnT726 have also been found in mouse neuroretina, where they play a role in neuromodulation of dopaminergic pathways. ZnT3 is present in RIS/OLM, INL, GCL, OPL and IPL layers. In ¨ller cells,106 ZnT3 is localised in the apical villi, isolated rodent Mu soma and endfeet suggesting these cells may provide a system for zinc homeostasis, throughout the neuroretina. ZnT7 is expressed on ROS, amacrine and ganglion cells, and both plexiform layers in mouse retina. ZnT8 has been detected by immunocytochemistry in mouse ONL, OPL, ganglion cell layer and nerve fibre layer.107 Zinc sensing molecules such as metal response elementbinding transcription factor-1108 respond to zinc levels by regulating the expression of genes coding for homeostatic

Table 3

molecules (e.g. MT, zinc transporters) and do also contribute to zinc homeostasis. MT are cysteine-rich zinc-binding proteins present in significant amounts in the RPE, retinal ganglion cells, corneal epithelium and endothelium.109,110 MTs are involved in metal (particularly zinc and copper) homeostasis and so participate in different ocular functions. MTs are key zinc buffers intracellularly111 by accepting and releasing zinc ions in response to various stimuli. Given its role in the modulation of free zinc concentrations, MTs would be expected to be localized in regions where zinc is playing a regulatory role in a loosely-bound form readily exchanging binding sites. The posterior corneal stroma and retinal inner nuclear layer contain high amounts of zinc while they lack MTs suggesting that zinc is playing a static catalytic or structural role in these locations. The zinc found in the corneal epithelium and retinal photoreceptors is likely to be playing, at least in part, a regulatory function.7 The generation, transmission, termination of zinc signals involve proteins that use coordination dynamics to control metal association and dissociation (e.g. MTs95 and semenogelins112). MTs are present in significant amounts in the RPE and ganglion cells.109,110 MTs not only bind Zn(II) and act as storage molecules, but also transfer zinc to other proteins (zinc-dependent metalloproteins), which require zinc ions for their structure and/or activity, or whose activity is influenced by Zn(II). Semenogelin I and II,112 a second group of high-capacity zinc-binding proteins involved in zinc cellular homeostasis, have been detected in photoreceptor and ganglion cells.

Retinal dysfunction associated with zinc deficiency The body does not have storage of zinc. Approximately 1% of the total body zinc needs to be replenished daily with the diet.18,113 Long periods of zinc depletion cannot be compensated. Systemic zinc deficiency can result from mutations in the gene encoding the ZIP4-transporter (i.e. acrodermatitis enteropathica),114 which is important in intestinal uptake, or can be acquired in cases of decreased dietary intake, decreased absorption, increased elimination, tissue and cellular redistribution or use of certain medications (penicillamine, diuretics, antimetabolites, valproate and iron salts).113,115 Serum/plasma zinc levels (normal range 70–250 mg dl1) reflect intake and respond to alterations over

Retinal localisation of molecules involved in zinc homeostasis

RPE ROS RIS/OLM ONL OPL INL IPL GCL NFL ¨ller cells Mu Amacrine cells Ganglion cells

194 | Metallomics, 2014, 6, 189--200

ZIP

ZnT

ZIP1, 2, 3, 4, 12103,105

ZnT3,106 ZnT726 ZnT3106 ZnT8107 ZnT3,106 ZnT3106 ZnT3106, ZnT3106, ZnT87 ZnT3106 ZnT726 ZnT726

MT ZnT6,3,105 ZnT7103,105

MT110

ZnT7,26 ZnT8 ZnT726 ZnT8107

MT109,110 MT110 MT109


View Article Online


Metallomics

short periods of time. Other biomarkers of zinc status,116 such as the activity of zinc-dependent enzymes (e.g. alkaline phosphatase) and 24 h urinary zinc excretion can also be affected. There is evidence that retinal zinc bioavailability responds rapidly to alterations in serum levels.117,118 This may result from a fast turnover and retinal uptake mediated by concentration gradients via ZIP transporters. Experimental studies with pigs119 and pigmented rats28,29 fed zinc deficient diets have shown reduced zinc concentration in RPE melanosomes after 6 and 3 months, respectively. In the early stages of zinc deficiency, specific retinal regulatory mechanism of zinc homeostasis might be in place. Albino rats on zinc-deficient diet for 6 weeks, which developed depressed plasma zinc levels, did not show alterations in the total amount of zinc in the RPE or neuroretina.6 However, at 7 weeks, ultrastructural changes and vesiculation of RPE cells are known to develop in association with degeneration of photoreceptor ROS.120 The mechanisms are considered to include oxidative stress,121 lipofuscin accumulation in the RPE29 and photoreceptor disruption. In RPE cells in culture, zinc depletion results in reduced protein synthesis,122 disruption of growth factor signalling molecules43 and cell death.123 Ocular manifestations of zinc deficiency include poor dark adaptation. Mochizuki et al.117 reported the case of a 46-yearold Japanese man with liver dysfunction, low serum zinc levels (44 mg dl1) and vitamin A deficiency (10 IU dl1; normal range 97 to 316) with markedly reduced scotopic and phototopic ERG b-waves. Normalization of night vision and scotopic ERG responses followed improvement of liver function and recovery of blood zinc levels, despite persistent vitamin A deficiency and abnormal photopic ERGs. This suggested that rod function is more susceptible to zinc deficiency than cone function. Morrison et al.124 also demonstrated a patient with liver disease, low serum zinc and vitamin A levels, whose impaired dark adaptation improved by zinc supplementation alone. Blood zinc levels have also been found to be reduced in patients with retinitis pigmentosa (mean concentration 7.4 + 0.2 mg dl1)125–128 and children with night blindness.129,130 There have been suggestions in the past that zinc deficiency results in poor dark adaptation by affecting the activity of the zinc enzyme retinol dehydrogenase and the catabolism of ethanol necessary for rhodopsin regeneration. In the mid 70s, Huber and Gershoff131 assayed the retinol dehydrogenase activity in subcellular fractions of retina from zinc-deficient rats. They found the retinal zinc concentration, alcohol dehydrogenase activity and retinol–retinal conversion reduced in zinc deficient rats compared to ad-libitum animals. However, in the mid 80s, Dorea and Olson132 carried out an elegant study where they fed albino rats a zinc deficient diet for 4 weeks and found them to have reduced retinal zinc concentration and rhodopsin regeneration compared to ad-libitum animals but no difference compared to pair-fed, weight-matched rats fed a zinc-sufficient diet. Their findings do not support the idea that zinc deficiency causes poor dark adaptation by reducing the activity of retinol dehydrogenase. Zinc deficiency had no effect on the amount of retinal aldehyde in the eye after bleaching, the loosely-bound retinol level was not lower than in the ad-libitum rats. What is more, during dark adaptation,


Critical Review

the rate of rhodopsin regeneration was not lower and the steadystate level of loosely-bound retinol did not rise. There is the possibility that the poor dark adaptation resulting from zinc depletion might be the consequence of impaired loosely-bound zinc signals within the photoreceptors.

Retinal dysfunction associated with zinc excess High zinc intake, either intentional or inadvertent (e.g. ingestion of denture adhesive),133 occupational exposure (e.g. welding), high intestinal absorption or diminished intestinal excretion can result in hyperzincemia and elevated 24 h urinary zinc excretion. Systemic features of zinc overload include dysfunction of the immune system, fever, headaches, cramps, nausea, vomiting, diarrhea, loss of appetite and demyelination, which seem to be secondary to the zinc-induced copper deficiency.134,135 To our knowledge, no retinal abnormalities in animal studies have been described or in patients with zinc overload. This suggests that in vivo homeostatic mechanisms may prevent zinc accumulating in the healthy retina beyond physiological levels. Both the RPE and retinal neurones are highly sensitive to excess ‘‘loosely-bound’’ zinc. Intraocular injections of 150 mM zinc and brief exposure (15 min) of retinal cells in culture to high levels of zinc (300–600 mM) led to retinal cell degeneration and apoptosis of photoreceptors and RPE.14 The mechanisms of zinc-induced cell toxicity involve oxidative stress,46,96 apoptosis14 and mitochondrial injury.44,98 Zn(II) opens mitochondrial pores, initiates membrane hyperpolarisation and the release of pro-apoptotic proteins. An endogenous zinc-based cytotoxic mechanism is thought to operate in the retina, as in other parts of the CNS. Retinal ischaemia induced by high intraocular pressure,94 and light-induced injury136 caused intracellular accumulation of chelatable zinc in the INL and ganglion cell layer. The origin of this chelatable zinc is unclear. It could be zinc released from: (1) presynaptic terminals of the photoreceptors and bipolar cells during synaptic transmission, (2) MT or (3) intracellular organelles (mitochondria, nuclei, endoplasmic reticulum). While good evidence exists to show that zinc and glutamate are co-released to act synergistically on post synaptic neurones to account for the rapid death of such neurones in brain ischemia (stroke)137 no such evidence exists for the retina. Retinal ganglion cells are particularly susceptible in ischemia and optic neuropathy where loosely-bound zinc does not appear to particularly concentrate in pre-synaptic neuronal synapsis.

Retinal zinc homeostasis in aging and disease There are suggestions that aging is associated with zinc dyshomeostasis96 and that it may promote age-related changes and even degeneration in advanced cases.138,139 Aging has been associated with zinc depletion. Wills et al.16 detected a reduction in total zinc in the neuroretina of men, although they did not notice any change in women. Tate et al.122 found a

Metallomics, 2014, 6, 189--200 | 195

View Article Online


Critical Review

9% reduction in total RPE zinc and a 45% reduction in the solubilisable zinc (separate from pigment granule fractions) in eyes from donors more than 70 years of age compared to younger donors. They also found a decrease in the zinc storage molecule, MT, in RPE cells from the macular area.122 In vitro studies have also shown that RPE cells contain less endogenous zinc ions and zinc influx transporters ZIP2 and ZIP4 with increased aging.105 The content of zinc in human RPE/choroid in AMD is decreased by 24%.16 High levels of zinc colocalize with drusen140 (extracellular deposits between Bruch’s membrane and the RPE, which predispose to AMD), which might affect oligomerisation of complement factor H,141 the regulatory protein of the complement system immune response. In AMD maculas, the expression of ZIP2, ZIP4,105 MT122 and semenogelin I and II,112 are downregulated. It is still unclear whether the metal-related abnormalities are a cause or an effect of the retinal degeneration in AMD. It is possible that processes, such as inflammation, initiate the AMD abnormality and result in secondary alterations in trace element homeostasis. Dysregulation of systemic zinc homeostasis is also associated with chronic disease such as diabetes,142,143 cancer and immune system dysfunction.144,145 Further studies are required to investigate the retinal zinc homeostasis in these conditions.

Zinc supplements as potential treatments for retinal disease The changes detected in retinal zinc homeostasis in AMD have led to the idea that zinc supplements146–150 may be beneficial in the treatment of this debilitating disease. A recent systematic review151 of ten studies (4 randomized controlled trials, 4 prospective cohort and 2 retrospective cohort) examining the effect of zinc intake (both from food and supplements) in the primary prevention and treatment of AMD has shown there is no conclusive evidence of a beneficial effect. A large randomized controlled trial (AREDS)152 of daily supplementation with high-dose zinc alone (80 mg of zinc as zinc oxide) or in combination with antioxidants (500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta carotene) and copper (2 mg of copper as cupric oxide) found that both significantly reduced the risk of progression to advanced AMD compared to placebo in individuals with signs of moderate to AMD in at least one eye. The effect of AREDS supplements including zinc might depend on the patients’ genotype (e.g. complement factor H).153,154 A two-year randomized, double-masked, controlled trial155 with 151 patients showed that 200 mg per day of zinc sulfate (81 mg per day of elemental zinc) reduced visual loss in patients with dry AMD, although no effect was demonstrated with this treatment in wet AMD. A more recent trial156 with 40 patients treated with 25 g oral zinc–monocysteine complex twice daily for 6 months demonstrated that the visual acuity, contrast sensitivity and photorecovery time improved in zinc treated patients with dry AMD compared to placebo. However, 6 cohort studies had inconclusive findings. In vitro studies have suggested that treatment with zinc may affect the progression of AMD by attenuating endothelial cell activation.157

196 | Metallomics, 2014, 6, 189--200

Metallomics

Treatment of experimental animals with zinc supplements results in increases in zinc levels in the RPE and altered expression of genes related to cell growth, proliferation, cell cycle and cell death.158 Oral zinc has been suggested to protect the retina from oxidative stress in ischaemia, a ‘diabetes-like’ model by intraperitoneal injection of alloxan,51 light-induced retinal injury,158 axial elongation in myopia.159 In addition, intraperitoneal ZnCl2 and zinc-deferoxamine treatment of mice with a retinal dystrophy (i.e. rd10) showed improved retinal function by electroretinography and photoreceptor structure (assessed by quantitative histological and immunohistochemical techniques) at 4.5 weeks of age.160 Oral zinc supplementation has been suggested to improve the control of glucose levels in patients with diabetes.161 Zinc has also been reported to protect the retina from oxidative stress-induced pericyte apoptosis, capillary leakage and neovascularisation, therefore being potentially beneficial in the prevention of diabetic retinopathy.162 These interesting findings need further investigation.

Further directions Few tissues in the body have total zinc concentrations high enough to release biologically reactive zinc in the high micromolar range but the RPE choroid complex might be one, making this complex a potential target for pharmacological intervention. Zinc bufferingbased therapies represent one possible approach.163 Exchangeable zinc has been reported to be removed from plaques in Alzheimer’s disease by compounds that are relatively weak zinc binders.164 However, in AMD where the RPE choroid complex is affected, zinc supplements has been muted to represent a mode of treatment based on experimental studies where it is thought that the toxic effects of zinc in the aetiology of AMD is overridden by the antioxidant influences of zinc. Significantly, it was concluded in a recent publication by Visvanathan et al. (2013),151 from an analysis of information derived from ten randomized trials that zinc supplementation may be effective in preventing progression to advance AMD. Further studies are clearly necessary to determine whether zinc treatment of a defined nature has positive or negative effect on a particular retinal disease.

Acknowledgements ´tedra en Biomedicina, Fundacio ń BBVA is greatly Support by Ca appreciated.

References 1 T. Akagi, M. Kaneda, K. Ishii and T. Hashikawa, J. Histochem. Cytochem., 2001, 49, 87. 2 B. H. Grahn, P. G. Paterson, K. T. Gottschall-Pass and Z. Zhang, J. Am. Coll. Nutr., 2001, (Suppl 20), 106. 3 M. Ugarte and N. N. Osborne, Prog. Neurobiol., 2001, 64, 219. 4 M. Ugarte, G. W. Grime, G. Lord, K. Geraki, J. F. Collingwood, M. E. Finnegan, H. Farnfield, M. Merchant,


View Article Online

Metallomics

5 6 7


8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

31 32

M. J. Bailey, N. I. Ward, P. J. Foster, P. N. Bishop and N. N. Osborne, Metallomics, 2012, 4, 1245. M. Ugarte, N. N. Osborne, L. A. Brown and P. N. Bishop, Surv. Ophthalmol., 2013, 58, 585. J. S. Fabe, B. H. Grahn and P. G. Paterson, Biol. Trace Elem. Res., 2000, 75, 43. M. Ugarte, G. W. Grime and N. N. Osborne, Metallomics, DOI: 10.1039/c3mt00271c. N. Ha, K. Hellauer and B. Turcotte, Nucleic Acids Res., 1996, 24, 1453. D. Beyersmann and H. Haase, BioMetals, 2001, 14, 331. D. J. Tate Jr., M. V. Miceli and D. A. Newsome, Free Radicals Biol. Med., 1999, 26, 704. L. M. Henderson, J. B. Chappell and O. T. Jones, Biochem. J., 1988, 255, 285. B. Musset and T. Decoursey, Wiley Interdiscip. Rev.: Membr. Transp. Signaling, 2012, 1, 605. V. V. Cherny and T. E. DeCoursey, J. Gen. Physiol., 1999, 114, 819. J. P. Wood and N. N. Osborne, Arch. Ophthalmol., 2001, 119, 81. N. N. Osborne and J. P. Wood, Invest. Ophthalmol. Visual Sci., 2006, 47, 3178. N. K. Wills, V. M. Ramanujam, N. Kalariya, J. R. Lewis and F. J. van Kuijk, Exp. Eye Res., 2008, 87, 80. W. Maret and H. H. Sandstead, J. Trace Elem. Med. Biol., 2006, 20, 3. C. Andreini, L. Banci, I. Bertini and A. Rosato, J. Proteome Res., 2006, 5, 3173. S. Lynch, Am. J. Clin. Nutr., 2011, 94, 673S. R. J. Cousins, J. P. Liuzzi and L. A. Lichten, J. Biol. Chem., 2006, 281, 24085. W. Maret, BioMetals, 2011, 24, 411. J. C. Erie, J. A. Good, J. A. Butz and J. S. Pulido, Am. J. Ophthalmol., 2009, 147, 276. J. M. Bowness, R. A. Morton, M. H. Shakir and A. L. Stubbs, Biochem. J., 1952, 51, 521. S. Nusetti, V. Salazar and L. Lima, Adv. Exp. Med. Biol., 2009, 643, 233. S. C. Lee, Y. M. Zhong, R. X. Li, Z. Yu and X. L. Yang, Synapse, 2008, 62, 352. X. Wang, Z. Y. Wang, H. L. Gao, G. Danscher and L. Huang, Brain Res. Bull., 2006, 71, 91. ń, T. Rousso ´, M. Quintal, Z. Benzo and L. Lima, F. Obrego C. Auladell, Neurochem. Res., 2004, 29, 247. A. Biesemeier, S. Julien, D. Kokkinou, U. Schraermeyer and O. Eibl, Metallomics, 2012, 4, 323. S. Julien, A. Biesemeier, D. Kokkinou, O. Eibl and U. Schraermeyer, PLoS One, 2011, 6, e29245. D. Kokkinou, H. U. Kasper, T. Schwarz, K. U. Bartz-Schmidt and U. Schraermeyer, Graefes Arch. Clin. Exp. Ophthalmol., 2005, 243, 1050. D. J. Tate and D. A. Newsome, Curr. Eye Res., 2006, 31, 675. C. Owsley, G. McGwin, G. R. Jackson, D. C. Heimburger, C. J. Piyathilake, R. Klein, M. F. White and K. Kallies, Invest. Ophthalmol. Visual Sci., 2006, 47, 1310.


Critical Review

33 K. Komatsu, K. Kikuchi, H. Kojima, Y. Urano and T. Nagano, J. Am. Chem. Soc., 2005, 127, 10197. 34 K. Vogt, J. Mellor, G. Tong and R. Nicoll, Neuron, 2000, 26, 187. 35 J. Qian and J. L. Noebels, J. Physiol., 2005, 566, 747. 36 C. J. Frederickson, L. J. Giblin 3rd, R. V. Balaji, R. Masalha, C. J. Frederickson, Y. Zeng, E. V. Lopez, J. Y. Koh, U. Chorin, L. Besser, M. Hershfinkel, Y. Li, R. B. Thompson and A. Krezel, J. Neurosci. Methods, 2006, 154, 19. 37 I. Sekler and W. F. Silverman, Glia, 2012, 60, 843. 38 R. A. Colvin, W. R. Holmes, C. P. Fontaine and W. Maret, Metallomics, 2010, 2, 306. 39 W. Maret, Biometals, 2009, 22, 149. 40 N. F. Krebs, K. M. Hambidge, J. E. Westcott, L. V. Miller, L. Sian, M. Bell and G. Grunwald, J. Nutr., 2003, 133(5 Suppl 1), 1498S. 41 Y. Tamada, R. D. Walkup, T. R. Shearer and M. Azuma, Curr. Eye Res., 2007, 32, 565. 42 K. S. Shindler, D. Zurakowski and E. B. Dreyer, NeuroReport, 2000, 11, 2299. 43 H. J. Hyun, J. Sohn, Y. H. Ahn, H. C. Shin, J. Y. Koh and Y. H. Yoon, Brain Res., 2000, 869, 39. ˙ and P. Bernardi, Biochim. Biophys. 44 F. Ricchelli, J. Sileikyte Acta, 2011, 1807, 482. 45 S. L. Sensi, D. Ton-That, P. G. Sullivan, E. A. Jonas, K. R. Gee, L. K. Kaczmarek and J. H. Weiss, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 6157. 46 J. S. Choi, K. A. Kim, Y. J. Yoon, T. Fujikado and C. K. Joo, Vision Res., 2006, 46, 2721. 47 D. C. Otteson, Y. Liu, H. Lai, C. Wang, S. Gray, M. K. Jain and D. J. Zack, Invest. Ophthalmol. Visual Sci., 2004, 45, 2522. 48 R. K. Crouch and J. K. Chambers, Br. J. Ophthalmol., 1982, 66, 417. 49 N. Nakamichi, G. Chidlow and N. N. Osborne, Neuropharmacology, 2003, 45, 637. 50 V. Arranz, C. Dreuillet, P. Crisanti, J. Tillit, M. Kress and M. Ernoult-Lange, J. Biol. Chem., 2001, 276, 11963. 51 S. A. Moustafa, Toxicol. Appl. Pharmacol., 2004, 201, 149. 52 R. Sharif, P. Thomas, P. Zalewski and M. Fenech, Mutat. Res., 2012, 733, 111. 53 Y. Watabe, Y. Baba, H. Nakauchi, A. Mizota and S. Watanabe, Biochem. Biophys. Res. Commun., 2011, 415, 42. 54 C. Allington, I. L. Shamovsky, G. M. Ross and R. J. Riopelle, Cell Death Differ., 2001, 8, 451. 55 R. Schippert, E. Burkhardt, M. Feldkaemper and F. Schaeffel, Invest. Ophthalmol. Visual Sci., 2007, 48, 11. 56 J. Zhang, Z. Jin and Z. Z. Bao, Development, 2004, 131, 1553. 57 E. Herrera, L. Brown, J. Aruga, R. A. Rachel, G. Dolen, K. Mikoshiba, S. Brown and C. A. Mason, Cell, 2003, 114, 545. 58 D. J. Wilson, Trans. Am. Ophthalmol. Soc., 2002, 100, 353. 59 H. Li, H. Wang, F. Wang, Q. Gu and X. Xu, PLoS One, 2011, 6, e23322. 60 S. A. Siapich, H. Wrubel, W. Albanna, M. Alnawaiseh, ¨ber, M. Lu ¨ke and T. Schneider, J. Hescheler, M. Weiergra Curr. Eye Res., 2010, 35, 322.

Metallomics, 2014, 6, 189--200 | 197

View Article Online


Critical Review

61 M. A. Kreitzer, A. D. Birnbaum, H. Qian and R. P. Malchow, Vis. Neurosci., 2009, 26, 375. 62 Z. Sun, D. Q. Zhang and D. G. McMahon, J. Neurophysiol., 2009, 101, 1774. 63 R. L. Chappell, I. Anastassov, P. Lugo and H. Ripps, Exp. Eye Res., 2008, 87, 394. 64 S. Redenti, H. Ripps and R. L. Chappell, Exp. Eye Res., 2007, 85, 580. 65 D. Q. Zhang, Z. Sun and D. G. McMahon, Vis. Neurosci., 2006, 23, 825. 66 S. Redenti and R. L. Chappel, Vision Res., 2005, 45, 3520. 67 M. Kaneda, K. Ishii, T. Akagi, T. Tatsukawa and T. Hashikawa, J. Mol. Histol., 2005, 36, 179. 68 S. Redenti and R. L. Chappell, Biol. Bull., 2003, 205, 213. 69 F. J. Rosenstein and R. L. Chappell, Neurosci. Lett., 2003, 345, 81. 70 D. G. Luo and X. L. Yang, Brain Res., 2002, 958, 222. 71 S. Redenti and R. L. Chappell, Biol. Bull., 2002, 203, 200. 72 D. G. Luo, G. L. Li and X. L. Yang, Brain Res. Bull., 2002, 58, 461. 73 D. Q. Zhang, C. Ribelayga, S. C. Mangel and D. G. McMahon, J. Neurophysiol., 2002, 88, 1245. 74 R. L. Chappell and S. Redenti, Biol. Bull., 2001, 201, 265. 75 D. G. Luo and X. L. Yang, Brain Res., 2001, 900, 95. ´sfalvy and A. Kaneko, Vis. Neurosci., 76 M. Kaneda, B. Andra 2000, 17, 273. 77 I. Anastassov, W. Shen, H. Ripps and R. L. Chappell, Exp. Eye Res., 2013, 112, 37. 78 S. J. Yin, C. F. Chou, C. L. Lai, S. L. Lee and C. L. Han, Chem.–Biol. Interact., 2003, 143, 219. 79 M. Saghizadeh, N. B. Akhmedov, C. K. Yamashita, Y. Gribanova, V. Theendakara, E. Mendoza, S. F. Nelson, A. V. Ljubimov and D. B. Farber, Invest. Ophthalmol. Visual Sci., 2009, 50, 3580. 80 S. Satarug, M. Kikuchi, R. Wisedpanichkij, B. Li, K. Takeda, K. Na-Bangchang, M. R. Moore, K. Hirayama and S. Shibahara, Exp. Eye Res., 2008, 87, 587. 81 M. Bernard and P. Voisin, J. Neurochem., 2008, 105, 595. ń, M. Quintal, Z. Benzo and L. Lima, 82 S. Nusetti, F. Obrego Neurochem. Res., 2005, 30, 1483. 83 S. Gleim, A. Stojanovic, E. Arehart, D. Byington and J. Hwa, Biochemistry, 2009, 48, 1793. ´ ski, S. Filipek, K. Palczewski 84 P. S. Park, K. T. Sapra, M. Kolin and D. J. Muller, J. Biol. Chem., 2007, 282, 11377. 85 H. Nakamichi and T. Okada, Photochem. Photobiol., 2007, 83, 232. ˜ avate, P. Dias and 86 L. J. del Valle, E. Ramon, X. Can P. Garriga, J. Biol. Chem., 2003, 278, 4719. 87 S. E. Permyakov, A. M. Cherskaya, L. A. Wasserman, T. I. Khokhlova, I. I. Senin, A. A. Zargarov, D. V. Zinchenko, E. Y. Zernii, V. M. Lipkin, P. P. Philippov, V. N. Uversky and E. A. Permyakov, J. Proteome Res., 2003, 2, 51. 88 F. He, A. B. Seryshev, C. W. Cowan and T. G. Wensel, J. Biol. Chem., 2000, 275, 20572. 89 J. P. Vilardaga, M. Frank, C. Krasel, C. Dees, R. A. Nissenson and M. J. Lohse, J. Biol. Chem., 2001, 276, 33435.

198 | Metallomics, 2014, 6, 189--200

Metallomics

90 A. Feigenspan, S. Gustincich and E. Raviola, J. Neurophysiol., 2000, 84, 1697. 91 Y. Sun, Y. T. Zhang, H. Q. Gong and P. J. Liang, Brain Res., 2010, 1345, 103. ´ska, S. Tubek, R. Szyguła and A. Bunio, 92 M. Sobieszczan Adv. Clin. Exp. Med., 2012, 21, 245. 93 R. A. Bozym, F. Chimienti, L. J. Giblin, G. W. Gross, I. Korichneva, Y. Li, S. Libert, W. Maret, M. Parviz, C. J. Frederickson and R. B. Thompson, Exp. Biol. Med., 2010, 235, 741. 94 M. H. Yoo, J. Y. Lee, S. E. Lee, J. Y. Koh and Y. H. Yoon, Invest. Ophthalmol. Visual Sci., 2004, 45, 1523. 95 W. Maret, Exp. Gerontol., 2008, 43, 363. 96 V. Frazzini, E. Rockabrand, E. Mocchegiani and S. L. Sensi, Biogerontology, 2006, 7, 307. 97 E. Mocchegiani, L. Costarelli, R. Giacconi, C. Cipriano, E. Muti, L. Rink and M. Malavolta, Rejuvenation Res., 2006, 6, 351. 98 A. M. Brown, B. S. Kristal, M. S. Effron, A. I. Shestopalov, P. A. Ullucci, K. F. Sheu, J. P. Blass and A. J. Cooper, J. Biol. Chem., 2000, 275, 13441. 99 S. Suemori, M. Shimazawa, K. Kawase, M. Satoh, H. Nagase, T. Yamamoto and H. Hara, Invest. Ophthalmol. Visual Sci., 2006, 47, 3975. ¨ndstatter and R. Enz, J. Biol. Chem., 2003, 100 C. Croci, J. H. Bra 278, 6128. 101 K. Smidt and J. Rungby, Biometals, 2012, 25, 1. 102 T. Fukada and T. Kambe, Metallomics, 2011, 3, 662. 103 K. W. Leung, M. Liu, X. Xu, M. J. Seiler, C. J. Barnstable and J. Tombran-Tink, Invest. Ophthalmol. Visual Sci., 2008, 49, 1221. 104 H. L. Gao, W. Y. Feng, X. L. Li, H. Xu, L. Huang and Z. Y. Wang, Histol. Histopathol., 2009, 24, 567. 105 K. W. Leung, A. Gvritishvili, Y. Liu and J. Tombran-Tink, J. Mol. Neurosci., 2012, 46, 122. 106 S. Redenti and R. L. Chappell, Mol. Med., 2007, 13, 376. 107 M. Deniro and F. A. Al-Mohanna, PLoS One, 2012, 7, e50360. 108 G. K. Andrews, Biometals, 2001, 14, 223. 109 L. Alvarez, H. Gonzalez-Iglesias, M. Garcia, S. Ghosh, A. Sanz-Medel and M. Coca-Prados, J. Biol. Chem., 2012, 287, 28456. 110 H. Nishimura, N. Nishimura, S. Kobayashi and C. Tohyama, Histochemistry, 1991, 95, 535. 111 W. Maret, Adv. Nutr., 2013, 85, 379. 112 V. L. Bonilha, M. E. Rayborn, K. G. Shadrach, Y. Li, A. Lundwall, J. Malm and J. G. Hollyfield, Exp. Eye Res., 2008, 86, 150. 113 G. W. Evans, Clin. Physiol. Biochem., 1986, 4, 94. ńo, M. Kharfi and ¨ry, M. Giraud, B. Dre 114 S. Schmitt, S. Ku ´zieau, Hum. Mutat., 2009, 30, 926. S. Be 115 A. S. Prasad, J. Am. Coll. Nutr., 2009, 28, 257. 116 B. de Benoist, I. Darnton-Hill, L. Davidsson, O. Fontaine and C. Hotz, Food Nutr. Bull. Suppl., 2007, 28(3 Suppl), S480. 117 K. Mochizuki, H. Murase, M. Imose, H. Kawakami and A. Sawada, Jpn J. Ophthalmol., 2006, 50, 532.


View Article Online


Metallomics

¨ro ¨k, Klin. Monbl. Augenheilkd., 2006, 118 D. Lengyel and B. To 223, 453. 119 D. A. Samuelson, P. Smith, R. J. Ulshafer, D. G. Hendricks, R. D. Whitley, H. Hendricks and N. C. Leone, Exp. Eye Res., 1993, 56, 63. 120 A. E. Leure-duPree and C. J. McClain, Invest. Ophthalmol. Visual Sci., 1982, 23, 425. 121 M. V. Miceli, D. J. Tate Jr., N. W. Alcock and D. A. Newsome, Invest. Ophthalmol. Visual Sci., 1999, 40, 1238. 122 D. J. Tate Jr., D. A. Newsome and P. D. Oliver, Invest. Ophthalmol. Visual Sci., 1993, 34, 2348. 123 M. S. Clegg, L. A. Hanna, B. J. Niles, T. Y. Momma and C. L. Keen, IUBMB Life, 2005, 57, 661. 124 S. A. Morrison, R. M. Russell, E. A. Carney and E. V. Oaks, Am. J. Clin. Nutr., 1978, 31, 276. 125 S. A. Shukolyukov, Biochemistry, 2013, 78, 660. 126 L. S. Atmaca, A. Arcasoy, A. O. Cavdar and E. Ozmert, Br. J. Ophthalmol., 1989, 73, 29. 127 Z. A. Karcioglu, R. Stout and H. J. Hahn, Curr. Eye Res., 1984, 3, 1043. ´ska, T. Skubiszewska, M. Krajewska128 J. Kubalska, J. Sliwin Walasek, E. Pietraszek and E. Pronicka, Pediatr. Pol., 1984, 59, 209. 129 H. I. Afridi, T. G. Kazi, N. Kazi, G. A. Kandhro, J. A. Baig, A. Q. Shah, S. K. Wadhwa, S. Khan, N. F. Kolachi, F. Shah, M. K. Jamali, M. B. Arain and Sirajuddin, Biol. Trace Elem. Res., 2011, 143, 20. 130 H. I. Afridi, T. G. Kazi, N. Kazi, G. A. Kandhro, J. A. Baig, A. Q. Shah, S. K. Wadhwa, S. Khan, N. F. Kolachi, F. Shah, M. K. Jamali, M. B. Arain and Sirajuddin, Biol. Trace Elem. Res., 2011, 142, 323. 131 A. M. Huber and S. N. Gershoff, J. Nutr., 1975, 105, 1486. 132 J. G. Dorea and J. A. Olson, J. Nutr., 1986, 116, 121. 133 K. Doherty, M. Connor and R. Cruickshank, Br. Dent. J., 2011, 210, 523. 134 S. A. Greenberg and H. R. Briemberg, J. Neurol., 2004, 251, 111. 135 P. Hedera and J. K. Fink, Arch. Neurol., 2003, 60, 1303. 136 C. T. Sheline, Y. Zhou and S. Bai, Mol. Vision, 2010, 16, 2639. 137 J. M. Lee, G. J. ZIPfel, K. H. Park, Y. Y. He, C. Y. Hsu and D. W. Choi, Neuroscience, 2002, 115, 871. 138 C. P. Wong, K. R. Magnusson and E. Ho, J. Nutr. Biochem., 2013, 24, 353. 139 C. P. Wong and E. Ho, Mol. Nutr. Food Res., 2012, 56, 77. 140 I. Lengyel, J. M. Flinn, T. Peto, D. H. Linkous, K. Cano, A. C. Bird, A. Lanzirotti, C. J. Frederickson and F. J. van Kuijk, Exp. Eye Res., 2007, 84, 772. 141 R. Nan, J. Gor, I. Lengyel and S. J. Perkins, J. Mol. Biol., 2008, 384, 1341. 142 J. Jansen, W. Karges and L. Rink, J. Nutr. Biochem., 2009, 20, 399. 143 P. Faure, Clin. Chem. Lab. Med., 2003, 41, 995. 144 H. I. Afridi, T. G. Kazi, N. Kazi and F. Shah, Clin. Lab., 2012, 58, 705.


Critical Review

145 S. Overbeck, L. Rink and H. Haase, Arch. Immunol. Ther. Exp., 2008, 56, 15. 146 J. R. Evans, Cochrane Database Syst. Rev., 2006, 19, CD000254. 147 W. L. McBee, A. S. Lindblad and F. L. Ferris 3rd, Curr. Opin. Ophthalmol., 2003, 14, 159. 148 J. R. Evans, Cochrane Database Syst. Rev., 2006, 2, CD000254. 149 J. R. Evans, Cochrane Database Syst. Rev., 2002, 11, CD000254. 150 E. Cho, M. J. Stampfer, J. M. Seddon, S. Hung, D. Spiegelman, E. B. Rimm, W. C. Willett and S. E. Hankinson, Ann. Epidemiol., 2001, 11, 328. 151 R. Vishwanathan, M. Chung and E. J. Johnson, Invest. Ophthalmol. Visual Sci., 2013, 54, 3985. 152 Age-Related Eye Disease Study Research Group. AREDS report no. 8. Arch. Ophthalmol., 2001, 119, 1417. 153 M. L. Klein, P. J. Francis, B. Rosner, R. Reynolds, S. C. Hamon, D. W. Schultz, J. Ott and J. M. Seddon, Ophthalmology, 2008, 115, 1019. 154 A. Y. Lee and M. A. Brantley Jr., Pharmacogenomics, 2008, 9, 1547. 155 D. A. Newsome, M. Swartz, N. C. Leone, R. C. Elston and E. Miller, Arch. Ophthalmol., 1988, 106, 192. 156 D. A. Newsome, Curr. Eye Res., 2008, 33, 591. ńdez and R. F. Mullins, Invest. Ophthalmol. 157 S. Zeng, J. Herna Visual Sci., 2012, 53, 1041. 158 D. Organisciak, P. Wong, C. Rapp, R. Darrow, A. Ziesel, R. Rangarajan and J. Lang, Photochem. Photobiol., 2012, 88, 1396. 159 X. Huibi, H. Kaixun, G. Qiuhua, Z. Yushan and H. Xiuxian, Biol. Trace Elem. Res., 2001, 79, 39. 160 A. Obolensky, E. Berenshtein, M. Lederman, B. Bulvik, R. Alper-Pinus, R. Yaul, E. Deleon, I. Chowers, M. Chevion and E. Banin, Free Radicals Biol. Med., 2011, 51, 1482. 161 J. Capdor, M. Foster, P. Petocz and S. Samman, J. Trace Elem. Med. Biol., 2013, 27, 137. 162 X. Miao, W. Sun, L. Miao, Y. Fu, Y. Wang, G. Su and Q. Liu, J. Diabetes Res., 2013, 425854. 163 S. W. Suh, S. J. Won, A. M. Hamby, B. H. Yoo, Y. Fan, C. T. Sheline, H. Tamano, A. Takeda and J. Liu, J. Cereb. Blood Flow Metab., 2009, 29, 1579. 164 M. Wilson, C. Hogstrand and W. Maret, J. Biol. Chem., 2012, 287, 9322. 165 L. C. Costello and R. B. Franklin, Prostate, 1998, 35, 285. 166 J. Lemire, R. Mailloux and V. D. Appanna, J. Appl. Toxicol., 2008, 28, 175. 167 I. A. Brand and H. D. Soling, J. Biol. Chem., 1986, 261, 5892. 168 C. T. Sheline, M. M. Behrens and D. W. Choi, J. Neurosci., 2000, 20, 3139. 169 D. W. Lee, Y. El Khoury, F. Francia, B. Zambelli, S. Ciurli, G. Venturoli, P. Hellwig and F. Daldal, Biochemistry, 2011, 50, 4263. 170 L. T. Knapp and E. Klann, J. Biol. Chem., 2000, 275, 24136. 171 Y. H. Kim and J. Y. Koh, Exp. Neurol., 2002, 177, 407. 172 J. A. Park and J. Y. Koh, J. Neurochem., 1999, 73, 450.

Metallomics, 2014, 6, 189--200 | 199

View Article Online


Critical Review

173 Y. Ho, R. Samarasinghe, M. E. Knoch, M. Lewis, E. Aizenman and D. B. DeFranco, Mol. Pharmacol., 2008, 74, 1141. 174 L. M. Malaiyandi, A. S. Honick, G. L. Rintoul, Q. J. Wang and I. J. Reynolds, J. Neurosci., 2005, 25, 9507. 175 Y. Shi, Y. Li, D. Zhang, H. Zhang, Y. Li, F. Lu, X. Liu, F. He, B. Gong, L. Cai, R. Li, s. Liao, S. Ma, H. Lin, J. Cheng, H. Zheng, Y. Shan, B. Chen, J. Hu, X. Jin, P. Zhao, Y. Chen, Y. Zhang, Y. Lin, X. Li, Y. Fan, H. Yang, J. Wang and Z. Yang, PLoS Genet., 2011, 7, e1002084.

200 | Metallomics, 2014, 6, 189--200

Metallomics

176 R. W. Collin, K. Nikopoulos, M. Dona, C. Gilissen, A. Hoischen, F. N. Boonstra, J. A. Poulter, H. Kondo, W. Berger, C. Toomes, T. Tahira, L. R. Mohn, E. A. Blokland, L. Hetterschijt, M. Ali, J. M. Groothuismink, L. Duijkers, C. F. Inglehearn, L. Sollfrank, T. M. Strom, E. Uchio, C. E. van Nouhuys, H. Kremer, J. A. Veltman, E. van Wijk and F. P. Cremers, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 9856. 177 J. de Melo, G. H. Peng, S. Chen and S. Blackshaw, Development, 2011, 138, 2325.


Recent advances in the understanding of acupuncture.

Recent advances in understanding dengue.

Recent advances in understanding psoriasis.

Recent advances in understanding vitiligo.

Recent advances in understanding photosynthesis.

Recent advances in understanding noroviruses.

Recent advances in understanding neutrophils.

Recent advances in understanding the role of cellulose accessibility in enzymatic hydrolysis of lignocellulosic substrates.

Recent advances in understanding the role of lamins in health and disease.

Recent advances in the understanding and management of rosacea.

Recent advances in understanding the cellular roles of GSK-3.

Recent advances in understanding the pathogenesis of Lawsonia intracellularis infections.

Recent advances in understanding the role of oxidative stress in diabetic neuropathy.

Recent advances in the understanding of acute kidney injury.

Recent advances in the understanding and management of IgA nephropathy.

Recent advances in the understanding of ambulatory electrocardiography.

Recent advances in the understanding of Fusarium trichothecene mycotoxicoses.

Recent Advances in the Understanding and Treatment of Trichotillomania.

Recent advances in ocular drug delivery system.

Recent advances in zinc-air batteries.

Recent Advances in Understanding Gadolinium Retention in the Brain.

Recent advances in understanding urethral lichen sclerosus.

Recent advances in understanding and treating ARDS.

Recent advances in understanding apicomplexan parasites.