MetallomicsPub Date : 2024-11-07DOI: 10.1093/mtomcs/mfae049
Leah E Zahn, Paige M Gannon, Lauren J Rajakovich
{"title":"Iron-sulfur cluster-dependent enzymes and molybdenum-dependent reductases in the anaerobic metabolism of human gut microbes.","authors":"Leah E Zahn, Paige M Gannon, Lauren J Rajakovich","doi":"10.1093/mtomcs/mfae049","DOIUrl":"10.1093/mtomcs/mfae049","url":null,"abstract":"<p><p>Metalloenzymes play central roles in the anaerobic metabolism of human gut microbes. They facilitate redox and radical-based chemistry that enables microbial degradation and modification of various endogenous, dietary, and xenobiotic nutrients in the anoxic gut environment. In this review, we highlight major families of iron-sulfur (Fe-S) cluster-dependent enzymes and molybdenum cofactor-containing enzymes used by human gut microbes. We describe the metabolic functions of 2-hydroxyacyl-CoA dehydratases, glycyl radical enzyme activating enzymes, Fe-S cluster-dependent flavoenzymes, U32 oxidases, and molybdenum-dependent reductases and catechol dehydroxylases in the human gut microbiota. We demonstrate the widespread distribution and prevalence of these metalloenzyme families across 5000 human gut microbial genomes. Lastly, we discuss opportunities for metalloenzyme discovery in the human gut microbiota to reveal new chemistry and biology in this important community.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-11-07DOI: 10.1093/mtomcs/mfae051
Teresa Pinheiro, Luís C Alves, António P Matos, Isabel Correia, João Costa Pessoa, Fernanda Marques
{"title":"Cellular targets of cytotoxic copper phenanthroline complexes: a multimodal imaging quantitative approach in single PC3 cells.","authors":"Teresa Pinheiro, Luís C Alves, António P Matos, Isabel Correia, João Costa Pessoa, Fernanda Marques","doi":"10.1093/mtomcs/mfae051","DOIUrl":"10.1093/mtomcs/mfae051","url":null,"abstract":"<p><p>Metal complexes are emerging as promising alternatives to traditional platinum-based cancer treatments, offering reduced side effects. However, understanding their cellular uptake and distribution and quantifying their presence at the single cell level remains challenging. Advanced imaging techniques, including transmission electron microscopy, synchrotron radiation X-ray fluorescence, and energetic ion beam-based nuclear microscopy (scanning transmission ion microscopy, particle-induced X-ray emission, elastic backscattering spectrometry), allow detailed high-resolution visualization of structure and morphology, high sensitivity for elemental detection with quantification within single cells, and the construction of 3D models of metal distribution, positioning them as powerful tools for assessing the cellular uptake and compartmentalization of complexes. Three Cu(II) complexes [Cu(phen)2(H2O)](NO3)2 (1), [Cu(Me2phen)2(NO3)]NO3 (2) and [Cu(amphen)2(H2O)](NO3)2 (3), (phen = 1,10-phenanthroline, Me2phen = 4,7-dimethyl-1,10-phen, amphen = 5-amino-phen) were investigated for Cu uptake and distribution in PC3 prostate cancer cells. All complexes show significant Cu uptake regardless of media concentration. Cu concentrations in the cytoplasm and nucleus are similar between treatments. Complexes 1 and 3 concentrate Cu in the nuclear region and show a vesicle-like pattern around the nucleus, while 2 shows a dispersed cytoplasmic pattern with large vesicles. The 3D models confirm that Cu is not retained at the plasma membrane, with complex 1 targeting the nucleus and 2 remaining in the cytoplasm. These results highlight the importance of quantifying metal distribution and correlating it with structural changes to understand the relevance of the ligand in the mechanisms of cellular uptake and targeting, crucial for the development of effective metal-based cancer therapies.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-10-04DOI: 10.1093/mtomcs/mfae044
Ashley E Pall, Silas Bond, Danielle K Bailey, Christopher S Stoj, Isabel Deschamps, Penny Huggins, Jack Parsons, Margaret J Bradbury, Daniel J Kosman, Timothy L Stemmler
{"title":"ATH434, a promising iron-targeting compound for treating iron regulation disorders.","authors":"Ashley E Pall, Silas Bond, Danielle K Bailey, Christopher S Stoj, Isabel Deschamps, Penny Huggins, Jack Parsons, Margaret J Bradbury, Daniel J Kosman, Timothy L Stemmler","doi":"10.1093/mtomcs/mfae044","DOIUrl":"10.1093/mtomcs/mfae044","url":null,"abstract":"<p><p>Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4 µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59 µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-10-04DOI: 10.1093/mtomcs/mfae046
Fa'alataitaua M Fitisemanu, Teresita Padilla-Benavides
{"title":"Emerging perspectives of copper-mediated transcriptional regulation in mammalian cell development.","authors":"Fa'alataitaua M Fitisemanu, Teresita Padilla-Benavides","doi":"10.1093/mtomcs/mfae046","DOIUrl":"10.1093/mtomcs/mfae046","url":null,"abstract":"<p><p>Copper (Cu) is a vital micronutrient necessary for proper development and function of mammalian cells and tissues. Cu mediates the function of redox active enzymes that facilitate metabolic processes and signaling pathways. Cu levels are tightly regulated by a network of Cu-binding transporters, chaperones, and small molecule ligands. Extensive research has focused on the mammalian Cu homeostasis (cuprostasis) network and pathologies, which result from mutations and perturbations. There are roles for Cu-binding proteins as transcription factors (Cu-TFs) and regulators that mediate metal homeostasis through the activation or repression of genes associated with Cu handling. Emerging evidence suggests that Cu and some Cu-TFs may be involved in the regulation of targets related to development-expanding the biological roles of Cu-binding proteins. Cu and Cu-TFs are implicated in embryonic and tissue-specific development alongside the mediation of the cellular response to oxidative stress and hypoxia. Cu-TFs are also involved in the regulation of targets implicated in neurological disorders, providing new biomarkers and therapeutic targets for diseases such as Parkinson's disease, prion disease, and Friedreich's ataxia. This review provides a critical analysis of the current understanding of the role of Cu and cuproproteins in transcriptional regulation.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-10-04DOI: 10.1093/mtomcs/mfae042
Trevor Arino, David Faulkner, Karen C Bustillo, Dahlia D An, Danielle Jorgens, Solène Hébert, Carla McKinley, Michael Proctor, Alex Loguinov, Christopher Vulpe, Rebecca J Abergel
{"title":"Electron microscopy evidence of gadolinium toxicity being mediated through cytoplasmic membrane dysregulation.","authors":"Trevor Arino, David Faulkner, Karen C Bustillo, Dahlia D An, Danielle Jorgens, Solène Hébert, Carla McKinley, Michael Proctor, Alex Loguinov, Christopher Vulpe, Rebecca J Abergel","doi":"10.1093/mtomcs/mfae042","DOIUrl":"10.1093/mtomcs/mfae042","url":null,"abstract":"<p><p>Past functional toxicogenomic studies have indicated that genes relevant to membrane lipid synthesis are important for tolerance to the lanthanides. Moreover, previously reported imaging of patient's brains following administration of gadolinium-based contrast agents shows gadolinium lining the vessels of the brain. Taken together, these findings suggest the disruption of cytoplasmic membrane integrity as a mechanism by which lanthanides induce cytotoxicity. In the presented work we used scanning transmission electron microscopy and spatially resolved elemental spectroscopy to image the morphology and composition of gadolinium, europium, and samarium precipitates that formed on the outside of yeast cell membranes. In no sample did we find that the lanthanide contaminant had crossed the cell membrane, even in experiments using yeast mutants with disrupted genes for sphingolipid synthesis-the primary lipids found in yeast cytoplasmic membranes. Rather, we have evidence that lanthanides are co-located with phosphorus outside the yeast cells. These results lead us to hypothesize that the lanthanides scavenge or otherwise form complexes with phosphorus from the sphingophospholipid head groups in the cellular membrane, thereby compromising the structure or function of the membrane, and gaining the ability to disrupt membrane function without entering the cell.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-10-04DOI: 10.1093/mtomcs/mfae043
Milankumar Prajapati, Lauren Chiu, Jared Z Zhang, Grace S Chong, Nicholas A DaSilva, Thomas B Bartnikas
{"title":"Bile from the hemojuvelin-deficient mouse model of iron excess is enriched in iron and ferritin.","authors":"Milankumar Prajapati, Lauren Chiu, Jared Z Zhang, Grace S Chong, Nicholas A DaSilva, Thomas B Bartnikas","doi":"10.1093/mtomcs/mfae043","DOIUrl":"10.1093/mtomcs/mfae043","url":null,"abstract":"<p><p>Iron is an essential nutrient but is toxic in excess. Iron deficiency is the most prevalent nutritional deficiency and typically linked to inadequate intake. Iron excess is also common and usually due to genetic defects that perturb expression of hepcidin, a hormone that inhibits dietary iron absorption. Our understanding of iron absorption far exceeds that of iron excretion, which is believed to contribute minimally to iron homeostasis. Prior to the discovery of hepcidin, multiple studies showed that excess iron undergoes biliary excretion. We recently reported that wild-type mice raised on an iron-rich diet have increased bile levels of iron and ferritin, a multi-subunit iron storage protein. Given that genetic defects leading to excessive iron absorption are much more common causes of iron excess than dietary loading, we set out to determine if an inherited form of iron excess known as hereditary hemochromatosis also results in bile iron loading. We employed mice deficient in hemojuvelin, a protein essential for hepcidin expression. Mutant mice developed bile iron and ferritin excess. While lysosomal exocytosis has been implicated in ferritin export into bile, knockdown of Tfeb, a regulator of lysosomal biogenesis and function, did not impact bile iron or ferritin levels. Bile proteomes differed between female and male mice for wild-type and hemojuvelin-deficient mice, suggesting sex and iron excess impact bile protein content. Overall, our findings support the notion that excess iron undergoes biliary excretion in genetically determined iron excess.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-10-04DOI: 10.1093/mtomcs/mfae045
Marta Ugarte, Craig Lawless
{"title":"Putative retina metal/metalloid-binding proteins: molecular functions, biological processes and retina disease associations.","authors":"Marta Ugarte, Craig Lawless","doi":"10.1093/mtomcs/mfae045","DOIUrl":"10.1093/mtomcs/mfae045","url":null,"abstract":"<p><p>The mammalian retina contains high amounts of metals/metalloid-selenium. Their dyshomeostases are associated with certain retinal diseases. We carried out this bioinformatics study to identify the relationships between putative retinal metal/selenium binding proteins, their molecular functions, and biological processes. Identification of putative mouse metal/selenium binding proteins was based on known binding motifs, domains, patterns, and profiles. Annotations were obtained from Uniprot keywords 'metal binding', 'metal ion co-factors', 'selenium proteins'. Protein functions were estimated by associative frequency with key words in UniProt annotations. The raw data of five mouse proteomics PRIDE datasets (available to date) were downloaded and processed with Mascot against the mouse taxa of Uniprot (SwissProt/Trembl) and MaxQuant (version 1.6.10.43) for qualitative and quantitative datasets, respectively. Clinically relevant variants were evaluated using archives and aggregated information in ClinVar. The 438 proteins common to all the retina proteomics datasets were used to identify over-represented Gene Ontology categories. The putative mouse retinal metal/metalloid binding proteins identified are mainly involved in: (1) metabolic processes (enzymes), (2) homeostasis, (3) transport (vesicle mediated, transmembrane, along microtubules), (4) cellular localization, (5) regulation of signalling and exocytosis, (6) organelle organization, (7) (de)phosphorylation, and (8) complex assembly. Twenty-one proteins were identified as involved in response to light stimulus and/or visual system development. An association of metal ion binding proteins rhodopsin, photoreceptor specific nuclear receptor, calcium binding protein 4 with disease-related mutations in inherited retinal conditions was identified, where the mutations affected an area within or in close proximity to the metal binding site or domain. These findings suggest a functional role for the putative metal/metalloid binding site in retinal proteins in certain retinal disorders.</p>","PeriodicalId":89,"journal":{"name":"Metallomics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-09-17DOI: 10.1093/mtomcs/mfae041
Colette F Quinn,Dean E Wilcox
{"title":"Thermodynamic origin of the affinity, selectivity and domain specificity of metallothionein for essential and toxic metal ions.","authors":"Colette F Quinn,Dean E Wilcox","doi":"10.1093/mtomcs/mfae041","DOIUrl":"https://doi.org/10.1093/mtomcs/mfae041","url":null,"abstract":"The small Cys-rich protein metallothionein (MT) binds several metal ions in clusters within its two domains. While the affinity of MT for both toxic and essential metals has been well studied, the thermodynamics of this binding has not. We have used isothermal titration calorimetry measurements to quantify the change in enthalpy (ΔH) and change in entropy (ΔS) when metal ions bind to the two ubiquitous isoforms of MT. The seven Zn2+ that bind sequentially at pH 7.4 do so in two populations with different coordination thermodynamics, an initial four that bind randomly with individual tetra-thiolate coordination and a subsequent three that bind with bridging thiolate coordination to assemble the metal clusters. The high affinity of MT for both populations is due to a very favourable binding entropy that far outweighs an unfavourable binding enthalpy. This originates from a net enthalpic penalty for Zn2+ displacement of protons from the Cys thiols and a favourable entropic contribution from the displaced protons. The thermodynamics of other metal ions binding to MT were determined by their displacement of Zn2+ from Zn7MT and subtraction of the Zn2+-binding thermodynamics. Toxic Cd2+, Pb2+ and Ag+, and essential Cu+, also bind to MT with a very favourable binding entropy but a net binding enthalpy that becomes increasingly favourable as the metal ion becomes a softer Lewis acid. These thermodynamics are the origin of the high affinity, selectivity and domain specificity of MT for these metal ions and the molecular basis for their in vivo binding competition.","PeriodicalId":89,"journal":{"name":"Metallomics","volume":"41 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-09-13DOI: 10.1093/mtomcs/mfae040
Bobby G Duersch,Steven A Soini,Yanqi Luo,Xiaoyang Liu,Si Chen,Vivian M Merk
{"title":"Nanoscale elemental and morphological imaging of nitrogen-fixing cyanobacteria.","authors":"Bobby G Duersch,Steven A Soini,Yanqi Luo,Xiaoyang Liu,Si Chen,Vivian M Merk","doi":"10.1093/mtomcs/mfae040","DOIUrl":"https://doi.org/10.1093/mtomcs/mfae040","url":null,"abstract":"Nitrogen-fixing cyanobacteria bind atmospheric nitrogen and carbon dioxide using sunlight. This experimental study focused on a laboratory-based model system, Anabaena sp., in nitrogen-depleted culture. When combined nitrogen is scarce, the filamentous procaryotes reconcile photosynthesis and nitrogen fixation by cellular differentiation into heterocysts. To better understand the influence of micronutrients on cellular function, 2D and 3D synchrotron X-ray fluorescence mappings were acquired from whole biological cells in their frozen-hydrated state at the Bionanoprobe, Advanced Photon Source. To study elemental homeostasis within these chain-like organisms, biologically relevant elements were mapped using X-ray fluorescence spectroscopy and energy-dispersive X-ray microanalysis. Higher levels of cytosolic K+, Ca2+, and Fe2+ were measured in the heterocyst than in adjacent vegetative cells, supporting the notion of elevated micronutrient demand. P-rich clusters, identified as polyphosphate bodies involved in nutrient storage, metal detoxification and osmotic regulation, were consistently co-localized with K+ and occasionally sequestered Mg2+, Ca2+, Fe2+, and Mn2+ ions. Machine-learning based k-mean clustering revealed that P/K clusters were associated with either Fe or Ca, with Fe and Ca clusters also occurring individually. In accordance with XRF nanotomography, distinct P/K-containing clusters close to the cellular envelope were surrounded by larger Ca-rich clusters. The transition metal Fe, which is part of nitrogenase enzyme, was detected as irregular shaped clusters. The elemental composition and cellular morphology of diazotrophic Anabaena sp. was visualized by multimodal imaging using AFM, SEM, and fluorescence microscopy. This paper discusses the first experimental results obtained with a combined in-line optical and X-ray fluorescence microscope at the Bionanoprobe.","PeriodicalId":89,"journal":{"name":"Metallomics","volume":"40 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MetallomicsPub Date : 2024-09-09DOI: 10.1093/mtomcs/mfae036
J R Liddell,J B W Hilton,Y J Wang,J L Billings,S Nikseresht,K Kysenius,J P Fuller-Jackson,D J Hare,P J Crouch
{"title":"Decreased spinal cord motor neuron numbers in mice depleted of central nervous system copper.","authors":"J R Liddell,J B W Hilton,Y J Wang,J L Billings,S Nikseresht,K Kysenius,J P Fuller-Jackson,D J Hare,P J Crouch","doi":"10.1093/mtomcs/mfae036","DOIUrl":"https://doi.org/10.1093/mtomcs/mfae036","url":null,"abstract":"Disrupted copper availability in the central nervous system (CNS) is implicated as a significant feature of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Solute carrier family 31 member 1 (Slc31a1; Ctr1) governs copper uptake in mammalian cells and mutations affecting Slc31a1 are associated with severe neurological abnormalities. Here, we examined the impact of decreased CNS copper caused by ubiquitous heterozygosity for functional Slc31a1 on spinal cord motor neurons in Slc31a1+/- mice. Congruent with the CNS being relatively susceptible to disrupted copper availability, brain and spinal cord tissue from Slc31a1+/- mice contained significantly less copper than wild-type littermates, even though copper levels in other tissues were unaffected. Slc31a1+/- mice had less spinal cord α-motor neurons compared to wild-type littermates but they did not develop any overt physical signs of motor impairment. By contrast, ALS model SOD1G37R mice had fewer α-motor neurons than control mice and exhibited clear signs of motor function impairment. With the expression of Slc31a1 notwithstanding, spinal cord expression of genes related to copper handling revealed only minor differences between Slc31a1+/- and wild-type mice. This contrasted with SOD1G37R mice where changes in the expression of copper handling genes were pronounced. Similarly, the expression of genes related to toxic glial activation were unchanged in spinal cords from Slc31a1+/- mice but highly up-regulated in SOD1G37R mice. Together, results from the Slc31a1+/- mice and SOD1G37R mice indicate that although depleted CNS copper has a significant impact on spinal cord motor neuron numbers, the manifestation of overt ALS-like motor impairment requires additional factors.","PeriodicalId":89,"journal":{"name":"Metallomics","volume":"7 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142204052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}