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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

ABSTRACT: Copper is an essential component of cytochrome C oxidase (i.e. complex IV of the electron transport chain), and is thus critical for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains using microarrays.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE47175 | GEO | 2013/05/23

SECONDARY ACCESSION(S): PRJNA204982

REPOSITORIES: GEO

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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

Project description:Copper is an essential component of cytochrome C oxidase (i.e. complex IV of the electron transport chain), and is thus critical for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains using microarrays. In the yeast homozygous gene deletion collection, both copies of every non-essential gene are deleted in a diploid strain. Each strain contains unique 20-bp M-bM-^@M-^\barcodeM-bM-^@M-^] sequences flanked by common priming sites, allowing the relative abundance of individual strains to be quantitatively monitored within a pool of competitively-grown strains. To identify genes that are important for Cu-dependent respiratory growth, we measured the fitness of 5050 homozygous deletion strains in parallel in rich media (i.e. Yeast Extract, Peptone) using either dextrose, ethanol, glycerol, or lactate as a carbon source, in the presence or absence of 500 M-BM-5M CuSO4 for 9 generations. Each condition was tested in triplicate. Please note that there is a large percentage of null-values (i.e. Not Available) in the respiration deficient-pool samples because the respiration deficient pool consists of only a small subset of the complete pool (represented by 331 barcodes instead of 9937). For our analysis we discarded the remaining barcodes by assigning the null-value to them.

2013-05-23 | E-GEOD-47175 | biostudies-arrayexpress

Role of copper in progression of clear cell renal cell carcinoma [RNA-seq]

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A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system.

Project description:BackgroundCopper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health.ResultsWe found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu's positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson's disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin.ConclusionsA functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations.

| S-EPMC4023593 | biostudies-literature

The role of multi-copper oxidase CueO

2007-04-28 | GSE5177 | GEO

Role of copper in progression of clear cell renal cell carcinoma [Spatial transcriptomics]

Project description:Copper (Cu) is an essential trace element required for mitochondrial respiration. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis and promotes tumor growth and progression of clear cell renal cell carcinoma (ccRCC). Late-stage ccRCCs accumulate Cu and allocate it to cytochrome c oxidase stimulating bioenergy production. Cu induces TCA cycle-dependent oxidation of glucose and its utilization for biosynthesis of a glutathione pool that protects against H2O2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. Single cell transcriptomics determined induction of mitochondrial electron transport chain, expression of NRF2 targets and glutathione biosynthesis, and decrease in HIF activity, the hallmark of ccRCC, during disease progression. Spatial transcriptomics identified that cancer cells with proliferative phenotype are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC.

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The role of multi-copper oxidase CueO

Project description:The effect of a cueO mutation on global gene expression in E. coli has been analysed using whole genome oligonucleotide microarrays. A cueO mutant lacks a periplasmic multi-copper oxidase, an enzyme that is believed to be involved in the oxidation of cuprous and ferrous ions as well as phenolic compounds in the periplasm. Deletion renders the cell sensitive to copper and this toxicity is likely associated with increased oxidative stress in a cueO mutant. Triplicate cultures of E. coli MG1655 and the isogenic cueO mutant were grown to mid-exponential phase (OD600 0.8) in M9C supplemented with 2ïM FeSO4. RNA was extracted using Qiagen RNAprotect and RNeasy Mini Kit. Reference RNA was similarly purified from triplicate cultures of E. coli MG1655 grown on M9C supplemented with 2ïM FeCl3. RNA concentration and quality was assessed using an Aligent Bioanalyser 2100 NanoLabchip.

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Expression data from livers from Sco1 liver-specific KO and WT adult mice

Project description:Sco1 is a gene required for cytochrome c oxidase biogenesis and the regulation of copper homeostasis. We characterized the transcriptional changes that occur as a result of liver-specific deletion of Sco1 in mice at 27 days of age In this dataset, we include the expression data obtained from dissected wild-type mouse livers and mouse livers in which Sco1 has been specifically deleted.

2014-07-02 | GSE58997 | GEO

Expression data from livers from Sco1 liver-specific KO and WT adult mice

2014-07-02 | E-GEOD-58997 | biostudies-arrayexpress

Comparison of Corynebacterium glutamicum cultivated under copper starvation with copper sufficiency

Project description:To identify genes which are differentially expressed in Corynebacterium glutamicum in the absence of copper, we performed DNA microarray analyses of cells cultivated under copper starvation conditions compared to copper sufficiency.

2018-08-28 | GSE117530 | GEO

Copper metabolism in Naegleria gruberi and its deadly relative Naegleria fowleri.

Project description:Although copper is an essential nutrient crucial for many biological processes, an excessive concentration can be toxic and lead to cell death. The metabolism of this two-faced metal must be strictly regulated at the cell level. In this study, we investigated copper homeostasis in two related unicellular organisms: nonpathogenic Naegleria gruberi and the “brain-eating amoeba” Naegleria fowleri. We identified and confirmed the function of their specific copper transporters securing the main pathway of copper acquisition. Adjusting to different environments with varying copper levels during the life cycle of these organisms requires various metabolic adaptations. Using comparative proteomic analyses, measuring oxygen consumption, and enzymatic determination of NADH dehydrogenase, we showed that both amoebas respond to copper deprivation by upregulating the components of the branched electron transport chain: the alternative oxidase and alternative NADH dehydrogenase. Interestingly, analysis of iron acquisition indicated that this system is copper-dependent in N. gruberi but not in its pathogenic relative. Importantly, we identified a potential key protein of copper metabolism of N. gruberi, the homolog of human DJ-1 protein, which is known to be linked to Parkinson’s disease. Altogether, our study reveals the mechanisms underlying copper metabolism in the model amoeba N. gruberi and the fatal pathogen N. fowleri and highlights the differences between the two amoebas.

2022-05-20 | PXD032745 | Pride

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