Role of copper in progression of clear cell renal cell carcinoma [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE250028 | GEO | 2024/10/18
REPOSITORIES: GEO
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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.
2024-10-18 | GSE250163 | GEO
Project description:Chemotaxis is a widespread strategy used by unicellular and multicellular living organisms to maintain their fitness in stressful environments. We previously showed that bacteria can trigger a negative chemotactic response to a copper (Cu)-rich environment. Cu ions toxicity on bacterial cell physiology has been mainly linked to mismetallation events and ROS production, although the precise role of Cu-generated ROS remains largely debated. Here, we found that the cytoplasmic Cu ions content mirrors variations of the extracellular Cu ions concentration and triggers a dose-dependent oxidative stress, which can be abrogated by superoxide dismutase and catalase overexpression. The inhibition of ROS production in the cytoplasm not only improves bacterial growth but also impedes Cu-chemotaxis, indicating that ROS derived from cytoplasmic Cu ions mediate the control of bacterial chemotaxis to Cu. We also identified the Cu chemoreceptor McpR, which binds Cu ions with low affinity, suggesting a labile interaction. In addition, we demonstrate that the cysteine 75 and histidine 99 within the McpR sensor domain are key residues in Cu chemotaxis and Cu coordination. Finally, we discovered that in vitro both Cu(I) and Cu(II) ions modulate McpR conformation in a distinct manner. Overall,our study provides mechanistic insights on a redox-based control of Cu chemotaxis, indicating that the cellular redox status can play a key role in bacterial chemotaxis.
2023-09-05 | PXD044512 | Pride
Project description:Copper is a powerful antimicrobial and antiviral agent, which has interest through several biomedical applications. Nevertheless, how copper induces the cellular damage is not fully understood. Two main mechanisms are claimed to be involved, i.e. Cu catalyzed reactive oxygen species production (ROS) and replacements of other essential metal ions, such as Fe in Fe-S clusters by Cu. In the present work, we cumulate strong evidence for the importance of a third mechanism, which proposes that Cu damaging effects are due to its ability to cause massive protein aggregation in a ROS independent mechanism. We further show that Hsp33, a redox-regulated molecular chaperone in Escherichia coli, can prevent Cu-induced protein aggregation, suggesting an important role of the chaperoning system in defense against Cu-toxicity. A closer inspection of the mechanism of how Cu can activate Hsp33 revealed two intriguing features, i) a redox-state specificity of Cu+ vs Cu2+, and ii) an unprecedented mechanism of Hsp33-activation via a non-redox trans-metalation. Indeed, our data suggest that two Cu+ bind to the Zn-Cys4-finger site in Hsp33, which lead to a replacement of one Zn2+ by two Cu+ without Cys oxidation. In contrast, Cu2+ oxidizes the Cys in the Zn-finger, analogue to other oxidative stress effectors of Hsp33. Hence, the present results give several new insights in the antimicrobial mechanism of Cu and how bacteria defend against it.
2022-02-10 | PXD019288 | Pride
Project description:α-Lipoic acid (LA) is an essential cofactor for mitochondrial dehydrogenases and is required for cell growth, metabolic fuels production, and antioxidant defense. In vitro, LA binds copper (Cu) with high affinity, and as an endogenous membrane permeable metabolite could be advantageous in mitigating the consequences of Cu overload in human diseases. We tested this hypothesis in 3T3-L1 preadipocytes with inactivated Cu transporter Atp7a; these cells accumulate Cu and show morphologic changes and mitochondria impairment. Treatment with LA corrected the morphology of Atp7a-/- 60 cells similar to the Cu chelator bathocuproinedisulfonate (BCS) and improved mitochondria function; however, the mechanisms of LA and BCS action were different. Unlike BCS, LA did not decrease intracellular Cu, but instead increased selenium levels that were low in Atp7a-/- cells. Proteome analysis confirmed distinct cell responses to these compounds and identified upregulation of selenoproteins as the major effect of LA on preadipocytes. Upregulation of selenoproteins was associated with improved GSH:GSSG ratio in cellular compartments, which was lowered by elevated Cu, and reversal of protein oxidation. Thus, LA diminishes toxic effects of elevated Cu by improving cellular redox environment. We also show that selenium levels are decreased in tissues of Wilson disease animal model, especially in the liver, making LA an attractive candidate for supplemental treatment of this disease.
2024-05-23 | PXD045233 | Pride
Project description:Copper and iron are essential micronutrients for most living organisms because they participate as cofactors in biological processes including respiration, photosynthesis and oxidative stress protection. In many eukaryotic organisms, including yeast and mammals, copper and iron homeostases are highly interconnected; however such interdependence is not well established in higher plants. Here we propose that COPT2, a high-affinity copper transport protein, functions under copper and iron deficiencies in Arabidopsis thaliana. COPT2 is a plasma membrane protein that functions in copper acquisition and distribution. Characterization of the COPT2 expression pattern indicates a synergic response to copper and iron limitation in roots. We have characterized a knockout of COPT2, copt2-1, that leads to increased resistance to simultaneous copper and iron deficiencies, measured as reduced leaf chlorosis and improved maintenance of the photosynthetic apparatus. We propose that COPT2 expression could play a dual role under Fe deficiency. First, COPT2 participates in the attenuation of copper deficiency responses driven by iron limitation maybe aimed to minimize further iron consume. On the other hand, global expression analyses of copt2-1 mutants versus wild type Arabidopsis plants indicate that low phosphate responses are increased in copt2-1 plants. In this sense, COPT2 function under Fe deficiency counteracts low phosphate responses. These results open up new biotechnological approaches to fight iron deficiency in crops. Four biological replicates of Arabidopsis seedlings were generated for 2 genotypes, Col-0 and copt2-1 mutant; and 3 growth condictions; first one an iron(Fe) and copper(Cu) sufficient medium (+Fe + Cu), second one an Fe deficient and Cu sufficient medium (-Fe+Cu) and third one an Fe and Cu deficient medium (-Fe-Cu). For each growth one comparasion was made, copt2-1 mutant versus Col-0; in each comparasion four biological replicates were made, two replicas were labeled with Cy5 for the mutant sample and Cy3 for the Col-0 sample, while the other two replicas were reversed-labeled.
2013-06-05 | E-GEOD-42642 | biostudies-arrayexpress
Project description:A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference of bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid-induced differentiation. To accommodate this elevated energy demand, retinoic acid signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. In addition, inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway blocked the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon retinoic acid-induced differentiation by both RNA-seq analyses and quantitative proteomics. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration which is required for spermatogonial proliferation and differentiation.
2021-09-09 | PXD019136 | Pride
Project description:Gene expression in response to Cu stress in rice leaves was quantified using DNA microarray (Agilent 22K Rice Oligo Microarray) and real-time PCR technology. Rice plants were grown in hydroponic solutions containing 0.3 (control), 10, 45 or 130 µM of CuCl2, and Cu accumulation and photosynthesis inhibition were observed in leaves within 1 day of the start of treatment. Microarray analysis flagged 305 Cu-responsive genes, and their expression profile showed that a large proportion of general and defense stress response genes are up-regulated under excess Cu conditions, whereas photosynthesis and transport-related genes are down-regulated. The Cu sensitivity of each Cu-responsive gene was estimated by the median effective concentration value (EC50) and the range of fold-changes (F) under the highest (130 µM) Cu conditions (|log2F|130). Defense-related genes involved in phytoalexin and lignin biosynthesis were the most sensitive to Cu. Our results indicate that plant management of abiotic and pathogen stresses has overlapping components, possibly including signal transduction. Keywords: dose response, stress response
2008-04-30 | GSE11021 | GEO
Project description:Copper (Cu) is an essential trace element for diverse biological reactions such as respiration, neurotransmitter synthesis, oxidative stress and transcriptional regulation. If Cu homeostasis is disrupted, several pathological conditions can develop, leading to alterations of neuronal, cognitive, and muscular development. Known Cu+-binding transcription factors in mammalian cells are Atox1, Mtf1 and Sp1. We identified Crip2 as a novel Cu+-responsive transcriptional regulator that is required for the differentiation of primary myoblasts derived from mouse satellite cells. Functional characterization of CRISPR/Cas9-mediated deletion of Crip2 showed that myoblasts fail to differentiate and manifest a decrease in expression of the differentiation markers Myogenin and Myosin heavy chain. RNA-seq and CUT&RUN analysis were performed to understand the effect on Crip2 in the regulation of gene expression in proliferating and differentiating primary myoblasts stimulated with Cu.
2024-05-30 | GSE252158 | GEO
Project description:Copper (Cu) is an essential trace element for diverse biological reactions such as respiration, neurotransmitter synthesis, oxidative stress and transcriptional regulation. If Cu homeostasis is disrupted, several pathological conditions can develop, leading to alterations of neuronal, cognitive, and muscular development. Known Cu+-binding transcription factors in mammalian cells are Atox1, Mtf1 and Sp1. We identified Crip2 as a novel Cu+-responsive transcriptional regulator that is required for the differentiation of primary myoblasts derived from mouse satellite cells. Functional characterization of CRISPR/Cas9-mediated deletion of Crip2 showed that myoblasts fail to differentiate and manifest a decrease in expression of the differentiation markers Myogenin and Myosin heavy chain. RNA-seq and CUT&RUN analysis were performed to understand the effect on Crip2 in the regulation of gene expression in proliferating and differentiating primary myoblasts stimulated with Cu.
2024-05-30 | GSE252156 | GEO
Project description:The transition metal copper (Cu) is an essential element for all living organisms. In plants, Cu plays key roles in electron transport chains of chloroplasts and mitochondria, as well as in cell wall metabolism, ethylene perception, molybdenum cofactor synthesis and oxidative stress protection. Because of its physiological importance, suboptimal concentrations of Cu trigger a re-organization of metabolism to economize on Cu, and pronounced Cu deficiency causes severe growth reduction and defects in male fertility. However, when present in excess, Cu can be highly toxic. Therefore, Cu uptake, utilization and cellular concentrations are strictly regulated. A number of components of the Cu-homeostatic network of Arabidopsis have already been identified. However, the mechanisms that control responses of plant gene expression to Cu-deficiency are only partly understood. In Chlamydomonas reinhardtii, the transcription factor Crr1 is required for activating and/or repressing the expression of a number of genes in response to Cu deficiency. This protein contains a plant-specific DNA-binding domain (SBP domain), ankyrin repeats and a C-terminal cysteine-rich region with similarity to a Drosophila metallothionein (MT). In Arabidopsis, there is a family of 16 proteins with SBP domains named SPL family (SBP-like) of which a subset of proteins have been implicated in flowering time control and floral development. Among all of them, AtSPL7 is the most similar to Crr1 (27 % identity), and AtSPL1 (25 % identity), AtSPL12 (24 % identity) and AtSPL14 (23 % identity) share a common protein architecture. The goal of this work was to obtain a complete account of the response of the Arabidopsis thaliana transcriptome to Cu deficiency, as well as to determine the role of AtSPL7 in the transcriptional response to Cu deficiency. For this purpose, three independent experiments were carried out including Col-0 wild-type and spl7-2 mutant plants grown in Cu-sufficient and Cu-deficient hydroponic media, respectively. Root and shoot transcriptomes were established by RNA-Seq for quantitative comparisons.
2013-10-14 | GSE24696 | GEO