Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport

ABSTRACT: Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here, we show that expression of Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables the growth of mtDNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314127 | GEO | 2025/12/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The mevalonate pathway is required for pyrimidine synthesis and survival of p53-deficient colon cancer cells in metabolically compromised environments

Project description:In this study, we have investigated the effect of p53 deletion on the metabolic activity of colon cancer cells exposed to metabolic stress. In order to recreate the simultaneous reduction in oxygen and nutrient availability found in tumors, we cultured cancer cells as multicellular tumor spheroids. Under these conditions, p53 deficient cancer cells activate the expression of enzymes of the mevalonate pathway via the sterol regulatory element binding protein 2 (SREBP2). Moreover, inhibition of mevalonate pathway activity with statins selectively induced apoptosis in p53 deficient cancer cells exposed to metabolic stress. This effect was mediated by the requirement of p53 deficient cancer cells to synthesise ubiquinone (coenzyme Q10) to maintain TCA cycle activity, respiration and the production of pyrimidine nucleotides. Our study has revealed a novel link between isoprenoid synthesis by the mevalonate pathway and the electron transport function of ubiquinone, which is required for nucleotide biosynthesis. As a consequence, maintaining mevalonate pathway activity is essential for p53 deficient cancer cells to proliferate and survive under the metabolic constraints of the tumor microenvironment.

2019-11-15 | GSE124189 | GEO

Transcript level responses of Plasmodium falciparum to antimycin A

Project description:Abstract: The mitochondrial electron transport chain is essential to Plasmodium and is the target of the antimalarial drug atovaquone. The mitochondrial genomes of Plasmodium sp. are the most reduced known, and the majority of mitochondrial proteins are encoded in the nucleus and imported into the mitochondrion post-translationally. Many organisms have signalling pathways between the mitochondria and the nucleus to regulate the expression of nuclear-encoded mitochondrially-targeted proteins, for example in response to mitochondrial dysfunction. We have studied the gene expression profiles of synchronous Plasmodium falciparum treated with an LD50 concentration of the complex III inhibitor antimycin A, to investigate whether such pathways exist in the parasite. There was a broad perturbation of gene expression. Some effects were attributable to a delay in the gene expression phase of drug-treated parasites. However, our data also indicated regulation of mitochondrial stress response genes and genes involved in pyrimidine biosynthesis. 3 biological replicates each for treated and untreated: control (1/2000 DMSO) and LD50 antimycin A, respectively. Normalised microarray data for antimycin A-treated parasites were contrasted against untreated (DMSO) controls.

2012-04-19 | E-GEOD-28625 | biostudies-arrayexpress

Transcriptomic analysis by array of reactivation of dihydroorotate dehydrogenase by respiration restores tumor growth of mitochondrial DNA-depleted cancer cells.

Project description:Tumor cells without mitochondrial DNA (mtDNA) reconstitute oxidative phosphorylation (OXPHOS) by acquiring host mitochondria from stromal cells, but the reasons why functional respiration is crucial for tumorigenesis remain unclear. To address this issue, we used time-resolved analysis of the initial stages of tumor formation by cells devoid of mtDNA and genetic manipulations of components of OXPHOS. We show that pyrimidine biosynthesis, supported by respiration-linked dihydroorotate dehydrogenase (DHODH), is strictly required to overcome cell cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis.

2018-10-01 | E-MTAB-6150 | biostudies-arrayexpress

Transcript level responses of Plasmodium falciparum to antimycin A

2012-04-20 | GSE28625 | GEO

Mitochondrial respiration is necessary for CD8 T cell proliferation and cell fate

Project description:CD8 T cell proliferation and memory formation are linked to changes in metabolism, which has important implications for improving CD8 T cell fitness in therapies against chronic infections and cancer. The mitochondrial electron transport chain (ETC) is essential for antigen-specific CD8 T cell proliferation. Mitochondrial ETC function is linked to the generation of ATP, production of metabolites to sustain proliferation, and signaling molecules including reactive oxygen species (ROS), which determine T cell function and fate. However, it is not fully understood which mitochondrial ETC functions are necessary for CD8 T cell proliferation in vivo. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production, and superoxide production, decreases CD8 T cell proliferation and memory formation. CD8 T cells lacking functional mitochondrial complex III also exhibit an exhausted-like phenotype following acute stimulation. The expression of Ciona intestinalis alternative oxidase (AOX), which accepts electrons from coenzyme Q, thus compensating for the loss of mitochondrial complex III function without generating ROS or proton pumping, restores respiration, proliferation and largely prevents the exhausted phenotype in vitro and in vivo. However, AOX did not sustain memory CD8 T cells, suggesting mitochondrial complex III ROS is necessary for optimal memory formation. These findings demonstrate that the primary function of the mitochondrial ETC in CD8 T cells is enabling respiration to sustain proliferation and memory formation as well as to prevent an exhausted phenotype.

2025-06-20 | GSE296763 | 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.

2024-10-18 | GSE250163 | GEO

Complexome profiling of heart mitochondria from mouse expressing alternative oxidase

Project description:Ciona intestinalis alternative oxidase (AOX) is a mitochondrial respiratory enzyme that acts as an alternative electron sink for ubiquinol (reduced quinone) when the cytochrome bc1 complex (complex III) and/or cytochrome c oxidase (complex IV) are inhibited or impaired (El-Khoury et al., 2014). AOX thus enables electron flux through the mitochondrial electron transport chain (ETC) and thereby prevents reverse electron transport from succinate dehydrogenase (complex II) to NADH:ubiquinone oxidoreductase (complex I) and mitochondrial ROS production, restores redox balance and Krebs cycle activity. As a non-proton-motive enzyme, however, AOX does not directly support ATP production. Previously, a mouse model was generated that despite ubiquitous expression of AOX revealed no deviations from normal physiology and which now is used as model to test mitochondrial disease paradigms (Szibor et al., 2017).

2019-12-13 | PXD014016 | Pride

Proteomic Analysis Suggests Altered Mitochondrial Metabolic Profile Associated with Diabetic Cardiomyopathy

Project description:Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, often leading to heart failure and death. To elucidate the molecular mechanisms involved in the DbCM progress, we performed quantitative proteomic profiling analysis in the left ventricle (LV) of leptin receptor‐deficient mice. Six‐month‐old C57BL/6Jlepr/ lepr (db/db) mice exhibited a phenotype of DbCM. By quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in db/db mice, mainly associated with energy metabolism. The subunits of ATP synthase that form the F1 domain and Cytochrome c1, a catalytic core subunit of the complex III that is responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by the diabetic heart resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1 beta subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, an atypical kinase COQ8A, an essential lipid‐soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from the diabetic mice to augment mitochondrial ATP production, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production.

2021-12-02 | PXD029566 | Pride

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

Project description:Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression

| PRJEB98732 | ENA

Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

Project description:Reducing mitochondrial electron transport induces a Warburg-like shift to accommodate for the energetic burden caused by brain trauma without overwhelming mitochondrial cellular respiration and cellular redox to salvage dopaminergic neurons. This metabolic shift is evident in the transcriptional upregulation of key genes in the Pyruvate Dehydrogenase Complex and glycolytic pathway.

2021-08-26 | GSE179905 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data