Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Analysis of gene expression profiles from the liver of rats treated with the mitochondrial electron transport chain complex III inhibitor GSK932121A (50mg/kg) or vehicle control

ABSTRACT: BACKGROUND: Correlating in vitro mitochondrial data to outcomes in vivo remains a challenge and improving methods to assess mitochondrial function in vivo would both guide safer candidate selection and support the growing number of discovery programmes targeting mitochondria for pharmacological intervention. OBJECTIVES: The aim was to assess the toxicity profile of a compound with complex III electron transport chain inhibitory activity (GSK932121A) in order to identify markers and mechanisms of mitochondrial perturbation in vivo. METHODS:Crl:CD(SD) rats were dosed IP with GSK932121A for up to 5 hours depending upon the severity of observed clinical signs. Respirometry, microscopy, lactate/pyruvate and transcriptomics profiling were used to aid identification of a mode of action and this data was compared with functional data in isolated mitochondria. RESULTS AND DISCUSSION: GSK932121A administered in vivo caused hypothermia and a metabolic shift in energy production provoking an increased lactate/pyruvate ratio, microvesicular steatosis and glycogen depletion; alongside gene expression changes indicative of a fasted state. Our data improves current understanding of the toxicological consequences of drug induced respiratory chain inhibition and guides endpoint selection for future investigative safety studies with mitochondrially active molecules.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE65374 | GEO | 2015/01/29

SECONDARY ACCESSION(S): PRJNA273845

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Analysis of gene expression profiles from the liver of rats treated with the mitochondrial electron transport chain complex III inhibitor GSK932121A (50mg/kg) or vehicle control

Project description:BACKGROUND: Correlating in vitro mitochondrial data to outcomes in vivo remains a challenge and improving methods to assess mitochondrial function in vivo would both guide safer candidate selection and support the growing number of discovery programmes targeting mitochondria for pharmacological intervention. OBJECTIVES: The aim was to assess the toxicity profile of a compound with complex III electron transport chain inhibitory activity (GSK932121A) in order to identify markers and mechanisms of mitochondrial perturbation in vivo. METHODS:Crl:CD(SD) rats were dosed IP with GSK932121A for up to 5 hours depending upon the severity of observed clinical signs. Respirometry, microscopy, lactate/pyruvate and transcriptomics profiling were used to aid identification of a mode of action and this data was compared with functional data in isolated mitochondria. RESULTS AND DISCUSSION: GSK932121A administered in vivo caused hypothermia and a metabolic shift in energy production provoking an increased lactate/pyruvate ratio, microvesicular steatosis and glycogen depletion; alongside gene expression changes indicative of a fasted state. Our data improves current understanding of the toxicological consequences of drug induced respiratory chain inhibition and guides endpoint selection for future investigative safety studies with mitochondrially active molecules. 50mg/kg GSK932121A treated rat livers (n=10) were used to assess differential gene expression when compared with 0mg.kg GSK932121A Vehicle Control (n=12). Two samples were excluded from the 50mg/kg group due to low plasma exposure to GSK932121A

2015-01-29 | E-GEOD-65374 | biostudies-arrayexpress

Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes

Project description:Metformin-induced lactate production can lead to lactate acidosis as life-threatening side effect, whereas lactate in a physiological range might also be involved in the therapeutic effect. How metformin increases systemic lactate concentrations is only partly understood. Since human skeletal muscle has a high capacity to produce lactate, we aim to elucidate the potential contribution of skeletal muscle and the dose-dependent regulation of metformin-induced lactate production in primary human myotubes after 48 h of metformin treatment (16-776 μM). At 78 µM, metformin induced lactate production and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, p<0.01) along with a decreased [NAD+]:[NADH] ratio (776 µM, p<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of PDH complex (39 µM, p<0.01). In vivo in human skeletal muscle, we found pyruvate metabolism altered by exercise and not by metformin. Nonetheless, blood lactate levels in the pre-exercise condition are increased under metformin treatment (p<0.05). Metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state, both shift the equilibrium of the LDH reaction leading to enhanced lactate production of human myotubes.

2023-09-04 | GSE229658 | GEO

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation

Project description:Lactate is the most abundant circulating metabolic intermediate in mammals and an important energy source for many organs. To use lactate as a fuel, it must be oxidized to pyruvate for entry into the TCA cycle. It is usually described that this reaction occurs in the cytosol and requires the mitochondrial pyruvate carrier (MPC) for pyruvate transport into the mitochondria. Here, using 13C stable isotope tracing, we report that lactate can be oxidized in the heart tissue of mice even when the MPC is genetically deleted. MPC-independent lactate import and oxidation within mitochondria is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1). Mitochondria isolated from Mct1iCKO hearts have impaired respiration on lactate but not pyruvate. Lactate import coupled to mitochondrial lactate dehydrogenase activity functions as an electron shuttle which can produce NADH sufficient for respiration even when the TCA cycle is blocked. Cardiac-specific loss of MCT1 leads to rapid decompensation into heart failure with reduced ejection fraction in response to diverse cardiac injuries. Thus, we identify a new mitochondrial electron shuttle that enables the oxidation of lactate and is required to support cardiac energetics under stress conditions.

2024-11-22 | GSE276036 | GEO

Prostate Cancer mitochondrial DNA heteroplasmies and mitochondrial gene expression

Project description:Altered mitochondrial function in prostate cancer was characterized using paired malignant/non-malignant (benign) tissue samples. Mitochondrial DNA heteroplasmies (mtDNA-NGS) and mitochondria associated gene transcript levels (RNAseq-NGS) were analyzed and correlated to mitochondrial respiration (high-resolution respirometry), to each other and to the tumor stage and grade.

| EGAS00001004186 | EGA

Imaging metabolic heterogeneity in breast cancer using hyperpolarized 13C-MRI

Project description:Higher 13C-lactate labeling was seen in the more aggressive tumors, including all triple negative breast cancers. There was a significant correlation between lactate labeling and expression of the monocarboxylate transporter (MCT1), which mediates tumor cell pyruvate uptake, and a weaker correlation with expression of LDHA, which catalyzes label exchange between the injected pyruvate and the endogenous lactate pool.

| EGAS00001004118 | EGA

ATAC-sequencing of primary basal-derived mouse prostate organoids treated with vehicle, the mitochondrial pyruvate carrier inhibitor UK5099, or lactate supplementation

Project description:The goal of this study was to understand how the mitochondrial pyruvate carrier inhibitor,UK5099, and lactate supplementation alter chromatin accessibility in primary basal-derived mouse prostate organoids.

2023-09-01 | GSE221442 | GEO

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Project description:Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

2023-01-26 | GSE220663 | GEO

Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

Project description:The transporter which uptakes pyruvate into the mitochondria during pyruvate oxidation, called the Mitochondrial Pyruvate Carrier (MPC), was only recently identified. While the MPC has been studied in a variety of cell types, including cancer cells and stem cells, very little is known about the importance of MPC in immune cells. Here, we delete MPC from hematopoietic cells and measure its impact on T cell gene expression.

2020-04-27 | GSE122711 | GEO

The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation

Project description:Effector CD8+ T cells engage glycolysis for both lactate fermentation and pyruvate oxidation, the latter requiring the mitochondrial pyruvate carrier (MPC). How mitochondrial pyruvate metabolism impacts T cell function and fate, remains incompletely understood. We found that genetic deletion of MPC drives CD8+ T cell differentiation towards a memory phenotype. Metabolic flexibility induced by MPC inhibition in a nutrient-rich environment allowed for increased acetyl-coenzyme-A production by glutamine and fatty acid oxidation. This correlated with histone acetylation and chromatin accessibility on pro-memory genes. However, in a nutrient-deprived tumor microenvironment, MPC is essential for sustaining lactate oxidation that limits the metabolic suppression of CD8+ T cell anti-tumor function. To optimally translate these findings, we used a small molecule MPC inhibitor to imprint a stable memory phenotype during chimeric antigen receptor (CAR) T manufacturing, and demonstrated that infusing metabolically conditioned MPC WT CAR T cells resulted in superior and long-lasting anti-tumor activity.

2022-04-20 | GSE184718 | GEO

Transcription profiling of lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with dichloroacetate reveals a mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis inhibits cancer growth

Project description:The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent. Experiment Overall Design: lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with DCA

2008-06-14 | E-GEOD-6014 | biostudies-arrayexpress

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