Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Re-expression of tafazzin isoforms in TAZ-deficient C6 glioma cells restores cardiolipin composition but not proliferation rate and alterations in gene expression

ABSTRACT: Tafazzin an acyltransferase is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exists in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study is to investigate if isoform Δ5, which is lacking exon 5, full length rat TAZ, and mutant full-length rat Taz (enzymatically dead H69L) could restore wild type phenotype in C6 TAZ cells with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aim to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells can fully restore CL composition and – as proven for 5 – this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZmut3). The re-expression of none of the TAZ isoforms used led to the restoration of the proliferation rate and gene expression profiles. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE207004 | GEO | 2022/07/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Wild-type and tafazzin-deficient clones of granulocyte-monocyte progenitors (GMP), ER-HOXB8 conditionally immortalized, immature, in estrogen.

Project description:Evaluate changes in gene expression resulting from the loss of the gene TAZ (protein tafazzin). Tafazzin is an enzyme involved in cardiolipin maturation and cardiolipin is a phospholipid found only in the inner mitochondrial membrane. Gene expression profiling was performed in a murine granulocyte-monocyte progenitor in vitro cell system. We identified a limited number of changes in gene expression, which was not surprising given that the tafazzin protein is localized in the mitochondria and has a very specific enzymatic activity. Genes involved in cholesterol and fatty acid metabolism (Acss1, Acat2, Ldlr), apoptosis (Bcl2, Casp3, Casp6, Cycs), and ER-stress induced apoptosis (Ddit3, Atf4) were differentially expressed.

2020-05-22 | GSE151006 | GEO

Gene expression analysis of wild-type and Tafazzin-deficient granulocyte-monocyte progenitor (GMP) clones (ER-HOXB8 conditionally immortalized)

2020-05-22 | GSE151007 | GEO

Reduced basal insulin secretion from islets isolated from tafazzin deficient mice is associated with reduced mitochondrial function

Project description:Tafazzin is a transacylase which causes the content and molecular structure of cardiolipin (CL) to be altered in the inner mitochondrial membrane. The enzymatic machinery responsible for oxidative respiration are localized to the inner mitochondrial membrane and require CL for activity. As a result, tafazzin is critical for maintaining mitochondrial function. In beta-cells, which are the insulin secreting cells in pancreatic islets, mitochondrial function is linked to insulin secretion. We previously established that tafazzin knock-down mice were lean and maintained insulin sensitivity compared to the obese insulin resistant control litter mates. However, it was unknown whether tafazzin deficiency also influenced insulin secretion in the establishment of the lean phenotype. Using X week-old mice, we ascertained that the number of beta-cells was similar between genotypes. Ex vivo insulin secretion under low glucose conditions was reduced (52%) from islets isolated from tafazzin knock-down mice. Consistent with this tafazzin knock-down mice exhibited reduced fasting insulin plasma insulin levels. Measurement of mitochondrial oxygen consumption revealed that basal oxygen consumption was reduced (58%) in islets from tafazzin-deficient animals. The addition of etomoxir, an inhibitor of mitochondrial fatty acid translocation, significantly elevated basal mitochondrial respiration (5-fold) in islets from tafazzin knockdown mice, indicating a significant fatty acid-mediated inhibitory effect. In contrast, etomoxir lacked any measurable effect on control wild-type islets. The altered mitochondrial function identified in taffazin knock-down islets was not associated with reduced CL content or elevated oxyCL species. Our experiments indicate that tafazzin plays a key role in regulating normal islet beta-cell function.

2021-07-31 | GSE136242 | GEO

Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

Project description:Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription.

2018-09-12 | GSE119775 | GEO

Tafazzin Regulates Cell State by Modulating Phosphatidylethanolamine and Phosphatidylserine levels

Project description:Inhibiting tafazzin a cardiolipin remodeling enzyme reduces stemness of AML by modulating the level of phosphatidylserine

2019-03-28 | GSE107045 | GEO

Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane

Project description:Mitochondrial cristae are more crowded with proteins than other cellular membranes. However, protein crowding stresses the bilayer organization of lipids, which challenges membrane stability. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin (CL) to reduce stress on the lipid bilayer

2021-06-10 | MSV000087602 | MassIVE

Metabolic reprogramming from fatty acid oxidation to glycolysis in a patient mutation knock-in mouse model of Barth Syndrome. [human]

Project description:Mitochondria are central for cellular metabolism and energy supply. Barth Syndrome (BTHS) is a severe disorder due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patient. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPS cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid driven OXPHOS and protects mice against cardiac failure.

2023-07-15 | GSE221663 | GEO

Metabolic reprogramming from fatty acid oxidation to glycolysis in a patient mutation knock-in mouse model of Barth Syndrome.[mouse]

2023-07-15 | GSE221662 | GEO

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome

Project description:Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

2023-11-15 | GSE247576 | GEO

Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis

Project description:The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in resulted in different mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

2020-07-08 | GSE148178 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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