Re-expression of tafazzin isoforms in TAZ-deficient C6 glioma cells restores cardiolipin composition but not proliferation rate and alterations in gene expression
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PROVIDER: PRJNA853298 | ENA |
REPOSITORIES: ENA
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Project description: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.
2022-07-25 | GSE207004 | GEO
Project description: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 exist in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study was to investigate if specific isoforms like Δ5 can restore the wild type phenotype with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aimed to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and (Ingenuity Pathway Analyis) IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells could fully restore CL composition and-as proven for Δ5-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; TAZMut). Re-expression of only rat full length TAZ could restore proliferation rate. Surprisingly, the Δ5 variant failed to restore wild-type proliferation. Further, as expected, re-expression of the TAZMut variant completely failed to reverse the gene expression changes, whereas re-expression of the TAZ-FL variant largely did so and the Δ5 variant to somewhat less extent. 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.
| S-EPMC9358009 | biostudies-literature
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
Project description:Inhibiting tafazzin a cardiolipin remodeling enzyme reduces stemness of AML by modulating the level of phosphatidylserine
2019-03-28 | GSE107045 | GEO
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
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 (with a fold change ≥ 1.2 and p value < 0.05).
2020-05-22 | GSE151007 | GEO
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
Project description:Analysis of the transcriptome of cardiac tissue from mice trangenically engineered with a doxycycline inducible Tafazzin shRNA knockdown to mimic the loss of function of Tafazzin in Barth syndrome. ShRNA induced knockdown mice were compared to wildtype littermates also fed the doxycyline diet. The hypothesis was to investigate adaptive metabolic and compensatory gene transcriptional changes in myocardium of the mouse model of Barth syndrome Total RNA obtained from 2 month old cardiac tissue from the doxycycline inducible shRNA Tafazzin knockdown mouse model of Barth syndrome compared to wildtype littermates also fed 625 mg/Kg doxycycline diet
2011-11-05 | E-GEOD-33452 | biostudies-arrayexpress
Project description:Analysis of the transcriptome of cardiac tissue from mice transgenically expressing human cardiolipin synthesis. The hypothesis tested was that cardiac specific transgenic expression of cardiolipin synthase alters myocardial lipidomic flux resulting in compensatory metabolic gene transcriptional changes that will attenuate pathological environmental and dietary insults on bioenergetics. Total RNA obtained from cardiac tissue from transgenic cardiac specific expressing human cardiolipin synthase 1 (hCLS1) mouse model at 4 months of age compared to wildtype littermates
2011-11-05 | E-GEOD-33451 | biostudies-arrayexpress
Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.
2018-07-19 | GSE110297 | GEO