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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE221662 | GEO | 2023/07/15

REPOSITORIES: GEO

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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 switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth Syndrome.

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 iPSC 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.

2023-06-07 | MSV000092116 | MassIVE

Genome-wide analysis of gene transcription in myocardium of the doxycycline inducible Tafazzin shRNA knockdown mouse model of Barth syndrome

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

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.

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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

Genome-wide analysis of gene transcription in myocardium of the doxycycline inducible Tafazzin shRNA knockdown mouse model of Barth syndrome

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Single Cell Transcriptomic Analysis in a Mouse Model of Barth Syndrome Reveals Cell-Specific Alterations in Gene Expression and Intercellular Communication

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2023-06-20 | GSE235047 | GEO

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

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