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

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

PROVIDER: PRJNA1039764 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26807523_1.fastq.gz	Fastqsanger.gz
	SRR26807523_2.fastq.gz	Fastqsanger.gz
	SRR26807524_1.fastq.gz	Fastqsanger.gz
	SRR26807524_2.fastq.gz	Fastqsanger.gz
	SRR26807525_1.fastq.gz	Fastqsanger.gz

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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

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, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/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.

| S-EPMC10628049 | biostudies-literature

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

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

2011-11-05 | GSE33452 | GEO

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

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Project description:Barth syndrome (BTHS) is an X-linked recessive multisystem disorder caused by mutations in the TAZ gene (TAZ, G 4.5, OMIM 300394) that encodes for the acyltransferase tafazzin. This protein is highly expressed in the heart and plays a significant role in cardiolipin biosynthesis. Heart disease is the major clinical manifestation of BTHS with a high incidence in early life. Although the genetic basis of BTHS and tetralinoleoyl cardiolipin deficiency in BTHS-affected individuals are well-established, downstream metabolic changes in cardiac metabolism are still uncovered. Our study aimed to characterize TAZ-induced metabolic perturbations in the heart. Control (PGP1-TAZWT) and TAZ mutant (PGP1-TAZ517delG) iPS-CM were incubated with 13C6-glucose and 13C5-glutamine and incorporation of 13C into downstream Krebs cycle intermediates was traced. Our data reveal that TAZ517delG induces accumulation of cellular long chain acylcarnitines and overexpression of fatty acid binding protein (FABP4). We also demonstrate that TAZ517delG induces metabolic alterations in pathways related to energy production as reflected by high glucose uptake, an increase in glycolytic lactate production and a decrease in palmitate uptake. Moreover, despite mitochondrial dysfunction, in the absence of glucose and fatty acids, TAZ517delG-iPS-CM can use glutamine as a carbon source to replenish the Krebs cycle.

| S-EPMC6950123 | biostudies-literature

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

Project description:To identify novel, cell-specific, pathological pathways that mediate heart dysfunction in Barth Syndrome, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild type and Tafazzin-knockout mouse hearts.

2023-06-20 | GSE235047 | GEO

Metabolic Aberrations in Barth Syndrome

Project description:1) Characterize plasma metabolome in Barth Syndrome 2) To implement targeted, quantitative studies on prospective biomarkers and metabolites of interest derived from the non-targeted phase.

2015-06-29 | ST000223 | MetabolomicsWorkbench

Porphyrin overdrive rewires cancer cell metabolism

Project description:Porphyrin overdrive rewires cancer cell metabolism

| PRJNA1099386 | ENA