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ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome [CRISPR]

ABSTRACT: Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes the electron transport chain protein complexes. The final step in CL biosynthesis concerns its remodeling: the exchange of nascent acyl chains with longer, unsaturated chains. However, the enzyme responsible for cleaving nascent CL has remained elusive. Here, we describe ABDH18 as the candidate de-acylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro and its inactivation in cells and mice results in accumulation of nascent CL in serum and tissues. Strikingly, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth Syndrome. This rare genetic disease is characterized by the build-up of MLCL due to inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL remodeling cascade. We also identified a selective, covalent small molecule inhibitor of ABHD18 that restores TAZ mutant phenotypes in patient fibroblasts and fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276191 | GEO | 2025/05/29

REPOSITORIES: GEO

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ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome [RNA-Seq]

Project description:Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes the electron transport chain protein complexes. The final step in CL biosynthesis concerns its remodeling: the exchange of nascent acyl chains with longer, unsaturated chains. However, the enzyme responsible for cleaving nascent CL has remained elusive. Here, we describe ABDH18 as the candidate de-acylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro and its inactivation in cells and mice results in accumulation of nascent CL in serum and tissues. Strikingly, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth Syndrome. This rare genetic disease is characterized by the build-up of MLCL due to inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL remodeling cascade. We also identified a selective, covalent small molecule inhibitor of ABHD18 that restores TAZ mutant phenotypes in patient fibroblasts and fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.

2025-05-29 | GSE297335 | 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.

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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

Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by Cardiolipin-interacting small molecules

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

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Analysis of neutrophil proteome of Barth syndrome patients

Project description:Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy, and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet the molecular and physiological causes of this phenomenon are poorly understood. We conducted proteome analysis of circulating neutrophils from BTHS patients to identify upregulated and downregulated canonical pathways that may explain the disruptions in neutrophil maturation and function.

2025-02-12 | PXD052714 | Pride

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.

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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.

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Metabolic Aberrations in Barth Syndrome

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