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

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

PROVIDER: PRJNA1155664 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30510510.fastq.gz	Fastqsanger.gz
	SRR30510511.fastq.gz	Fastqsanger.gz
	SRR30510512.fastq.gz	Fastqsanger.gz
	SRR30510513.fastq.gz	Fastqsanger.gz
	SRR30510514.fastq.gz	Fastqsanger.gz

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

Project description:ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome

| PRJNA1263869 | ENA

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

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 | GSE276191 | GEO

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

2025-05-29 | GSE297335 | GEO

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

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

| PRJNA1263536 | ENA

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

Loss of protein association causes cardiolipin degradation in Barth syndrome

Project description:Loss of protein association causes cardiolipin degradation in Barth syndrome

2016-03-22 | MSV000079600 | MassIVE

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-28 | GSE297454 | GEO

Loss of protein association causes cardiolipin degradation in Barth syndrome

Project description:Loss of protein association causes cardiolipin degradation in Barth syndrome Dataset1: effect of bromopyruvate EH_011316_Forward1.raw (treated: heavy label; control: medium label) EH_011316_Reverse1.raw (treated: medium label; control: heavy label) Dataset2: Barth versus control cell (Barth cells: heavy label; control cells: medium label) EH_020514_mix24H.raw (24 hr incubation, replicate 1) EH_020514_mix32H.raw (32 hr incubation, replicate 1) EH_020614_mix24H.raw (24 hr incubation, replicate 2) EH_020614_mix32H.raw (32 hr incubation, replicate 2) EH_020714_mix24H.raw (24 hr incubation, replicate 3) EH_020714_mix32H.raw (32 hr incubation, replicate 3)

2016-03-22 | MSV000079599 | 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