Loss of protein association causes cardiolipin degradation in Barth syndrome
Ontology highlight
ABSTRACT:
INSTRUMENT(S): qexactive
ORGANISM(S): Human
SUBMITTER: Michael Schlame; Thomas Neubert
PROVIDER: MSV000079600 | MassIVE | Tue Mar 22 12:46:00 GMT 2016
REPOSITORIES: MassIVE
Similar Datasets
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
Project description:Cardiolipin is a specific mitochondrial phospholipid that has a high affinity for proteins and that stabilizes the assembly of supercomplexes involved in oxidative phosphorylation. We found that sequestration of cardiolipin in protein complexes is critical to protect it from degradation. The turnover of cardiolipin is slower by almost an order of magnitude than the turnover of other phospholipids. However, in subjects with Barth syndrome, cardiolipin is rapidly degraded via the intermediate monolyso-cardiolipin. Treatments that induce supercomplex assembly decrease the turnover of cardiolipin and the concentration of monolyso-cardiolipin, whereas dissociation of supercomplexes has the opposite effect. Our data suggest that cardiolipin is uniquely protected from normal lipid turnover by its association with proteins, but this association is compromised in subjects with Barth syndrome, leading cardiolipin to become unstable, which in turn causes the accumulation of monolyso-cardiolipin.
| S-EPMC4955704 | biostudies-literature
Project description:The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in resulted in different mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.
2020-07-08 | GSE148178 | GEO
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: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
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
Project description:Autosomal recessive SBNO2 deficiency causes an immunodysregulatory syndrome
| PRJNA781339 | ENA
Project description:ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome
| PRJNA1263869 | ENA
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