PUBLICATION
Genetic suppression features ABHD18 as a Barth syndrome therapeutic target
- Authors
- Masud, S.N., Srivastava, A., Mero, P., Echezarreta, V.S., Anderson, E., van Buren, L., Wei, J., Taylor, D.T., Farias, A.G., Mikolajewicz, N., Shaw, A., Murareanu, B.M., Lohbihler, M., Carney, O.S., van Heeringen, S., Clijsters, L., Sizova, O., van Ameijde, J., Nye, F., Habsid, A., Nedyalkova, L., McDonald, L., Simpson, C., Wybenga-Groot, L., Brown, K.R., Nho, N., Suciu, R.M., Chan, K., Tong, A.H.Y., Vaz, F.M., Evers, B., Lesurf, R., Papaz, T., Nutter, L.M.J., Protze, S., Billmann, M., Costanzo, M., Andrews, B.J., Myers, C.L., Mital, S., Vernon, H., Brummelkamp, T.R., Boone, C., Scott, I.C., Niphakis, M.J., Strathdee, D., Nijman, S.M.B., Blomen, V.A., Moffat, J.
- ID
- ZDB-PUB-250925-2
- Date
- 2025
- Source
- Nature 645: 102910381029-1038 (Journal)
- Registered Authors
- McDonald, Laura, Scott, Ian
- Keywords
- none
- MeSH Terms
-
- Monoacylglycerol Lipases*/antagonists & inhibitors
- Monoacylglycerol Lipases*/genetics
- Monoacylglycerol Lipases*/metabolism
- Mutation
- Cardiolipins*/biosynthesis
- Cardiolipins*/metabolism
- Animals
- Phenotype
- Barth Syndrome*/drug therapy
- Barth Syndrome*/enzymology
- Barth Syndrome*/genetics
- Barth Syndrome*/metabolism
- Barth Syndrome*/pathology
- Female
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Transcription Factors/deficiency
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Mitochondria/drug effects
- Mitochondria/metabolism
- Mitochondria/pathology
- Molecular Targeted Therapy*
- Humans
- Disease Models, Animal
- Lysophospholipids/biosynthesis
- Lysophospholipids/metabolism
- Mice
- Male
- Acyltransferases
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 40903572 Full text @ Nature
Citation
Masud, S.N., Srivastava, A., Mero, P., Echezarreta, V.S., Anderson, E., van Buren, L., Wei, J., Taylor, D.T., Farias, A.G., Mikolajewicz, N., Shaw, A., Murareanu, B.M., Lohbihler, M., Carney, O.S., van Heeringen, S., Clijsters, L., Sizova, O., van Ameijde, J., Nye, F., Habsid, A., Nedyalkova, L., McDonald, L., Simpson, C., Wybenga-Groot, L., Brown, K.R., Nho, N., Suciu, R.M., Chan, K., Tong, A.H.Y., Vaz, F.M., Evers, B., Lesurf, R., Papaz, T., Nutter, L.M.J., Protze, S., Billmann, M., Costanzo, M., Andrews, B.J., Myers, C.L., Mital, S., Vernon, H., Brummelkamp, T.R., Boone, C., Scott, I.C., Niphakis, M.J., Strathdee, D., Nijman, S.M.B., Blomen, V.A., Moffat, J. (2025) Genetic suppression features ABHD18 as a Barth syndrome therapeutic target. Nature. 645:102910381029-1038.
Abstract
Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes electron transport chain protein complexes1. The final step in CL biosynthesis relates to its remodelling: the exchange of nascent acyl chains with longer, unsaturated chains1. However, the enzyme responsible for cleaving nascent CL (nCL) has remained elusive. Here, we describe ABHD18 as a candidate deacylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro, and its inactivation in cells and mice results in a shift to nCL in serum and tissues. Notably, 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 resulting from inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL-remodelling cascade1. We also identified a selective, covalent, small-molecule inhibitor of ABHD18 that rescues TAZ mutant phenotypes in fibroblasts from human patients and in fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping