Genetic suppression features ABHD18 as a Barth syndrome therapeutic target

• 成果类型: Article
• 署名作者: Masud, Sanna N.; Srivastava, Anchal; Mero, Patricia; Echezarreta, Victoria Saba; Anderson, Eve; van Buren, Lennard; Wei, Jiarun; Taylor, David Thomson; Farias, Adrian Granda; Mikolajewicz, Nicholas; Shaw, Angela; Murareanu, Brandon M.; Lohbihler, Michelle; Carney, Olivia Sniezek; van Heeringen, Simon; Clijsters, Linda; Sizova, Olga; van Ameijde, Jeroen; Nye, Freya; Habsid, Andrea; Nedyalkova, Lucy; Mcdonald, Laura; Simpson, Craig; Wybenga-Groot, Leanne; Brown, Kevin R.; Nho, Nhi; Suciu, Radu M.; Chan, Katherine; Tong, Amy H. Y.; Vaz, Frederic M.; Evers, Bastiaan; Lesurf, Robert; Papaz, Tanya; Nutter, Lauryl M. J.; Protze, Stephanie; Billmann, Maximilian; Costanzo, Michael; Andrews, Brenda J.; Myers, Chad L.; Mital, Seema; Vernon, Hilary; Brummelkamp, Thijn R.; Boone, Charles; Scott, Ian C.; Niphakis, Micah J.; Strathdee, Douglas; Nijman, Sebastian M. B.; Blomen, Vincent A.; Moffat, Jason
• 署名单位: University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Bonn; University of Toronto; University Health Network Toronto; Johns Hopkins University; Johns Hopkins Medicine; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Amsterdam; University of Amsterdam; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Labatt Family Heart Centre; University of Toronto; Hospital for Sick Children (SickKids); University of Minnesota System; University of Minnesota Twin Cities; Netherlands Cancer Institute; RIKEN
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09373-5
• 发表日期: 2025-09-25
• 关键词: cytochrome-c-oxidase; mass-spectrometry; cardiolipin; protein; complexes; disorder; cox7a2l; MODEL; tools

摘要

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.