Genetic suppression features ABHD18 as a Barth syndrome therapeutic target

Sanna N. Masud, Anchal Srivastava, Patricia Mero, Victoria Saba Echezarreta, Eve Anderson, Lennard Buren, Jiarun Wei, David Thomson Taylor, Adrian Granda Farias, Nicholas Mikolajewicz, Angela Shaw, Brandon M. Murareanu, Michelle Lohbihler, Olivia Sniezek Carney, Simon Heeringen, Linda Clijsters, Olga Sizova, Jeroen Ameijde, Freya Nye, Andrea Habsid, Lucy Nedyalkova, Laura McDonald, Craig Simpson, Leanne Wybenga-Groot, Kevin R. Brown, Nhi Nho, Radu M. Suciu, Katherine Chan, Amy H. Y. Tong, Frédéric M. Vaz, Bastiaan Evers, Robert Lesurf, Tanya Papaz, Lauryl M. J. Nutter, Stephanie Protze, Maximilian Billmann, Michael Costanzo, Brenda J. Andrews, Chad L. Myers, Seema Mital, Hilary Vernon, Thijn R. Brummelkamp, Charles Boone, Ian C. Scott, Micah J. Niphakis, Douglas Strathdee, Sebastian M. B. Nijman (), Vincent A. Blomen () and Jason Moffat ()
Additional contact information
Sanna N. Masud: The Hospital for Sick Children
Anchal Srivastava: Scenic Biotech
Patricia Mero: The Hospital for Sick Children
Victoria Saba Echezarreta: University of Toronto
Eve Anderson: CRUK Scotland Institute
Lennard Buren: Scenic Biotech
Jiarun Wei: The Hospital for Sick Children
David Thomson Taylor: The Hospital for Sick Children
Adrian Granda Farias: The Hospital for Sick Children
Nicholas Mikolajewicz: The Hospital for Sick Children
Angela Shaw: University of Bonn
Brandon M. Murareanu: University of Toronto
Michelle Lohbihler: University of Toronto
Olivia Sniezek Carney: Johns Hopkins School of Medicine
Simon Heeringen: Scenic Biotech
Linda Clijsters: Scenic Biotech
Olga Sizova: The Hospital for Sick Children
Jeroen Ameijde: Scenic Biotech
Freya Nye: CRUK Scotland Institute
Andrea Habsid: The Hospital for Sick Children
Lucy Nedyalkova: University of Toronto
Laura McDonald: The Hospital for Sick Children
Craig Simpson: The Hospital for Sick Children
Leanne Wybenga-Groot: The Hospital for Sick Children
Kevin R. Brown: The Hospital for Sick Children
Nhi Nho: Lundbeck La Jolla Research Center
Radu M. Suciu: Lundbeck La Jolla Research Center
Katherine Chan: The Hospital for Sick Children
Amy H. Y. Tong: Hong Kong Genome Institute
Frédéric M. Vaz: Amsterdam UMC
Bastiaan Evers: Scenic Biotech
Robert Lesurf: The Hospital for Sick Children
Tanya Papaz: University of Toronto
Lauryl M. J. Nutter: The Hospital for Sick Children
Stephanie Protze: University of Toronto
Maximilian Billmann: University of Bonn
Michael Costanzo: University of Toronto
Brenda J. Andrews: University of Toronto
Chad L. Myers: University of Minnesota
Seema Mital: The Hospital for Sick Children
Hilary Vernon: Johns Hopkins School of Medicine
Thijn R. Brummelkamp: Scenic Biotech
Charles Boone: University of Toronto
Ian C. Scott: University of Toronto
Micah J. Niphakis: Lundbeck La Jolla Research Center
Douglas Strathdee: CRUK Scotland Institute
Sebastian M. B. Nijman: Scenic Biotech
Vincent A. Blomen: Scenic Biotech
Jason Moffat: The Hospital for Sick Children

Nature, 2025, vol. 645, issue 8082, 1029-1038

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09373-5

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