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

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.