Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome

Cardiolipin (CL) and phosphatidylglycerol (PG) are the major polyglyceropho spholipids observed in mammalian tissues. CL is exclusively found in the in ner mitochondrial membrane and is required for optimal function of many of the respiratory and ATP-synthesizing enzymes. The role of CL in oxidative p hosphorylation is, however, not fully understood and although reduced CL co ntent leads to aberrant cell function, no human disorders with a primary de fect in cardiolipin metabolism have been described. In this paper we presen t evidence that patients with the rare disorder X-linked cardioskeletal myo pathy and neutropenia (Barth syndrome, MIM 302060) have a primary defect in CL and PG remodeling. We investigated phospholipid metabolism in cultured skin fibroblasts of patients and show that the biosynthesis rate of PG and CL is normal but that the CL pool size is 75% reduced, indicating accelerat ed degradation. Moreover, the incorporation of linoleic acid, which is the characteristic acyl side chain found in mammalian CL, into both PG and CL i s significantly reduced, whereas the incorporation of other fatty acids int o these phospholipids is normal. We show that this defect was only observed in Barth syndrome patients' cells and not in cells obtained from patients with primary defects in the respiratory chain, demonstrating that the obser ved defect is not secondary to respiratory chain dysfunction. These results imply that the G4.5 gene product, which is mutated in Earth syndrome patie nts, is specifically involved in the remodeling of PG and CL and for the fi rst time identify an essential factor in this important cellular process. ( C) 2000 Academic Press.