Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis

Barth syndrome (BTHS) is an X-linked recessive disorder that is biochemically characterized by low cellular lev- els of the mitochondrial phospholipid cardiolipin (CL). Pre- viously, we discovered that the yeast disruptant of the TAZ ortholog in Saccharomyces cerevisiae not only displays CL de- ficiency but also accumulates monolysocardiolipins (MLCLs), which are intermediates in CL remodeling. Therefore, we set out to investigate whether MLCL accumulation also occurs in BTHS. Indeed, we observed MLCL accumulation in heart, muscle, lymphocytes, and cultured lymphoblasts of BTHS patients; however, only very low levels of these lysophos- pholipids were found in platelets and fibroblasts of these patients. Although the fatty acid composition of the MLCLs was different depending on the tissue source, it did parallel the fatty acid composition of the (remaining) CLs. The pos- sible implications of these findings for the two reported CL remodeling mechanisms, transacylation and deacylation/ reacylation, are discussed. Because MLCLs have been pro- posed to be involved in the initiation of apoptosome-medi- ated cell death by the sequestration of the proapoptotic protein (t)BH3-interacting domain death agonist (Bid) to the mitochondrial membrane, we used control and BTHS lymphoblasts to investigate whether the accumulation of MLCLs results in higher levels of apoptosis. We found no differences in susceptibility to death receptor-mediated apop- tosis or in cellular distribution of Bid, cytochrome c , and other parameters, implying that MLCL accumulation does not lead to enhanced apoptosis in cultured BTHS lymphoblasts. — Valianpour, F., V. Mitsakos, D. Schlemmer, J. A. Towbin, J. M. Taylor, P. G. Ekert, D. R. Thorburn, A. Munnich, R. J. A. Wanders, P. G. Barth, and F. M. Vaz. Monolysocardiolipins accumulate in Barth syndrome but do not lead to enhanced apoptosis. J. Lipid Res. 2005. 46: 1182-1195.