Cardiolipin metabolism and its causal role in the etiology of the inherited cardiomyopathy Barth syndrome.

Cardiolipin (CL) is a phospholipid with many unique characteristics. CL is synthesized in the mitochondria and resides almost exclusively within the mitochondrial inner membrane. Unlike most phospholipids that have two fatty acyl chains, CL possesses four fatty acyl chains resulting in unique biophysical characteristics that impact several biological processes including membrane fission and fusion. In addition, several proteins directly bind CL including proteins within the electron transport chain, the ADP/ATP carrier, and proteins that mediate mitophagy. Tafazzin is an enzyme that remodels saturated fatty acyl chains within CL to unsaturated fatty acyl chains, loss of function mutations in the TAZ gene encoding tafazzin are causal for the inherited cardiomyopathy Barth syndrome. Cells from Barth syndrome patients as well as several models of Barth have reduced mitochondrial functions including impaired electron transport chain function and increased reactive oxygen species (ROS) production. Mitochondria in cells from Barth syndrome patients, as well as several model organism mimics of Barth syndrome, are large and lack cristae consistent with the recently described role of CL participating in the generation of mitochondrial membrane contact sites. Cells with an inactive TAZ gene have also been shown to have a decreased capacity to undergo mitophagy when faced with stresses such as increased ROS or decreased mitochondrial quality control. This review describes CL metabolism and how defects in CL metabolism cause Barth syndrome, the etiology of Barth syndrome, and known modifiers of Barth syndrome phenotypes some of which could be explored for their amelioration of Barth syndrome in higher organisms.