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.