UC Berkeley

Barth Syndrome (BTHS) is a rare genetic disorder caused by mutations in the gene that encodes tafazzin, a protein whose sole function is to remodel the mitochondrial phospholipid cardiolipin (CL). Despite comprising a small proportion of the body’s total phospholipid pool, the critical role CL plays in the structure and function of the mitochondrial inner membrane means that defects in CL composition lead to profound mitochondrial impairment. These mitochondrial defects, in turn, lead to the failure of high energy-demand systems, resulting in neutropenia, skeletal muscle weakness, and cardiomyopathy. While some researchers have suggested gene therapy or protein replacement as potential future treatments, it is conceivable that, if CL could be delivered to the defective mitochondria, the need for a functional tafazzin could be bypassed entirely. In the current study, we use the amphipathic plasma protein apolipoprotein A-I to solubilize CL into discoidal nanoparticles resembling HDL. These CL nanodisks (CLND) were incubated with a cell culture model of the neutropenia seen in BTHS. CL-ND treatment increased cellular CL levels and ameliorated the BTHS phenotype. To extend these findings to whole animals, a 10 week study was carried out using a mouse model of BTHS. However, at the end of the study, while the BTHS mice developed significant differences in CL composition characteristic of the disease, CL-ND treatment had no effect on CL content or composition. Thus, while CL-ND may eventually prove to be a useful therapy for BTHS, the current study highlights the difficulty of translating cell culture results to intact animals.