Mitochondrial Dysfunction and Barth Syndrome

Barth syndrome (BTHS) is an X-linked inborn error of mitochondrial phospholipid metabolism, caused by pathogenic variants in the gene tafazzin (TAZ). TAZ encodes for a transacylase involved in the final remodeling step of cardiolipin (CL). The four acyl chains of CL allow for an array of CL species, however the determinants of the acyl chain composition of remodeled CL are still under debate. CL, localized to the inner mitochondrial membrane, has key roles in mitochondrial function including in cristae formation, organization of the mitochondrial respiratory chain, apoptosis, and mitophagy, among many others. As is typical of most primary mitochondrial diseases, BTHS is a multi-system disorder and is characterized by cardiomyopathy, skeletal myopathy, and neutropenia. Though the primary biochemical defect in BTHS has been known for several decades, there are no disease specific treatments, and the burden of morbidity and mortality in affected individuals is high. Treatment strategies under investigation include: lipid replacement, enzyme replacement, gene replacement, and drug therapy. This review summarizes Barth syndrome, with a focus on CL and its essential role in mitochondria.