Cardiac Mitochondrial Phenotype of the taz shRNA Mouse Model of Human Barth Syndrome

Abstract

Barth syndrome (BTHS) is an X‐linked cardioskeletal myopathy that results from a mutation in the Tafazzin (taz) gene. Tafazzin is a phospholipid transacylase required for the optimal synthesis of cardiolipin (CL), a mitochondrial phospholipid that provides functional support to several mitochondrial proteins. In this study, the cardiac mitochondrial phenotype of a new mouse model of BTHS (taz shRNA; TAZ) was characterized. Cardiac mitochondria were isolated from male TAZ and wild type (WT) mice at 3–4 months of age for assessment of respiratory parameters, H2O2 production and Ca2+ tolerance. Mitochondria from TAZ mice had 50–60% lower rates of state 3 and state 4 respiration, with little change in respiratory efficiency vs. WT. Response to increasing levels of ADP was also severely blunted in TAZ, indicating impaired respiratory control. Absolute levels of H2O2 production were similar in TAZ and WT but were higher in TAZ when normalized for electron flow rate. Ca2+‐induced swelling was impaired in TAZ, as was sensitivity to cyclosporin A, indicating resistance to mitochondrial permeability transition. These findings demonstrate that taz deficiency impairs several aspects of mitochondrial function and provide the basis for further inquiry into the precise roles of taz and cardiolipin metabolism in mitochondrial (patho)physiology. Funding: AHA and Barth Syndrome Foundation