Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies

nature medicine advance online publication BTHS is an X-linked cardiac and skeletal mitochondrial myopathy caused by mutation of the gene encoding tafazzin1, an acyltransferase responsible for normal acylation of cardiolipin, the major phospholipid of the mitochondrial inner membrane2 (Supplementary Fig. 1; data tables for supplementary data are available as Supplementary Data Sets). Cardiolipin abnormalities also occur in ischemic heart disease and aging and have been implicated in the cardiac dysfunction characteristic of these conditions3. The mechanisms that lead from abnormal cardiolipin biogenesis to cardiomyopathy are not well understood. Here, we combined patient-derived iPSCs, genome editing, modified RNA (modRNA)4 and bioengineered microchips that simulate myocardial tissue (‘heart-on-chip’)5 to replicate the pathophysiology of BTHS cardiomyopathy in tissue constructs. Using these approaches, we identified mitochondrial functional abnormalities caused by TAZ mutation and cardiolipin deficiency. We show that TAZ mutation is necessary and sufficient to disrupt sarcomere assembly and contractile stress generation and that these functional abnormalities are not due to global ATP depletion. Furthermore, we show that the BTHS cardiomyopathic phenotype is readily reversed by re-introduction of wild-type (WT) TAZ or by suppression of excessive reactive oxygen species (ROS) produced by BTHS mitochondria. These results provide new insights into the links between mitochondrial function, sarcomere assembly and muscle contractile activity and suggest new therapeutic strategies for BTHS.