The study by Wang et al combined patient-derived and genetically engineered induced pluripotent stem cells (iPSCs) and tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome, a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using Barth syndrome iPSC-derived cardiomyocytes (iPSC-CMs), they defined metabolic, structural and functional abnormalities associated with TAZ mutation. Barth syndrome iPSC-CMs assembled sparse and irregular sarcomeres, and engineered Barth syndrome ‘heart-on-chip’ tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation was necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. This study may serve as a model for elucidating pathophysiology and to investigate novel therapies for other diseases.
Posted by Nicola Brunetti-Pierri, MD, FACMG