PhD Student Pusan National University, Kyongsang-namdo, Republic of Korea
Abstract: Barth syndrome (BTHS) is a rare genetic disorder caused by a mutation in the Tafazzin (TAZ) gene on the X chromosome, affecting approximately 1 in 300-400,000 people worldwide. TAZ is an acyltransferase enzyme responsible for catalyzing the remodeling of cardiolipin, a phospholipid found in the inner mitochondrial membrane. Defects in cardiolipin biosynthesis and remodeling, caused by a mutant TAZ gene lead to excessive oxidative stress and mitochondrial dysfunction. In this study, I observed the morphogenesis of induced pluripotent stem cells (iPSCs) derived from somatic cells obtained from a patient with BTHS and differentiated them into BTHS cardiomyocytes (BTHS-CMs). BTHS-CMs have a significant reduction in mitochondrial elongation and cardiac structure formation for differentiation. When BTHS-CMs were treated with Compound A(CA) for 48 hours, mitochondrial fusion was significantly increased in 30-day BTHS-CMs. Furthermore, CA led to a significant increase in the expression of autophagy markers, such as Beclin-1, ATG5, SQSTM1/P62, and LAMP1. Additionally, CA treatment significantly upregulated the expression of PGC1a, a marker of mitochondrial biogenesis, and significantly increased the expression of markers associated with mitochondrial dynamics. In addition, long-term treatment for 1 week, myocardial-specific structure and mitochondrial morphology were restored. In conclusion, the results demonstrate that activation of mitophagy by CA can ameliorate mitochondrial dysfunction in BTHS-CMs. These results suggest that CA has a novel therapeutic potential for BTHS patients.
