Ph.D. Pusan National University Yangsan, Kyongsang-namdo, Republic of Korea
Abstract: Barth syndrome (BTHS) is an ultra-rare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. In this study, we explored the possibility of using stem cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem cells (iPSC) from normal and BTHS patients and differentiated them into cardiomyocytes. The BTHS patient-derived iPSC-differentiated cardiomyocytes (BTHS CMs) exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT, and cTnI, and smaller cell size than normal iPSC-derived cardiomyocytes (normal CMs). Multi-electrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired, and mitophagy was decreased in BTHS CMs compared to normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction, and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.
Funding Source: National Research Foundation of Korea (NRF-RS-2023-00208466), the Research Institute for Convergence of Biomedical Science and Technology (30-2021-000), Pusan National University Yangsan Hospital, and KHIDI (HI19C1085).
