The Chinese University of Hong Kong (CUHK), China (People's Republic)
Abstract: Mitochondrial transcription factor A (TFAM) is pivotal for mitochondrial DNA transcription and plays a critical role in regulating mitochondrial biogenesis. Embryonic stem cell-derived cardiomyocytes (ESC-CMs) are recognized as a promising cell source for drug screening and cell replacement therapy; however, their maturation presents significant scientific challenges. The processes of mitochondrial biogenesis and maturation are essential for cardiomyocyte function, yet the underlying mechanisms remain largely unexplored. This study aims to elucidate the influence of TFAM on the maturation of ESC-CMs and to investigate the mechanisms through which mitochondrial biogenesis regulates this maturation. Our preliminary findings showed that knockdown of TFAM decreased mitochondrial biogenesis in ESC-CMs, while overexpression of TFAM significantly enhanced it. Furthermore, knockdown of TFAM negatively regulates the maturation of ESC-CMs. TFAM knockdown was found to reduce upstroke and decay kinetics of calcium transients, and decrease the maximum depolarization rate of action potentials. In addition, TFAM knockdown also decreased the cell size and sarcomere length of ESC-CMs. Collectively, these results indicate that TFAM positively regulates mitochondrial biogenesis and contributes to the functional and morphological maturation of ESC-CMs. In summary, our research highlights the positive role of TFAM in the maturation of ESC-CMs, provides new insights into the development of ESC-CMs and facilitates the future application of ESC-CMs in disease modeling and drug screening.
