Studying Mitochondrial Dynamics and Energetics During Cardiac Reprogramming

Studying Mitochondrial Dynamics and Energetics During Cardiac Reprogramming Abstract: Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) shows promise for the treatment of cardiac injury, such as a myocardial infarction (MI). Barriers to clinical application include low reprogramming efficiency and relative immaturity of iCMs. A metabolic shift from glycolysis to mitochondrial respiration is required to transdifferentiate CFs to mature iCMs, but this aspect of cardiac reprogramming remains understudied. In preliminary experiments, mitochondria in native CMs showed higher fusion activity, more organizational complexity and higher trans-membrane potential than native CFs. By day 15 of standard cardiac reprogramming, only some of these changes are observable in reprogrammed cells. Knockdown of the mitochondrial fission regulator Mtfr1l led to improved reprogramming efficiency and iCM maturation. I therefore propose to characterize a time course of mitochondrial structural and functional changes during cardiac reprogramming. Additionally, I will investigate the molecular mechanisms of Mtfr1l as a barrier to cardiac reprogramming and evaluate other mitochondrial perturbations for impact on reprogramming efficiency and iCM maturation. This work will offer insights into the mitochondrial regulation of cardiac reprogramming and how mitochondria can be harnessed to improve reprogramming strategies. These insights will bring us closer to clinical translation of these strategies to benefit patients after MI.