Distinct mitochondrial remodeling during early cardiomyocyte development in a human-based stem cell model

Abstract

Post-mitotic tissues with high-energy demand rely on ATP generated by the mitochondrial respiratory chain through the process of oxidative phosphorylation (OXPHOS). There is common agreement that mitochondrial content and OXPHOS activity increase as cells exit from pluripotency state to meet the higher energy requirement of differentiated tissues such as heart. In this study, we examined the hypothesis that mitochondrial expansion during differentiation is necessary to compensate for higher energy demand in differentiated cells. We assessed mitochondrial and cellular metabolism during differentiation of human pluripotent stem cells to cardiac progenitors and further to functional cardiomyocytes. Contrary to expectations, we found that mitochondrial content decreased progressively during mesoderm differentiation. Nevertheless, we found that there was increased mitochondrial activity and higher levels of ATP-linked respiration, which we suggest more than compensate for the lower mitochondrial number. Our findings support a model whereby mitochondrial maturation during cardiomyocyte differentiation depends on increased efficiency of ATP generation through OXPHOS not increased mitochondrial biogenesis. Thus, the timing of the mitochondria expansion during cardiomyocyte differentiation will have to be revisited in light of these findings.