Trophoblast syncytialisation necessitates mitochondrial function through estrogen-related receptor-γ activation

Human pregnancy needs a correct placentation which depends on adequate cytotrophoblast proliferation, differentiation and invasion. In this study, using specific mitochondrial respiratory chain inhibitors, we observed a decrease of hormone production (hCG and leptin) and cell fusion of human primary villous cytotrophoblasts (CT). These results demonstrated that mitochondria are involved in the control of CT differentiation process. Moreover, we also observed a decrease of mitochondrial mass associated with an increase of mitochondrial DNA during CT differentiation. Furthermore, lactate production increased during CT differentiation suggesting that anaerobic metabolism was enhanced in differentiated CTs, and that the role of mitochondria in CT fusion is not only related to its energetic function. Otherwise, the orphan nuclear receptor, estrogen-related receptor gamma (ERR gamma) is known to orchestrate transcriptional control of energy metabolism genes. In this study, using RNA knockdown and transcriptional activation with DY131 (an ERR gamma agonist), we clearly demonstrated that ERR gamma promotes hormone production and cell fusion indicating that ERR gamma is a key positive transcriptional factor involved in CT differentiation. Finally, we showed that ERR gamma promotes mitochondrial biogenesis and function during CT differentiation, and that the role of ERR gamma during trophoblast differentiation is mainly mediated by the control of mitochondrial functions.