PT - JOURNAL ARTICLE AU - Barbara Pernaute AU - Juan Miguel Sánchez Nieto AU - Salvador Pérez-Montero AU - Aida di Gregorio AU - Ana Lima AU - Katerina Lawlor AU - Sarah Bowling AU - Gianmaria Liccardi AU - Alejandra Tomás AU - Pascal Meier AU - Guy A. Rutter AU - Ivana Barbaric AU - Tristan A. Rodríguez TI - DRP1-mediated regulation of mitochondrial dynamics determines the apoptotic response upon embryonic differentiation AID - 10.1101/835751 DP - 2019 Jan 01 TA - bioRxiv PG - 835751 4099 - http://biorxiv.org/content/early/2019/11/08/835751.short 4100 - http://biorxiv.org/content/early/2019/11/08/835751.full AB - The changes that drive differentiation create a large potential for the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. This removal is in part achieved by cells becoming hypersensitive to death upon exit of naïve pluripotency. What causes this change in apoptotic response is unknown. Here we identify that it is controlled by the regulator of mitochondrial dynamics DRP1. We show that in mouse, naïve pluripotent cells have fragmented mitochondria due to high DRP1-mediated fission, but upon differentiation, DRP1 activity decreases, inducing mitochondria to fuse and form complex networks. We demonstrate that this decrease in DRP1 activity lowers the apoptotic threshold, as mutation of DRP1 increases the sensitivity to cell death and its over-expression protects against apoptosis. Together, our findings highlight how regulation of mitochondrial dynamics allows cells to adapt their apoptotic response to the changing environment of differentiation.