DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism

The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response. [Display omitted] •Upon differentiation, embryonic stem cells become hypersensitive to apoptosis•DRP1 promotes mitophagy in pluripotent stem cells•During the onset of differentiation, DRP1 levels and mitophagy activity decrease•Decreased mitophagy during the onset of differentiation primes cells for apoptosis Pernaute et al. show that during the early stages of mouse embryo development, there is a decrease in the activity of the mechanisms that repair the mitochondria, which is the powerhouse of the cell. This helps eliminate abnormal cells and prevents them from contributing to the newborn organism.