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.

驱动分化的变化促进了异常细胞的出现，这些异常细胞需要在它们促进进一步发育或生殖系之前被去除。因此，在原肠胚形成之前的小鼠中，约 35% 的胚胎细胞被消除。这种消除是由对细胞凋亡的超敏反应引起的，但人们对它的调节方式知之甚少。在这里，我们发现，在退出幼稚多能性后，小鼠胚胎干细胞降低了线粒体凋亡阈值，这增加了它们对细胞死亡的敏感性。我们证明这种增强的细胞凋亡反应是由于动力相关蛋白 1 (DRP1) 活性降低而导致线粒体分裂减少所致。此外，我们发现在初始多能细胞中，DRP1 通过促进线粒体自噬来防止细胞凋亡。相反，在分化过程中，线粒体自噬水平降低促进细胞凋亡。总之，这些结果表明，在早期哺乳动物发育过程中，DRP1 对线粒体自噬的调节决定了细胞凋亡反应。