DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.
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DRP1水平通过线粒体自噬依赖机制决定胚胎分化过程中的凋亡阈值。
DOI：
10.1016/j.devcel.2022.04.020
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发表时间：
2022-06-06
影响因子：
11.8
通讯作者：
Rodriguez, Tristan A.
中科院分区：
文献类型：
--
作者：
Pernaute, Barbara;Perez-Montero, Salvador;Nieto, Juan Miguel Sanchez;Di Gregorio, Aida;Lima, Ana;Lawlor, Katerina;Bowling, Sarah;Liccardi, Gianmaria;Tomas, Alejandra;Meier, Pascal;Sesaki, Hiromi;Rutter, Guy A.;Barbaric, Ivana;Rodriguez, Tristan A.
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有助于进一步发育或生殖系之前被去除。因此，在小鼠中，在原肠胚形成之前，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，但对其如何调节知之甚少。在这里，我们表明，在幼稚多能性退出后，小鼠胚胎干细胞降低了它们的线粒体凋亡阈值，这增加了它们对细胞死亡的敏感性。我们证明，这种增强的凋亡反应是由于动力蛋白相关蛋白1（DRP1）的活性降低而引起的线粒体分裂减少。此外，我们发现，在幼稚多能细胞中，DRP1通过促进线粒体自噬来防止细胞凋亡。相反，在分化过程中减少线粒体自噬水平促进细胞凋亡。总之，这些结果表明，在早期哺乳动物发育期间，DRP1的线粒体自噬调控决定了凋亡反应。Pernaute等人表明，在小鼠胚胎发育的早期阶段，修复线粒体的机制的活性降低，线粒体是细胞的动力。这有助于消除异常细胞，并防止它们对新生生物体产生影响。
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 mouse in the lead-up to gastrulation, ~35% of embryonic cells are eliminated. This elimination is caused by a hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here we show that upon exit of naïve 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 facilitates apoptosis. Together, these results indicate that during early mammalian development DRP1 regulation of mitophagy determines the apoptotic response. 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 new-born organism.
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