The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.

将环境和细胞内刺激与线粒体功能联系起来的机制，包括裂变/融合、ATP 产生、代谢物生物发生和细胞凋亡，尚不清楚。在这里，我们证明了雷帕霉素复合物 1 (mTORC1) 的营养感应机制/哺乳动物靶标刺激线粒体裂变过程 1 (MTFP1) 的翻译以控制线粒体裂变和细胞凋亡。MTFP1 的表达与裂变 GTP 酶发动蛋白相关蛋白 1 (DRP1) 的裂变前磷酸化和线粒体募集相结合。由于 MTFP1 的翻译减少，有效的活性位点 mTOR 抑制剂会引起线粒体过度融合，而 MTFP1 是由翻译起始因子 4E (eIF4E) 结合蛋白 (4E-BPs) 介导的。在 mTOR 抑制后，将 MTFP1 水平与 mTORC1/4E-BP 通路解偶联可阻断过度融合反应，并通过将 mTOR 抑制剂作用从细胞抑制作用转变为细胞毒性作用而导致细胞凋亡。这些数据为通过使用 MTFP1 作为 mTORC1 的关键效应子来控制细胞命运决定的线粒体超融合抑制 mTOR 后的细胞存活提供了直接证据。