Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada; Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Mol Cell. 2017 Sep 21;67(6):922-935.e5. doi: 10.1016/j.molcel.2017.08.013. Epub 2017 Sep 14.
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.
目前，我们对于将环境和细胞内刺激与线粒体功能（包括分裂/融合、ATP 产生、代谢物生物发生和细胞凋亡）联系起来的机制还了解甚少。在这里，我们证明营养感应机制/雷帕霉素靶蛋白复合物 1（mTORC1）可刺激线粒体分裂过程 1（MTFP1）的翻译，从而控制线粒体分裂和细胞凋亡。MTFP1 的表达与促分裂磷酸化以及线粒体分裂 GTP 酶 dynamin 相关蛋白 1（DRP1）的募集相关。由于 mTORC1 抑制了 MTFP1 的翻译，导致线粒体过度融合，这是由翻译起始因子 4E（eIF4E）结合蛋白（4E-BP）介导的。mTOR 抑制后，将 MTFP1 的水平与 mTORC1/4E-BP 途径解偶联，可阻断过度融合反应，并通过将 mTOR 抑制剂的作用从细胞增殖抑制转变为细胞毒性，从而导致细胞凋亡。这些数据提供了直接证据，表明通过线粒体过度融合，利用 MTFP1 作为 mTORC1 的关键效应物来控制细胞命运决定，从而实现 mTOR 抑制后的细胞存活。
