Direct control of mitochondrial function by mTOR
Direct control of mitochondrial function by mTOR
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DOI：
10.1073/pnas.0912074106
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发表时间：
2009-12-29
影响因子：
11.1
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
--
作者：
Ramanathan, Arvind;Schreiber, Stuart L.
mTOR是细胞生长和代谢的中心调节因子。使用代谢谱和许多小分子探针，我们研究了mTOR是否通过翻译后机制影响对细胞代谢的直接控制。抑制白血病细胞中的FKBP 12/雷帕霉素敏感的mTOR功能子集增强有氧糖酵解，并在25分钟内减少非偶联线粒体呼吸。mTOR与线粒体外膜蛋白Bcl-xl和VDAC 1形成复合物。Bcl-xl，而不是VDAC 1，是体外mTOR的激酶底物，并且mTOR调节Bcl-xl与mTOR的缔合。抑制mTOR不仅增强有氧糖酵解，而且诱导白血病细胞中对有氧糖酵解的依赖性增加的状态，如糖酵解抑制剂2-脱氧葡萄糖和雷帕霉素在降低细胞活力中的协同作用所示。
mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability.