专题文章：mTOR 复合物 2-akt 信号在与内质网相关的线粒体膜（MAM）处调节线粒体生理学。
Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.
机构信息
Growth and Development, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
出版信息
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12526-34. doi: 10.1073/pnas.1302455110. Epub 2013 Jul 12.
Abstract
The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.
摘要
雷帕霉素靶蛋白（TOR）是一种高度保守的蛋白激酶，也是生长的核心控制器。哺乳动物 TOR 复合物 2（mTORC2）调节 AGC 激酶家族成员，与包括癌症和糖尿病在内的各种疾病有关。在这里，我们报告 mTORC2 定位于内质网（ER）亚区，称为线粒体相关 ER 膜（MAM）。生长因子刺激 mTORC2 定位于 MAM，并且 MAM 上的 mTORC2 与 IP3 受体（IP3R）-Grp75-电压依赖性阴离子选择性通道 1 ER-线粒体连接复合物相互作用。mTORC2 缺陷破坏了 MAM，导致线粒体缺陷，包括线粒体膜电位增加、ATP 产生和钙摄取增加。mTORC2 通过 Akt 介导的 MAM 相关蛋白 IP3R、己糖激酶 2 和酸性簇磷蛋白分选蛋白 2 的磷酸化来控制 MAM 的完整性和线粒体功能。因此，mTORC2 是控制生长和代谢的 MAM 信号枢纽的核心。
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