mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology

被引:451
作者
Betz, Charles [1 ]
Stracka, Daniele [1 ]
Prescianotto-Baschong, Cristina [1 ]
Frieden, Maud [2 ]
Demaurex, Nicolas [2 ]
Hall, Michael N. [1 ]
机构
[1] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland
[2] Univ Geneva, Dept Cell Physiol & Metab, CH-1211 Geneva 4, Switzerland
基金
瑞士国家科学基金会;
关键词
RAT-LIVER; PROTEOMIC ANALYSIS; CA2+ RELEASE; AKT; PHOSPHORYLATION; RAPAMYCIN; KINASE; GLYCOLYSIS; CALNEXIN; FRACTION;
D O I
10.1073/pnas.1302455110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:12526 / 12534
页数:9
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