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

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 endoplasmi...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2013-07, Vol.110 (31), p.12526-12534
Main Authors: Betz, Charles, Stracka, Daniele, Prescianotto-Baschong, Cristina, Frieden, Maud, Demaurex, Nicolas, Hall, Michael N.
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Apoptosis
Biological Sciences
Calcium
Cancer
Diabetes
Endoplasmic reticulum
HeLa cells
Insulin
Kinases
Liver
Membranes
Mitochondria
Phosphorylation
Physiological regulation
Ribosomes
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Summary: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 IP ₃ 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1302455110