title: Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology.
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.
authors.affiliation: Growth and Development, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Charles
authors.initials: C
authors.lastname: Betz
authors.forename: Daniele
authors.initials: D
authors.lastname: Stracka
authors.forename: Cristina
authors.initials: C
authors.lastname: Prescianotto-Baschong
authors.forename: Maud
authors.initials: M
authors.lastname: Frieden
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demaurex
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C018551:glucose-regulated proteins; D006593:Hexokinase; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases