mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology
Open accessAbstract
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.
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Data suggest that mTORC2 stimulates mitochondrial biogenesis in liver and myeloid dendritic cells, although equivocal data exist in macrophages from Rictor-knockout mice.
“Interestingly, data suggest that mTORC2 stimulates mitochondrial biogenesis in liver (Betz et al., 2013) and myeloid dendritic cells (Watson et al., 2019), although equivocal data exist in macrophages from Rictor-knockout mice (Oh et al., 2017).”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as Betz et al., 2013
The Results passage on MAM integrity reports reduced ER–mitochondrial contacts in rictor-knockout livers, while the total amount of mitochondria per cell was unchanged. The Discussion describes effects on mitochondrial physiology, but neither passage addresses mitochondrial biogenesis in liver. The dendritic-cell and macrophage clauses are attributed to other citations. (LLM, conf=0.72)
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Mesquita, P. H. C., Vann, C. G., Phillips, S. M., McKendry, J., Young, K. C., Kavazis, A. N., & Roberts, M. D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725866 · Cited by 62 · see citing works
Mammalian target of rapamycin complex 2 regulates muscle glucose uptake during exercise in mice
Kleinert, M., Parker, B. L., Fritzen, A. M., Knudsen, J. R., Jensen, T. E., Kjøbsted, R., Sylow, L., Ruegg, M., James, D. E., & Richter, E. A. (2017) · The Journal of Physiology · doi:10.1113/jp274203 · Cited by 59 · see citing works
- Authors
- Betz, C., Stracka, D., Prescianotto-Baschong, C., Frieden, M., Demaurex, N., & Hall, M. N.
- Affiliations
- University of Basel (CH)
- Growth and Development, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and
- University of Geneva (CH)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-07-12
- Volume
- 110
- Issue
- 31
- Pages
- 12526-12534
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3732980
- OpenAlex
- W2142583550
- Cited by
- 538
- References
- 75
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 38 · 2023: 36 · 2022: 43 · 2021: 51 · 2020: 57 · 2019: 51 · 2018: 34 · 2017: 64 · 2016: 36 · 2015: 38 · 2014: 26 · 2013: 7
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- SystemsX.ch
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mTORC2, Akt signaling, mitochondria-associated endoplasmic reticulum membranes, IP3 receptor, GRP75, VDAC1, ER-mitochondria tethering, mitochondrial membrane potential, mitochondrial calcium uptake, ATP production, hexokinase 2, AGC kinases, growth factor signaling
- MeSH terms
- Mechanistic Target of Rapamycin Complex 2, Animals, Endoplasmic Reticulum, HeLa Cells, Hexokinase, Humans, Intracellular Membranes, Membrane Proteins, Mitochondria, Signal Transduction, Mice, Knockout, HSP70 Heat-Shock Proteins, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Mice, Membrane Potential, Mitochondrial, Inositol 1,4,5-Trisphosphate Receptors, TOR Serine-Threonine Kinases
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