Energy & cellular stress
Falling ATP, glucose withdrawal and a range of other insults. They converge on mTORC1 chiefly through two routes: AMPK, which acts on both TSC2 and raptor, and physical relocation of the TSC complex to the lysosome.
Running out of fuel. A catch-all for problems like falling energy (ATP) levels or glucose shortage. These reach mTORC1 chiefly through two routes: the AMPK brake, and physically moving the TSC complex to the lysosome.
AMP and ADP binding to the AMPK γ-subunit plus LKB1-dependent T172 phosphorylation; also covers glucose withdrawal sensed via aldolase/lysosomal AXIN–LKB1.
TL;DR. Energy & cellular stress appears in 7 curated studies in Oliver's mTOR Atlas: 7 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Energy & cellular stress activates AMPK mechanism: allosteric-activation · this link in full · on the map table | When the cell's fuel runs low, AMPK switches on – it's the cell's low-battery alarm, and one of the first things it does is shut mTORC1 off. Holds under: XIA2011 (crystal structure and biochemistry of mammalian AMPK) demonstrates that AMP binding to the gamma regulatory domain promotes phosphorylation and protects against dephosphorylation, and that ADP binds too. GWI2008 and ZHO2001 show downstream consequences. DEM2026 (IDH3 and citrate in AML stem cells) does not test AMP/ADP binding; its place on this edge needs the curator's decision. Drawn as a fuel-gauge for readability. The proximal trigger is the AMP(ADP)/ATP ratio binding the AMPK gamma subunit, not 'ATP running down' as a single variable - AMP and ADP both compete with ATP for the same regulatory sites. plausible in people, not shown directly · settled in the literature | M | GWI2008, ZHO2001, DEM2026, XIA2011 |
| Energy & cellular stress recruits TSC1/TSC2 mechanism: translocation · this link in full · on the map table | Different kinds of stress all do the same physical thing: they drag TSC2 over to the lysosome, right next to Rheb. Moving it there is the switch, not making more of it. Holds under: Mammalian cell studies (DEM2016, MEN2014). Relocation of TSC2 to the lysosome is shown in cultured cells under several stresses; not tested in tissue or in people. plausible in people, not shown directly · emerging, few independent studies | M | DEM2016, MEN2014 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 7 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2016 | M | Lysosomal recruitment of TSC2 is a universal response to cellular stress DEM2016 Lysosomal recruitment of TSC2 is a universal response to cellular stress that inhibits mTORC1. |
| 2014 | M | Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome MEN2014 Spatial control of the TSC complex integrates insulin and nutrient inputs at the lysosome. |
| 2008 | M | AMPK phosphorylation of raptor mediates a metabolic checkpoint GWI2008 Found a SECOND way the energy sensor AMPK shuts mTORC1 down. Besides acting through TSC2, AMPK directly phosphorylates Raptor - the core mTORC1 subunit - to halt growth when energy runs low. This 'metabolic checkpoint' is exactly the switch that drugs like metformin and exercise tap into. |
| 2005 | M | AMP-activated protein kinase induces a p53-dependent metabolic checkpoint JON2005 Described a glucose checkpoint at the G1/S boundary run by AMPK. Cells arrested when glucose ran short even though amino acids were present and mTOR stayed active, so this arrest works in parallel to mTOR rather than through it. AMPK phosphorylated p53 on serine 15, which was needed for the arrest; arrested cells re-entered the cycle when glucose returned, while persistent AMPK activation pushed them into p53-dependent senescence. Boundary: worked from the abstract only (no PMC full text); cultured cells. |
| 2004 | M | The LKB1 tumor suppressor negatively regulates mTOR signaling SHAW2004 Reported that LKB1 is needed to switch mTOR signalling off when cellular ATP falls, and that this requires AMPK and TSC2. Lkb1-null fibroblasts and the hamartomatous gut polyps of Lkb1 mutant mice showed raised signalling downstream of mTOR. The authors proposed mTOR inhibitors as a treatment idea for Peutz-Jeghers syndrome. Published alongside Corradetti et al. 2004, which reached the same LKB1-AMPK-TSC2 link independently. Boundary: worked from the abstract only (no PMC full text); cell and mouse data, the treatment suggestion was not tested here. |
| 2001 | M | Role of AMP-activated protein kinase in mechanism of metformin action ZHO2001 Metformin activates AMPK, suppressing hepatic gluconeogenesis and lipogenesis. |
| 2001 | M | Mammalian TOR: a homeostatic ATP sensor DEN2001 The authors tested whether mTOR signalling responds to the cell's energy level, not only to amino acids. They reported that lowering intracellular ATP reduced signalling through the mTOR pathway, and that this happened independently of amino acid levels. Based on the kinase properties of mTOR, they proposed that mTOR itself senses ATP. Later work showed that much of the energy signal reaches mTORC1 through AMPK and TSC2, so the direct ATP-sensor model is one part of a larger picture. Boundary: cultured cells and in vitro kinase measurements; the ATP-sensor interpretation is the authors' model and has been revised by later AMPK work. |
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