Oliver's mTOR Atlas Evidence Platform
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Pathway link STRESS-AMPK

Energy & cellular stress AMPK

Energy & cellular stress activates AMPK.

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.

AMPK does not read ATP directly - it reads the ratio of AMP and ADP to ATP. As ATP is consumed, AMP and ADP accumulate and bind the gamma subunit, which is the actual switch: it activates AMPK allosterically and protects the activating Thr172 phosphate from removal. AMPK is the cell's low-fuel sensor, and mTORC1 is one of the first things it shuts off.

The conditions it 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.

Time it takes
seconds
Step
direct (one molecule acts on the other)
Measured in
mammalian cells
Where in the cell
cytosol
Reaches people?
plausible in people, not shown directly
How settled
settled in the literature

Studies behind it

YearEvidenceStudy
2008 M AMPK phosphorylation of raptor mediates a metabolic checkpointGWI2008 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.
2001 M Role of AMP-activated protein kinase in mechanism of metformin actionZHO2001 Metformin activates AMPK, suppressing hepatic gluconeogenesis and lipogenesis.
2026 M IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cellsDEM2026 IDH3A loss in AML leukemic stem cells reduces TCA cycle flux and raises intracellular citrate, activating AMPK and suppressing mTORC1 (lowering translation), which sensitizes cells to BCL2 inhibition by venetoclax - nominating the IDH3A-citrate-AMPK-mTORC1 axis as a target to overcome venetoclax/azacitidine resistance.
2011 M Structure of mammalian AMPK and its regulation by ADPXIA2011 AMP binding to the gamma regulatory domain promotes phosphorylation of AMPK and protects it from dephosphorylation. ADP binding to one site also protects against dephosphorylation but does not activate allosterically. Crystal structure of an active AMPK complex.

Points the other way

No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.

Who has checked this

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No researcher outside the project has checked this link yet.
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Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.
Curated by
Oliver Barton, with AI help for drafting; see how links are checked.

“How settled” describes how far researchers in the field agree. It is not the same as the sign-off above, which only says whether a named curator has checked this page.

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