AMPK

Gene/Protein · 26 studies in the Atlas · also known as AMP-activated protein kinase, AMPK alpha, PRKAA1, PRKAA2, AMPKα1, AMPKα2

AMP-activated protein kinase; cellular energy sensor; inhibits mTORC1 under low-energy conditions.

The low-fuel sensor. The cell's energy-shortage alarm. When energy is running low, it switches on and puts the brakes on mTORC1.

αβγ heterotrimer. Two independent arms onto mTORC1 plus a direct arm onto ULK1, classically read as activating; whether AMPK activates or restrains ULK1 under energy stress is now disputed (see AMPK-ULK1).

TL;DR. AMPK appears in 26 curated studies in Oliver's mTOR Atlas: 6 in animal models; 19 at the molecular level (cells, biochemistry, structure); 1 review. No study in people is recorded for it in the Atlas yet. It has 8 interactions in the curated pathway model.

In the pathway model

8 interactions in the curated mTOR pathway model (4 acting from AMPK, 4 acting on it). Each row is a claim with the evidence behind it; the evidence code is the kind of study, not its quality.

Interaction	Mechanism	Evidence	Studies
AMPK activates Mitophagy mechanism: functional-consequence · this link in full · on the map table	The cell's energy sensor can help clear out damaged mitochondria, partly by switching on an autophagy starter kinase. How much it matters depends on the cell and on the kind of stress.AMPK can promote the clearance of damaged mitochondria, in part by phosphorylating ULK1: cells whose ULK1 cannot be phosphorylated by AMPK show defective mitophagy under starvation. How much AMPK contributes depends on the cell type and on the kind of energy stress. Holds under: Two studies of different kinds: EGA2010 (cells and C. elegans, AMPK-site mutant of ULK1) and ZHU2026 (mouse toxicology model, where LKB1/AMPK loss also went with mitochondrial DNA leakage and liver inflammation; that downstream link is shown only there). The upstream step is disputed: PAR2023 (Park, Lee and Kim, Nat Commun 2023, PMID 37225695, in this corpus) reports that under glucose starvation and mitochondrial energy stress AMPK restrains ULK1 activation and autophagy induction; see AMPK-ULK1, where it is recorded as the conflicting study. PAR2023 measured ULK1 activity, bulk autophagy and aggrephagy rather than mitophagy itself, so it bears on the upstream step and not directly on the mitophagy readout here. plausible in people, not shown directly · emerging, few independent studies	A	EGA2010, ZHU2026
AMPK inhibits mTORC1 mechanism: phosphorylation · this link in full · on the map table	AMPK also hits mTORC1 directly, adding a second, energy-based checkpoint on top of TSC.AMPK also hits mTORC1 directly by phosphorylating Raptor, imposing a metabolic checkpoint independent of TSC. Holds under: Cell biochemistry in human and mouse cells (GWI2008) plus one study in aged mice (YAN2026B). Direct Raptor phosphorylation is shown in cells; how much it adds beside the TSC route in living tissue, and in people, is not shown. The Raptor arm is the TSC2-independent route, which is why it is measurable in TSC-null cells. Its relative contribution versus the TSC2 arm varies by cell type and by how deep the energy stress is. plausible in people, not shown directly · settled in the literature	A	GWI2008, YAN2026B
AMPK activates TSC1/TSC2 mechanism: phosphorylation · this link in full · on the map table	When energy is low, AMPK tags TSC2 and makes the brake on Rheb stronger.When energy runs low, AMPK phosphorylates TSC2 and strengthens the brake on Rheb. Holds under: Mammalian cell biochemistry (INO2003, INO2006). Not tested in whole animals or in people by the cited studies. Relative weight of this arm is cell-type dependent. AMPK reaches mTORC1 two ways – activating TSC2 and directly phosphorylating Raptor – and TSC2-null cells still suppress mTORC1 under energy stress, so the TSC2 arm is not universally the dominant one. Which arm carries the signal depends on TSC status, LKB1 status and the severity and duration of the energy stress. plausible in people, not shown directly · settled in the literature	M	INO2003, INO2006, BUD2008
AMPK activates ULK1 mechanism: phosphorylation · this link in full · on the map table	AMPK also tags ULK1 directly. The long-standing view is that this switches cleanup on; newer work suggests that during a sharp energy crisis AMPK instead holds ULK1 back while protecting it, so the direction is now debated.AMPK phosphorylates ULK1 at sites distinct from mTORC1's inhibitory S757 site. The classic reading is that low energy therefore switches autophagy on directly, not only by releasing the mTORC1 brake; that reading is now disputed (see boundary). Holds under: Contested direction. EGA2010 and KIM2011 report activating phosphorylation. PAR2023 (Park, Lee and Kim, Nat Commun 2023, PMID 37225695) reports that under glucose starvation and mitochondrial energy stress AMPK inhibits ULK1 activation and autophagy induction while protecting the ULK1 machinery from degradation. Which effect dominates appears to depend on the kind and depth of the energy stress. plausible in people, not shown directly · disputed: at least one study points the other way	M	EGA2010, KIM2011, DAL2016 conflicting: PAR2023
LKB1 (STK11) activates AMPK mechanism: phosphorylation · this link in full · on the map table	LKB1 is the main switch that turns AMPK on when energy runs low; in cells without it, AMPK no longer responds to low energy. A second kinase can still switch AMPK on when calcium rises, so AMPK is not completely silent.LKB1 is the main kinase that primes AMPK, phosphorylating AMPK-alpha directly on Thr172; in LKB1-null cells AMPK no longer responds to energy stress (SHW2004). It is not the only upstream kinase: CaMKK2 phosphorylates the same site when calcium rises, and LKB1-deficient cells keep some basal AMPK activity (Hawley 2005, PMID 16054095; Woods 2005, PMID 16054096; outside this corpus). Holds under: Canonical step, established in LKB1-null cells and in vitro kinase assays (SHW2004). Coded M – molecular – because that is what the supporting evidence is: cell and in vitro biochemistry, not an organismal phenotype. plausible in people, not shown directly · settled in the literature	M	SHW2004, COR2004
Metformin activates AMPK mechanism: signal-relay · this link in full · on the map table	Metformin shifts the cell's energy balance and switches AMPK on – its best-known route to affecting this pathway.Metformin shifts the cell's energy balance and AMPK switches on - the route it is usually credited to, and why it keeps appearing next to rapamycin in longevity discussions. Holds under: How much of metformin's effect actually runs through AMPK is disputed: it still suppresses hepatic gluconeogenesis in AMPK-null and LKB1-null mouse liver (FOR2010) and still inhibits mTORC1 in AMPK-null cells (KAL2010). See the parallel METFORMIN-MTORC1 edge. plausible in people, not shown directly · disputed: at least one study points the other way	A	ZHO2001, PEA2009 conflicting: KAL2010
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.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. 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
ULK1 inhibits AMPK mechanism: phosphorylation · this link in full · on the map table	ULK1 tags AMPK back and calms it down – a feedback loop that keeps cleanup from running out of control.ULK1 phosphorylates AMPK back, damping the signal that activated it - a negative feedback loop that stops autophagy running away. Holds under: One study in human cells and mouse (LOF2011). A single study. The feedback loop is shown in cell models, and the relation in the other direction (AMPK-ULK1) is contested. Closes a loop rather than acting as a one-way arrow; steady-state behaviour depends on the relative strength of both directions. plausible in people, not shown directly · settled in the literature	M	LOF2011

Evidence at a glance

Evidence	What it means	Studies
A	Animal model	6
M	Molecular — cells, biochemistry, structure	19
R	Review — secondary literature, not a new result	1

No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.

Studies

Year	Evidence	Study
2026	A	Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF SONH2026 Urolithin A ameliorates HFpEF cardiac remodeling in mice by activating AMPK and inhibiting mTOR to restore mitophagic flux, while simultaneously remodeling the gut microbiome-ceramide axis to reduce lipotoxic stress.
2026	A	LKB1/AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene. ZHU2026 LKB1/AMPK deficiency exacerbates trichloroethylene-induced liver injury by impairing mTOR-regulated mitophagy and causing mitochondrial DNA leakage; rapamycin and AMPK activation are protective, nominating the LKB1/AMPK/mTOR axis as a candidate therapeutic target in mice; no human data.
2026	A	Glutamine alleviates bisphenol A-induced jejunal injury in piglets involving mitochondrial function restoration and AMPK-mTOR signaling regulation. XIE2026 Glutamine supplementation alleviated bisphenol A-induced jejunal injury in piglets, restoring mitochondrial energy metabolism and barrier integrity alongside modulation of AMPK-mTOR signalling.
2026	A	Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK YAN2026B Hepassocin (HPS/FGL1), a hepatokine, activates AMPK via an ANXA2-ERK-p90RSK-LKB1 cascade, restraining mTOR activity. Aged HPS-knockout mice show reduced LKB1/AMPK activation and elevated mTOR activity, impaired autophagy, exacerbated cellular senescence, and severely compromised liver regeneration after partial hepatectomy. AMPK agonist AICAR or exogenous HPS rescued the aging/regeneration phenotype.
2010	A	Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state FOR2010 The paper that broke the simple 'metformin works through AMPK' story. Metformin still suppressed hepatic glucose production in mice and hepatocytes lacking AMPK or LKB1, acting instead through a fall in hepatic energy charge. Any claim that metformin's benefit is AMPK-mediated has to answer this result.
2009	A	Enhancing CD8 T-cell memory by modulating fatty acid metabolism PEA2009 Mice whose T cells lacked the adaptor protein TRAF6 mounted a normal effector CD8 T-cell response to Listeria infection, but the antigen-specific cells vanished during contraction and almost no memory cells formed. The TRAF6-deficient cells failed to activate AMPK and mitochondrial fatty acid oxidation when the growth factor IL-2 was withdrawn. Daily metformin restored fatty acid oxidation and memory formation, and also raised memory CD8 T-cell numbers in normal mice: in a tumour vaccine model 6 of 9 metformin-treated mice survived beyond day 33 against 1 of 8 controls. Daily rapamycin (1.5 mg/kg), used as a second drug that promotes fatty acid oxidation, likewise increased memory CD8 T-cell development and recall responses. Boundary: mouse only, one bacterial infection model and one transplantable tumour; the rapamycin arm is a secondary experiment and mTOR activity itself was not measured in these cells.
2026	R	Nutrient-sensing pathways in adult stem cells: Orchestrating homeostasis, aging, and disease XIA2026 Proposes an integrated framework in which mTOR, AMPK, sirtuins, and insulin/IGF-1 signaling jointly govern adult stem cell transitions between quiescence, activation, and differentiation; age-related dysregulation of this nutrient-sensing network drives stem cell exhaustion and tissue degeneration, and interventions (mTOR inhibitors, AMPK activators, NAD+ precursors, dietary strategies) can restore ASC function.
2026	M	IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells DEM2026 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.
2026	M	5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling HAL2026 FOLFOX and oxaliplatin disrupted mTORC1/AMPK regulation of autophagy flux and protein synthesis in cultured myotubes; the effect was not easily reversible on drug withdrawal. Rapamycin (but not metformin) restored autophagy flux and AMPK phosphorylation, though without restoring protein synthesis.
2023	M	Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis SPA2023 Live imaging of single MCF10A cells shows mTORC1-TFEB signalling adjusts continuously to amino acids and insulin, given alone, one after another or together; at physiological amino acid levels TFEB, AMPK and AKT activity fluctuate in step, and these graded changes track protein synthesis rate through a distributed set of mTORC1 effectors.
2017	M	Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex HOW2017 Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway.
2016	M	A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time.
2011	M	Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop LOF2011 ULK1 phosphorylates and inhibits AMPK in return, showing autophagy signaling is a bidirectional feedback loop, not a one-way switch.
2011	M	AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 KIM2011 Revealed the tug-of-war over ULK1: the energy sensor AMPK phosphorylates ULK1 at activating sites to turn autophagy ON when energy is low, while mTORC1 phosphorylates a different site (Ser757) to keep it OFF and even blocks AMPK from reaching ULK1. Two opposing kinases wired to the same switch.
2011	M	Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets MIC2011 Comparing CD4 T cells grown under effector and regulatory conditions, the authors showed that Th1, Th2 and Th17 cells carry high surface Glut1 and are strongly glycolytic, while inducible Treg carry little Glut1, oxidise lipid at a higher rate and have more phosphorylated AMPK. Blocking lipid oxidation with etomoxir selectively suppressed Treg generation and left effector differentiation intact, whereas removing glucose blocked Th17 but not Treg. Both rapamycin and metformin raised fatty acid oxidation in stimulated CD4 T cells, and etomoxir prevented the Treg increase produced by rapamycin or TGF-beta, which ties the pro-Treg effect of mTOR inhibition to lipid oxidation. In a mouse asthma model, metformin lowered Glut1 on activated CD4 T cells and increased the proportion and number of Treg in draining lymph nodes, although airway responsiveness itself did not change significantly. Boundary: mouse cells and one mouse allergic-airway model; mTOR inhibition is pharmacological (rapamycin) and mTOR activity was not measured directly, so the mTOR arm is inferred from drug effects.
2010	M	Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner KAL2010 Metformin inhibits mTORC1 even in cells lacking AMPK or TSC1/TSC2, and the effect requires the Rag GTPases instead. Together with Foretz 2010 this places a large part of metformin's action outside the AMPK axis it is usually credited to.
2010	M	ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS ALE2010 Described a cytoplasmic job for the DNA-damage kinase ATM. In response to raised ROS, ATM activated TSC2 through LKB1 and AMPK, which repressed mTORC1 and induced autophagy. ATM-deficient cells had high ROS and poorly controlled mTORC1, and rapamycin lowered both and delayed lymphoma formation in Atm-deficient mice. Boundary: worked from the abstract only (PMC record without retrievable text); cell lines and mice. Note that the Atlas edge ROS-MTORC1 describes the opposite sign in another context, so the effect of ROS on mTORC1 depends on source and setting.
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.
2008	M	p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling BUD2008 Connected DNA damage to mTOR. Two p53 target genes, Sestrin1 and Sestrin2, bound and activated AMPK and steered it to phosphorylate TSC2, which raised TSC2 GAP activity and lowered mTOR signalling. Sesn2-deficient mice failed to inhibit mTOR signalling after genotoxic challenge. This describes the stress-induced arm of Sestrin biology; the later leucine-sensing role of Sestrin2 through GATOR2 is a separate mechanism. Boundary: cell lines and mice under acute genotoxic stress; no human data.
2006	M	TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth INO2006 TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation.
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 tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress SHW2004 The paper that identified LKB1 as the upstream kinase for AMPK: LKB1 directly phosphorylates AMPK-alpha on Thr172, and LKB1-null cells cannot activate AMPK under energy stress. This is the canonical source for the LKB1 -> AMPK step that gates the whole energy-sensing arm upstream of mTORC1.
2004	M	Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome COR2004 Asked why two inherited tumour syndromes, tuberous sclerosis and Peutz-Jeghers syndrome, look so alike under the microscope. Re-expressing LKB1 in LKB1-null HeLa cells raised AMPK activation-loop phosphorylation and lowered phosphorylation of S6K and 4E-BP1, while knocking LKB1 down did the opposite. The effect on mTOR outputs needed both AMPK and TSC2, placing LKB1 upstream of the TSC2-mTOR axis through AMPK. Together with Shaw et al. 2004 this is one of the two papers that tied energy stress, via LKB1 and AMPK, to TSC2. Boundary: cultured cell lines with overexpression and knockdown; the tumour-syndrome link is an interpretation, not a test in patients.
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.
2003	M	TSC2 mediates cellular energy response to control cell growth and survival INO2003 Established the energy-sensing arm of the pathway. When energy runs low, AMPK phosphorylates TSC2, boosting its ability to shut mTOR down - protecting the cell from burning through resources and from starvation-induced death. One of the founding papers for how mTOR reads the cell's fuel gauge (complements the Akt-TSC2 growth-factor arm).
2001	M	Role of AMP-activated protein kinase in mechanism of metformin action ZHO2001 Metformin activates AMPK, suppressing hepatic gluconeogenesis and lipogenesis.

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Barton, O. (2026). AMPK [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/gene/ampk/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_gene_ampk,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: AMPK},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/gene/ampk/},
  doi          = {10.5281/zenodo.22059963}
}

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