{"gene":"PRKAA1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2018,"finding":"Endothelial PRKAA1/AMPKα1 drives increased aerobic glycolysis in endothelial cells exposed to disturbed flow; selective deletion of endothelial Prkaa1 reduces glycolysis and accelerates atherosclerotic lesion formation, while rescue via Slc2a1 (GLUT1) overexpression restores glycolysis, endothelial viability, and barrier integrity, reversing susceptibility to atherosclerosis.","method":"Endothelial-specific Prkaa1 knockout mice in hyperlipidemic background, Slc2a1 overexpression rescue, siRNA knockdown in human endothelial cells, in vitro disturbed flow models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic deletion + rescue experiment with defined molecular readout (glycolysis via Slc2a1), replicated in vivo and in vitro with multiple orthogonal methods","pmids":["30405100"],"is_preprint":false},{"year":2014,"finding":"PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance (mitophagy) during erythrocyte maturation; Prkaa1 deletion inhibits ULK1 phosphorylation at Ser555, prevents ULK1–BECN1–PtdIns3K complex formation, reduces autophagic flux, causes damaged mitochondrial accumulation, elevated ROS, hemolytic anemia, and splenomegaly. Rapamycin or mitochondria-targeted antioxidant treatment alleviates the phenotype; bone marrow transplantation experiments confirmed the cell-intrinsic nature of the defect.","method":"Prkaa1 knockout mice, bone marrow transplantation, ULK1 phosphorylation assays, autophagic flux measurement, ROS quantification, rapamycin and Mito-tempol treatment","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular mechanism (ULK1 Ser555 phosphorylation), multiple orthogonal methods (complex formation, flux, ROS, transplantation rescue), single rigorous study","pmids":["24988326"],"is_preprint":false},{"year":2015,"finding":"The CAMKK2–PRKAA1–ULK1 signaling pathway is required for CSF1-induced autophagy and human monocyte differentiation into macrophages; PRKAA1 links P2RY6 receptor engagement (activated by UDP) to autophagy induction and monocyte differentiation.","method":"siRNA knockdown, pharmacological inhibition, pathway epistasis experiments in primary human monocytes and CMML patient cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis ordering of CAMKK2→PRKAA1→ULK1 established by genetic knockdown in primary human cells, with functional differentiation readout and P2RY6 ligand rescue","pmids":["26029847"],"is_preprint":false},{"year":2014,"finding":"Acute inhibition of autophagy (muscle-specific Atg7 knockout) in skeletal muscle does not impair physical performance or PRKAA1 activation during exercise, demonstrating that PRKAA1 activation is upstream of and independent of autophagy during exercise; however, autophagy is required for mitochondrial quality control during damaging muscle contraction.","method":"Inducible muscle-specific Atg7 knockout mice, exercise performance assays, PRKAA1 activity measurement, mitochondrial function assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO model with defined phenotype, but mechanistic conclusion about PRKAA1 is a negative result (PRKAA1 activation is autophagy-independent), single lab","pmids":["25483961"],"is_preprint":false},{"year":2010,"finding":"PRKAA1/2 mediates stress-induced proteasome-dependent loss of ID2 protein in trophoblast stem cells (TSCs), promoting differentiation; at low stress levels PRKAA1/2 mediates metabolic adaptation (phosphorylation/inactivation of acetyl-CoA carboxylase) without ID2 loss, while high stress causes irreversible ID2 loss and TSC differentiation.","method":"Pharmacological AMPK inhibition/activation, proteasome inhibition, Western blot for ID2 and phospho-ACC in mouse TSCs","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with two orthogonal mechanistic readouts (ACC phosphorylation, ID2 proteasomal loss), single lab","pmids":["20876741"],"is_preprint":false},{"year":2010,"finding":"Benzo(a)pyrene (BaP) activates PRKAA1/2 and causes PRKAA1/2-dependent ID2 protein loss in trophoblast stem cells in a dose- and time-dependent manner, promoting TSC differentiation at doses corresponding to heavy smoking levels.","method":"BaP treatment of mouse TSCs, AMPK activity assays, ID2 Western blot, PRKAA1/2 siRNA knockdown","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PRKAA1/2 knockdown confirms dependence of BaP-induced ID2 loss, dose–response relationship established, single lab","pmids":["20422711"],"is_preprint":false},{"year":2019,"finding":"PRKAA1 promotes proliferation and inhibits apoptosis of gastric cancer cells through activation of JNK1 and Akt signaling pathways; shRNA-mediated PRKAA1 knockdown reduces PCNA and Bcl-2 expression and JNK1/Akt activity, and inactivation of either JNK1 or Akt blocks PRKAA1 overexpression-induced proliferation.","method":"shRNA knockdown, AMPK inhibitor (Compound C), signaling pathway inhibitors for JNK1 and Akt, xenograft mouse model, Western blot","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic pathway placement via pathway inhibitors combined with overexpression rescue, single lab with in vivo confirmation","pmids":["31558185"],"is_preprint":false},{"year":2021,"finding":"Endothelial PRKAA1 knockdown reduces endothelial glycolysis and fatty acid oxidation, decreases acetyl-CoA levels, and suppresses transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300; EC-specific Prkaa1 knockout unexpectedly alleviates HFD-induced metabolic syndrome including inflammation.","method":"EC-specific Prkaa1 knockout mice on HFD, siRNA knockdown in cultured ECs, metabolic flux measurements, gene expression analysis (qRT-PCR), flow cytometry","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined metabolic-epigenetic mechanism (acetyl-CoA/ATP citrate lyase/p300 axis), multiple methods, single lab","pmids":["34796475"],"is_preprint":false},{"year":2021,"finding":"Prkaa1 deficiency in myeloid cells downregulates glucose and lipid metabolism genes, compromises macrophage glucose and lipid metabolism, suppresses monocyte/macrophage recruitment to adipose tissue, liver, and arterial walls, and decreases macrophage viability in those tissues, resulting in reduced diet-induced metabolic disorders and atherosclerosis.","method":"Myeloid-specific Prkaa1 knockout mice on HFD and Western diet, gene expression profiling, metabolic assays in macrophages","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined metabolic and recruitment phenotype, multiple tissues examined, single lab","pmids":["33511118"],"is_preprint":false},{"year":2017,"finding":"Muscle-specific deletion of Prkaa1 enhances intramyocellular triacylglycerol accumulation under high-fat diet conditions, with upregulation of adipogenic gene expression, downregulation of mitochondrial oxidation genes, hyperlipidemia, and activation of skeletal muscle mTOR signaling.","method":"Muscle-specific Prkaa1 knockout mice on normal and high-fat diet, gene expression analysis, lipid quantification, mTOR signaling assays","journal":"Journal of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific genetic KO with defined lipid metabolic phenotype and pathway (mTOR) activation, single lab","pmids":["29288408"],"is_preprint":false},{"year":2023,"finding":"PRKAA1 induces aberrant mitophagy via the PINK1/Parkin pathway in fluoride-exposed neurons; NaF exposure increases PRKAA1 phosphorylation and upregulates PINK1, Parkin, TOMM-20, and Cyt C, promoting mitophagy and neuronal apoptosis. Both AMPK inhibitor (dorsomorphin) and autophagy inhibitor (3-MA) suppress NaF-induced neuronal apoptosis by restoring aberrant mitophagy.","method":"Rat NaF exposure model, SH-SY5Y cell model, phosphoproteomics, Western blot, pharmacological inhibition with dorsomorphin and 3-MA","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus pharmacological epistasis establishing PRKAA1→PINK1/Parkin pathway, dual inhibitor confirmation, single lab","pmids":["36924562"],"is_preprint":false},{"year":2022,"finding":"FTO (fat mass and obesity-associated protein) stabilizes PRKAA1 mRNA by reducing m6A modification; FTO demethylation of m6A marks on PRKAA1 3'-UTR decreases YTHDF2-mediated mRNA degradation, increasing PRKAA1 protein levels and promoting gastric cancer cell growth, glycolysis, and redox balance maintenance.","method":"RNA immunoprecipitation for m6A, YTHDF2 interaction assay, FTO overexpression/knockdown, PRKAA1 mRNA stability assays, Western blot, extracellular flux analyzer","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation plus functional rescue experiments establishing m6A-YTHDF2 axis, single lab with multiple orthogonal methods","pmids":["36305690"],"is_preprint":false},{"year":2010,"finding":"siRNA silencing of PRKAA1 in HEK293 cells increases susceptibility to methylmercury toxicity, while AMPK activator AICAR reduces methylmercury toxicity, indicating PRKAA1/AMPK activation is protective against methylmercury-induced cytotoxicity.","method":"siRNA knockdown in HEK293 cells, AICAR pharmacological activation, cell viability assay","journal":"The Journal of toxicological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pharmacological/RNAi approach, no mechanistic pathway defined beyond AMPK activation, single lab","pmids":["20686348"],"is_preprint":false},{"year":2017,"finding":"miR-181a targets PRKAA1 (validated by luciferase assay) in the dorsal hippocampus; after fear conditioning or object location training, miR-181a expression transiently increases while PRKAA1 expression and activity decrease; microinjection of PRKAA1 agonist AICAR or inhibitor compound C reverses the effects of miR-181a manipulation on hippocampus-dependent memory formation, placing PRKAA1 downstream of miR-181a in memory regulation.","method":"Luciferase reporter assay, miR-181a agomir/antagomir stereotaxic injection in mouse dorsal hippocampus, AICAR and compound C microinjection, fear conditioning and object location behavioral assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miR-181a target by luciferase assay, in vivo epistasis with pharmacological rescue, single lab with multiple behavioral readouts","pmids":["28814760"],"is_preprint":false},{"year":2024,"finding":"Gentiacaulein inhibits glucose transport into astrocytes, increasing AMP:ATP ratio and inducing PRKAA1-mediated autophagy, which enhances amyloid-β clearance and reduces NF-κB nuclear translocation and inflammatory cytokine (TNF-α, IL-6) release; PRKAA1 knockdown reverses these effects, confirming PRKAA1 as the mediating kinase.","method":"Pharmacological treatment of primary astrocytes, ATP/AMP measurement, PRKAA1 siRNA knockdown, autophagy flux assays, NF-κB translocation assay, ELISA for cytokines","journal":"Autophagy reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PRKAA1 knockdown confirms dependence of drug-induced autophagy and anti-inflammatory effects, multiple orthogonal readouts, single lab","pmids":["40395536"],"is_preprint":false},{"year":2025,"finding":"Selective deletion of Prkaa1 (AMPKα1) in tendon progenitors causes transcriptional alterations in cell cycle regulation and ECM organization by one month, leads to significant reductions in tendon mechanical strength and upregulation of senescence markers p21 and p16 by three months, and progresses to ectopic calcification with age; tendon fibroblasts lacking AMPKα1 show altered ECM substrate adhesion, and voluntary exercise partially rescues ECM organization and reduces senescence marker expression.","method":"Conditional Prkaa1 knockout in tendon progenitors, RNA sequencing, mechanical testing, senescence marker immunostaining, in vitro ECM adhesion assays, voluntary exercise intervention","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal readouts (transcriptomics, mechanical testing, senescence markers, in vitro assays), preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"PRKAA1/AMPKα1, the catalytic α1 subunit of AMPK, functions as a cellular energy sensor that phosphorylates ULK1 (Ser555) to drive autophagy and mitophagy (clearing damaged mitochondria during erythrocyte maturation and in response to stress), phosphorylates and inactivates acetyl-CoA carboxylase to suppress lipid synthesis, promotes glycolysis in endothelial cells (protecting against atherosclerosis under disturbed flow), orchestrates monocyte/macrophage metabolic fitness and recruitment, activates JNK1 and Akt signaling to regulate cell proliferation and apoptosis, links upstream kinase CAMKK2 and receptor P2RY6 to ULK1-dependent autophagy during monocyte differentiation, is regulated post-transcriptionally via FTO-mediated m6A demethylation that prevents YTHDF2-dependent mRNA degradation, and is targeted by multiple miRNAs (miR-181a, miR-137, miR-497-5p, miR-130b-3p) to modulate downstream biological processes including memory formation, trophoblast viability, and intervertebral disc homeostasis."},"narrative":{"mechanistic_narrative":"PRKAA1 encodes the catalytic α1 subunit of AMPK, an energy-sensing kinase that couples cellular metabolic state to autophagy, mitochondrial quality control, lipid handling, and cell fate across multiple tissues [PMID:24988326, PMID:26029847]. A central effector arm is phosphorylation of ULK1 at Ser555 to nucleate the ULK1–BECN1–PtdIns3K complex and drive autophagic flux; this axis is required for mitochondrial clearance (mitophagy) during erythrocyte maturation, where its loss causes accumulation of damaged mitochondria, elevated ROS, and hemolytic anemia [PMID:24988326], and is engaged downstream of CAMKK2 and the P2RY6 receptor to promote CSF1-induced monocyte-to-macrophage differentiation [PMID:26029847]. PRKAA1 phosphorylates and inactivates acetyl-CoA carboxylase as part of metabolic adaptation [PMID:20876741], and more broadly governs glucose and lipid metabolism: it drives aerobic glycolysis in endothelial cells via GLUT1/SLC2A1 to maintain barrier integrity and protect against atherosclerosis under disturbed flow [PMID:30405100], supports macrophage metabolic fitness and recruitment to metabolic tissues [PMID:33511118], and restrains intramyocellular lipid accumulation and mTOR signaling in skeletal muscle [PMID:29288408]. Through an acetyl-CoA/ATP-citrate-lyase/p300 axis it also feeds histone acetylation and inflammatory gene transcription in endothelium [PMID:34796475]. PRKAA1 additionally signals through PINK1/Parkin-dependent mitophagy in stressed neurons [PMID:36924562] and through JNK1 and Akt to promote proliferation and suppress apoptosis in gastric cancer [PMID:31558185]. PRKAA1 abundance is set post-transcriptionally by FTO-mediated m6A demethylation of its 3'-UTR, which protects the transcript from YTHDF2-dependent degradation [PMID:36305690], and by targeting miRNAs including miR-181a, which represses PRKAA1 to modulate hippocampal memory formation [PMID:28814760].","teleology":[{"year":2010,"claim":"Established that PRKAA1/2 acts as a stress-responsive switch in trophoblast stem cells, distinguishing low-stress metabolic adaptation from high-stress differentiation.","evidence":"Pharmacological AMPK modulation, proteasome inhibition, and PRKAA1/2 knockdown with phospho-ACC and ID2 readouts in mouse TSCs, including benzo(a)pyrene exposure","pmids":["20876741","20422711"],"confidence":"Medium","gaps":["Direct kinase-substrate relationship to ID2 loss not demonstrated","α1 versus α2 contribution not separated","single lab"]},{"year":2010,"claim":"First indication that PRKAA1 activation confers cytoprotection against an environmental toxicant, hinting at a stress-survival role.","evidence":"siRNA knockdown and AICAR activation with viability readout in HEK293 cells under methylmercury exposure","pmids":["20686348"],"confidence":"Low","gaps":["Single pharmacological/RNAi approach with no defined downstream pathway","AICAR is not PRKAA1-specific","not validated in primary cells"]},{"year":2014,"claim":"Defined the molecular mechanism by which PRKAA1 drives mitophagy, showing it phosphorylates ULK1 Ser555 to assemble the autophagy-initiation complex required for clearing mitochondria during erythrocyte maturation.","evidence":"Prkaa1 knockout mice, ULK1 Ser555 phosphorylation assays, complex-formation and autophagic-flux measurement, ROS quantification, bone marrow transplantation, rapamycin/Mito-tempol rescue","pmids":["24988326"],"confidence":"High","gaps":["Whether Ser555 phosphorylation is direct versus indirect not formally resolved by in vitro kinase assay","generalization beyond erythroid lineage untested here"]},{"year":2014,"claim":"Placed PRKAA1 activation upstream of and independent from autophagy during exercise, dissociating its sensor function from its autophagic output in skeletal muscle.","evidence":"Inducible muscle-specific Atg7 knockout mice with exercise performance, PRKAA1 activity, and mitochondrial function assays","pmids":["25483961"],"confidence":"Medium","gaps":["Negative result regarding PRKAA1 dependence on autophagy","does not address PRKAA1 substrates during exercise","single lab"]},{"year":2015,"claim":"Ordered an upstream-to-downstream signaling cascade, showing PRKAA1 transmits CAMKK2 and P2RY6 receptor input to ULK1-dependent autophagy to drive human monocyte differentiation.","evidence":"siRNA knockdown, pharmacological inhibition, and epistasis in primary human monocytes and CMML patient cells with P2RY6 ligand rescue","pmids":["26029847"],"confidence":"High","gaps":["Direct biochemical link between P2RY6/CAMKK2 and PRKAA1 activation not shown","structural basis of pathway coupling unknown"]},{"year":2017,"claim":"Identified PRKAA1 as a post-transcriptionally regulated node in memory, repressed by miR-181a in the hippocampus.","evidence":"Luciferase reporter validation, in vivo miR-181a agomir/antagomir injection with AICAR/compound C rescue, and behavioral memory assays in mouse dorsal hippocampus","pmids":["28814760"],"confidence":"Medium","gaps":["Downstream PRKAA1 substrates in neurons not defined","AICAR/compound C are not PRKAA1-selective","single lab"]},{"year":2017,"claim":"Showed PRKAA1 restrains lipid storage and mTOR signaling in skeletal muscle under dietary lipid load.","evidence":"Muscle-specific Prkaa1 knockout mice on high-fat diet with lipid quantification, gene expression, and mTOR signaling assays","pmids":["29288408"],"confidence":"Medium","gaps":["Direct substrate driving lipid phenotype not identified","redundancy with α2 not tested","single lab"]},{"year":2018,"claim":"Established a protective metabolic role for endothelial PRKAA1, driving GLUT1-dependent glycolysis that preserves endothelial integrity and limits atherosclerosis under disturbed flow.","evidence":"Endothelial-specific Prkaa1 knockout in hyperlipidemic mice with Slc2a1 overexpression rescue, siRNA in human ECs, and in vitro disturbed-flow models","pmids":["30405100"],"confidence":"High","gaps":["Mechanism by which PRKAA1 upregulates GLUT1 not detailed","flow-sensing input upstream of PRKAA1 unresolved"]},{"year":2019,"claim":"Implicated PRKAA1 as a pro-proliferative, anti-apoptotic kinase in gastric cancer acting through JNK1 and Akt.","evidence":"shRNA knockdown, compound C, JNK1/Akt inhibitors, overexpression rescue, and xenografts with Western blot","pmids":["31558185"],"confidence":"Medium","gaps":["Whether JNK1/Akt activation is direct is unresolved","context-dependence versus tumor-suppressive AMPK roles not reconciled","single lab"]},{"year":2021,"claim":"Revealed an unexpected pro-inflammatory, disease-promoting facet of PRKAA1 in endothelium and myeloid cells, linking its metabolic activity to acetyl-CoA-dependent epigenetic and recruitment programs.","evidence":"EC-specific and myeloid-specific Prkaa1 knockout mice on high-fat/Western diet, metabolic flux, gene expression, and flow cytometry with acetyl-CoA/ATP-citrate-lyase/p300 readouts","pmids":["34796475","33511118"],"confidence":"Medium","gaps":["Apparent contradiction with the atheroprotective endothelial role (idx 0) not reconciled","direct PRKAA1 substrate in the acetyl-CoA axis unknown","single lab each"]},{"year":2022,"claim":"Defined how PRKAA1 protein abundance is set post-transcriptionally, via FTO-mediated m6A demethylation that blocks YTHDF2-dependent transcript decay.","evidence":"m6A RNA immunoprecipitation, YTHDF2 interaction, FTO gain/loss, mRNA stability assays, and glycolysis measurement in gastric cancer cells","pmids":["36305690"],"confidence":"Medium","gaps":["m6A site mapping resolution limited","in vivo relevance of the FTO-PRKAA1 axis untested","single lab"]},{"year":2023,"claim":"Showed PRKAA1 can drive maladaptive PINK1/Parkin mitophagy that promotes neuronal apoptosis under toxicant stress.","evidence":"Rat NaF model and SH-SY5Y cells with phosphoproteomics, Western blot, and dorsomorphin/3-MA pharmacological epistasis","pmids":["36924562"],"confidence":"Medium","gaps":["Mechanistic link from PRKAA1 to PINK1/Parkin upregulation not defined","pharmacological inhibitors lack full specificity","single lab"]},{"year":2024,"claim":"Demonstrated PRKAA1-mediated autophagy as the effector enhancing amyloid-β clearance and dampening NF-κB inflammation in astrocytes when glucose uptake is restricted.","evidence":"Pharmacological glucose-transport inhibition in primary astrocytes with ATP/AMP measurement, PRKAA1 siRNA, autophagy flux, NF-κB translocation, and cytokine ELISA","pmids":["40395536"],"confidence":"Medium","gaps":["Direct PRKAA1 substrates linking autophagy to NF-κB suppression not identified","in vivo amyloid clearance not tested","single lab"]},{"year":2025,"claim":"Extended PRKAA1 function to tissue maintenance, showing its loss in tendon progenitors disrupts ECM organization, accelerates senescence, and causes mechanical decline and ectopic calcification.","evidence":"Conditional Prkaa1 knockout in tendon progenitors with RNA-seq, mechanical testing, senescence immunostaining, ECM adhesion assays, and exercise intervention (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","molecular substrate linking PRKAA1 to ECM/senescence programs unknown","single lab"]},{"year":null,"claim":"How PRKAA1 produces opposite outcomes in different contexts—atheroprotective glycolysis versus pro-inflammatory acetyl-CoA signaling, cytoprotective versus apoptotic mitophagy—remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying framework distinguishing context-specific substrate selection","α1 versus α2 subunit-specific functions rarely separated","direct in vitro kinase-substrate validation lacking for several reported targets"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,6,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,2,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,7,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,5,12]}],"complexes":[],"partners":["ULK1","CAMKK2","P2RY6","BECN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13131","full_name":"5'-AMP-activated protein kinase catalytic subunit alpha-1","aliases":["Acetyl-CoA carboxylase kinase","ACACA kinase","Hydroxymethylglutaryl-CoA reductase kinase","HMGCR kinase","Tau-protein kinase PRKAA1"],"length_aa":559,"mass_kda":64.0,"function":"Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357, PubMed:24563466, PubMed:31492851, PubMed:37821951, PubMed:40233740). In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively (By similarity). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160 (By similarity). Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (PubMed:11518699, PubMed:11554766, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). Acts as a key regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2 (PubMed:14651849, PubMed:18439900, PubMed:20160076, PubMed:21205641). Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation (PubMed:36732624). In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes (PubMed:37079666). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process, it also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). Regulates hepatic lipogenesis. Activated via SIRT3, represses sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance. Upon stress, regulates mitochondrial fragmentation through phosphorylation of MTFR1L (PubMed:36367943). Phosphorylates ALDH7A1 in response to cellular stress, such as hypoxia or ferroptotic stress, promoting ALDH7A1 recruitment to membranes (PubMed:31492851, PubMed:40233740)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13131/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKAA1","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132356","cell_line_id":"CID001244","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"PRKAB2","stoichiometry":10.0},{"gene":"PRKAG1","stoichiometry":10.0},{"gene":"PRKAB1","stoichiometry":10.0},{"gene":"AKR1A1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"SUB1","stoichiometry":0.2},{"gene":"PRKAR2A","stoichiometry":0.2},{"gene":"PRKAG2","stoichiometry":0.2},{"gene":"CLIP4","stoichiometry":0.2},{"gene":"INCENP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001244","total_profiled":1310},"omim":[{"mim_id":"619308","title":"PROTEIN PHOSPHATASE, MAGNESIUM/MANGANESE-DEPENDENT, 1E; PPM1E","url":"https://www.omim.org/entry/619308"},{"mim_id":"617471","title":"SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 12; SERPINA12","url":"https://www.omim.org/entry/617471"},{"mim_id":"615227","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 3; C1QL3","url":"https://www.omim.org/entry/615227"},{"mim_id":"613486","title":"MICRO RNA 33B; MIR33B","url":"https://www.omim.org/entry/613486"},{"mim_id":"612156","title":"MICRO RNA 33A; MIR33A","url":"https://www.omim.org/entry/612156"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRKAA1"},"hgnc":{"alias_symbol":["AMPKa1"],"prev_symbol":[]},"alphafold":{"accession":"Q13131","domains":[{"cath_id":"3.30.200.20","chopping":"21-106","consensus_level":"medium","plddt":86.8402,"start":21,"end":106},{"cath_id":"1.10.510.10","chopping":"108-286","consensus_level":"medium","plddt":94.682,"start":108,"end":286},{"cath_id":"1.10.8.10","chopping":"291-350","consensus_level":"high","plddt":73.4175,"start":291,"end":350},{"cath_id":"3.30.310.80","chopping":"410-478_540-557","consensus_level":"high","plddt":95.1575,"start":410,"end":557}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13131","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13131-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13131-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKAA1","jax_strain_url":"https://www.jax.org/strain/search?query=PRKAA1"},"sequence":{"accession":"Q13131","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13131.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13131/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13131"}},"corpus_meta":[{"pmid":"30405100","id":"PMC_30405100","title":"PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30405100","citation_count":122,"is_preprint":false},{"pmid":"25483961","id":"PMC_25483961","title":"Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25483961","citation_count":122,"is_preprint":false},{"pmid":"25225183","id":"PMC_25225183","title":"Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude.","date":"2014","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25225183","citation_count":94,"is_preprint":false},{"pmid":"26029847","id":"PMC_26029847","title":"The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26029847","citation_count":88,"is_preprint":false},{"pmid":"24895169","id":"PMC_24895169","title":"Gene of the month. 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integrity, reversing susceptibility to atherosclerosis.\",\n      \"method\": \"Endothelial-specific Prkaa1 knockout mice in hyperlipidemic background, Slc2a1 overexpression rescue, siRNA knockdown in human endothelial cells, in vitro disturbed flow models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic deletion + rescue experiment with defined molecular readout (glycolysis via Slc2a1), replicated in vivo and in vitro with multiple orthogonal methods\",\n      \"pmids\": [\"30405100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance (mitophagy) during erythrocyte maturation; Prkaa1 deletion inhibits ULK1 phosphorylation at Ser555, prevents ULK1–BECN1–PtdIns3K complex formation, reduces autophagic flux, causes damaged mitochondrial accumulation, elevated ROS, hemolytic anemia, and splenomegaly. Rapamycin or mitochondria-targeted antioxidant treatment alleviates the phenotype; bone marrow transplantation experiments confirmed the cell-intrinsic nature of the defect.\",\n      \"method\": \"Prkaa1 knockout mice, bone marrow transplantation, ULK1 phosphorylation assays, autophagic flux measurement, ROS quantification, rapamycin and Mito-tempol treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular mechanism (ULK1 Ser555 phosphorylation), multiple orthogonal methods (complex formation, flux, ROS, transplantation rescue), single rigorous study\",\n      \"pmids\": [\"24988326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The CAMKK2–PRKAA1–ULK1 signaling pathway is required for CSF1-induced autophagy and human monocyte differentiation into macrophages; PRKAA1 links P2RY6 receptor engagement (activated by UDP) to autophagy induction and monocyte differentiation.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, pathway epistasis experiments in primary human monocytes and CMML patient cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis ordering of CAMKK2→PRKAA1→ULK1 established by genetic knockdown in primary human cells, with functional differentiation readout and P2RY6 ligand rescue\",\n      \"pmids\": [\"26029847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Acute inhibition of autophagy (muscle-specific Atg7 knockout) in skeletal muscle does not impair physical performance or PRKAA1 activation during exercise, demonstrating that PRKAA1 activation is upstream of and independent of autophagy during exercise; however, autophagy is required for mitochondrial quality control during damaging muscle contraction.\",\n      \"method\": \"Inducible muscle-specific Atg7 knockout mice, exercise performance assays, PRKAA1 activity measurement, mitochondrial function assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO model with defined phenotype, but mechanistic conclusion about PRKAA1 is a negative result (PRKAA1 activation is autophagy-independent), single lab\",\n      \"pmids\": [\"25483961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKAA1/2 mediates stress-induced proteasome-dependent loss of ID2 protein in trophoblast stem cells (TSCs), promoting differentiation; at low stress levels PRKAA1/2 mediates metabolic adaptation (phosphorylation/inactivation of acetyl-CoA carboxylase) without ID2 loss, while high stress causes irreversible ID2 loss and TSC differentiation.\",\n      \"method\": \"Pharmacological AMPK inhibition/activation, proteasome inhibition, Western blot for ID2 and phospho-ACC in mouse TSCs\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with two orthogonal mechanistic readouts (ACC phosphorylation, ID2 proteasomal loss), single lab\",\n      \"pmids\": [\"20876741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Benzo(a)pyrene (BaP) activates PRKAA1/2 and causes PRKAA1/2-dependent ID2 protein loss in trophoblast stem cells in a dose- and time-dependent manner, promoting TSC differentiation at doses corresponding to heavy smoking levels.\",\n      \"method\": \"BaP treatment of mouse TSCs, AMPK activity assays, ID2 Western blot, PRKAA1/2 siRNA knockdown\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PRKAA1/2 knockdown confirms dependence of BaP-induced ID2 loss, dose–response relationship established, single lab\",\n      \"pmids\": [\"20422711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRKAA1 promotes proliferation and inhibits apoptosis of gastric cancer cells through activation of JNK1 and Akt signaling pathways; shRNA-mediated PRKAA1 knockdown reduces PCNA and Bcl-2 expression and JNK1/Akt activity, and inactivation of either JNK1 or Akt blocks PRKAA1 overexpression-induced proliferation.\",\n      \"method\": \"shRNA knockdown, AMPK inhibitor (Compound C), signaling pathway inhibitors for JNK1 and Akt, xenograft mouse model, Western blot\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic pathway placement via pathway inhibitors combined with overexpression rescue, single lab with in vivo confirmation\",\n      \"pmids\": [\"31558185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endothelial PRKAA1 knockdown reduces endothelial glycolysis and fatty acid oxidation, decreases acetyl-CoA levels, and suppresses transcription of inflammatory molecules mediated by ATP citrate lyase and histone acetyltransferase p300; EC-specific Prkaa1 knockout unexpectedly alleviates HFD-induced metabolic syndrome including inflammation.\",\n      \"method\": \"EC-specific Prkaa1 knockout mice on HFD, siRNA knockdown in cultured ECs, metabolic flux measurements, gene expression analysis (qRT-PCR), flow cytometry\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined metabolic-epigenetic mechanism (acetyl-CoA/ATP citrate lyase/p300 axis), multiple methods, single lab\",\n      \"pmids\": [\"34796475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Prkaa1 deficiency in myeloid cells downregulates glucose and lipid metabolism genes, compromises macrophage glucose and lipid metabolism, suppresses monocyte/macrophage recruitment to adipose tissue, liver, and arterial walls, and decreases macrophage viability in those tissues, resulting in reduced diet-induced metabolic disorders and atherosclerosis.\",\n      \"method\": \"Myeloid-specific Prkaa1 knockout mice on HFD and Western diet, gene expression profiling, metabolic assays in macrophages\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined metabolic and recruitment phenotype, multiple tissues examined, single lab\",\n      \"pmids\": [\"33511118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Muscle-specific deletion of Prkaa1 enhances intramyocellular triacylglycerol accumulation under high-fat diet conditions, with upregulation of adipogenic gene expression, downregulation of mitochondrial oxidation genes, hyperlipidemia, and activation of skeletal muscle mTOR signaling.\",\n      \"method\": \"Muscle-specific Prkaa1 knockout mice on normal and high-fat diet, gene expression analysis, lipid quantification, mTOR signaling assays\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific genetic KO with defined lipid metabolic phenotype and pathway (mTOR) activation, single lab\",\n      \"pmids\": [\"29288408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRKAA1 induces aberrant mitophagy via the PINK1/Parkin pathway in fluoride-exposed neurons; NaF exposure increases PRKAA1 phosphorylation and upregulates PINK1, Parkin, TOMM-20, and Cyt C, promoting mitophagy and neuronal apoptosis. Both AMPK inhibitor (dorsomorphin) and autophagy inhibitor (3-MA) suppress NaF-induced neuronal apoptosis by restoring aberrant mitophagy.\",\n      \"method\": \"Rat NaF exposure model, SH-SY5Y cell model, phosphoproteomics, Western blot, pharmacological inhibition with dorsomorphin and 3-MA\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus pharmacological epistasis establishing PRKAA1→PINK1/Parkin pathway, dual inhibitor confirmation, single lab\",\n      \"pmids\": [\"36924562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO (fat mass and obesity-associated protein) stabilizes PRKAA1 mRNA by reducing m6A modification; FTO demethylation of m6A marks on PRKAA1 3'-UTR decreases YTHDF2-mediated mRNA degradation, increasing PRKAA1 protein levels and promoting gastric cancer cell growth, glycolysis, and redox balance maintenance.\",\n      \"method\": \"RNA immunoprecipitation for m6A, YTHDF2 interaction assay, FTO overexpression/knockdown, PRKAA1 mRNA stability assays, Western blot, extracellular flux analyzer\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation plus functional rescue experiments establishing m6A-YTHDF2 axis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36305690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"siRNA silencing of PRKAA1 in HEK293 cells increases susceptibility to methylmercury toxicity, while AMPK activator AICAR reduces methylmercury toxicity, indicating PRKAA1/AMPK activation is protective against methylmercury-induced cytotoxicity.\",\n      \"method\": \"siRNA knockdown in HEK293 cells, AICAR pharmacological activation, cell viability assay\",\n      \"journal\": \"The Journal of toxicological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pharmacological/RNAi approach, no mechanistic pathway defined beyond AMPK activation, single lab\",\n      \"pmids\": [\"20686348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-181a targets PRKAA1 (validated by luciferase assay) in the dorsal hippocampus; after fear conditioning or object location training, miR-181a expression transiently increases while PRKAA1 expression and activity decrease; microinjection of PRKAA1 agonist AICAR or inhibitor compound C reverses the effects of miR-181a manipulation on hippocampus-dependent memory formation, placing PRKAA1 downstream of miR-181a in memory regulation.\",\n      \"method\": \"Luciferase reporter assay, miR-181a agomir/antagomir stereotaxic injection in mouse dorsal hippocampus, AICAR and compound C microinjection, fear conditioning and object location behavioral assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miR-181a target by luciferase assay, in vivo epistasis with pharmacological rescue, single lab with multiple behavioral readouts\",\n      \"pmids\": [\"28814760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gentiacaulein inhibits glucose transport into astrocytes, increasing AMP:ATP ratio and inducing PRKAA1-mediated autophagy, which enhances amyloid-β clearance and reduces NF-κB nuclear translocation and inflammatory cytokine (TNF-α, IL-6) release; PRKAA1 knockdown reverses these effects, confirming PRKAA1 as the mediating kinase.\",\n      \"method\": \"Pharmacological treatment of primary astrocytes, ATP/AMP measurement, PRKAA1 siRNA knockdown, autophagy flux assays, NF-κB translocation assay, ELISA for cytokines\",\n      \"journal\": \"Autophagy reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PRKAA1 knockdown confirms dependence of drug-induced autophagy and anti-inflammatory effects, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"40395536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Selective deletion of Prkaa1 (AMPKα1) in tendon progenitors causes transcriptional alterations in cell cycle regulation and ECM organization by one month, leads to significant reductions in tendon mechanical strength and upregulation of senescence markers p21 and p16 by three months, and progresses to ectopic calcification with age; tendon fibroblasts lacking AMPKα1 show altered ECM substrate adhesion, and voluntary exercise partially rescues ECM organization and reduces senescence marker expression.\",\n      \"method\": \"Conditional Prkaa1 knockout in tendon progenitors, RNA sequencing, mechanical testing, senescence marker immunostaining, in vitro ECM adhesion assays, voluntary exercise intervention\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal readouts (transcriptomics, mechanical testing, senescence markers, in vitro assays), preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRKAA1/AMPKα1, the catalytic α1 subunit of AMPK, functions as a cellular energy sensor that phosphorylates ULK1 (Ser555) to drive autophagy and mitophagy (clearing damaged mitochondria during erythrocyte maturation and in response to stress), phosphorylates and inactivates acetyl-CoA carboxylase to suppress lipid synthesis, promotes glycolysis in endothelial cells (protecting against atherosclerosis under disturbed flow), orchestrates monocyte/macrophage metabolic fitness and recruitment, activates JNK1 and Akt signaling to regulate cell proliferation and apoptosis, links upstream kinase CAMKK2 and receptor P2RY6 to ULK1-dependent autophagy during monocyte differentiation, is regulated post-transcriptionally via FTO-mediated m6A demethylation that prevents YTHDF2-dependent mRNA degradation, and is targeted by multiple miRNAs (miR-181a, miR-137, miR-497-5p, miR-130b-3p) to modulate downstream biological processes including memory formation, trophoblast viability, and intervertebral disc homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKAA1 encodes the catalytic α1 subunit of AMPK, an energy-sensing kinase that couples cellular metabolic state to autophagy, mitochondrial quality control, lipid handling, and cell fate across multiple tissues [#1, #2]. A central effector arm is phosphorylation of ULK1 at Ser555 to nucleate the ULK1–BECN1–PtdIns3K complex and drive autophagic flux; this axis is required for mitochondrial clearance (mitophagy) during erythrocyte maturation, where its loss causes accumulation of damaged mitochondria, elevated ROS, and hemolytic anemia [#1], and is engaged downstream of CAMKK2 and the P2RY6 receptor to promote CSF1-induced monocyte-to-macrophage differentiation [#2]. PRKAA1 phosphorylates and inactivates acetyl-CoA carboxylase as part of metabolic adaptation [#4], and more broadly governs glucose and lipid metabolism: it drives aerobic glycolysis in endothelial cells via GLUT1/SLC2A1 to maintain barrier integrity and protect against atherosclerosis under disturbed flow [#0], supports macrophage metabolic fitness and recruitment to metabolic tissues [#8], and restrains intramyocellular lipid accumulation and mTOR signaling in skeletal muscle [#9]. Through an acetyl-CoA/ATP-citrate-lyase/p300 axis it also feeds histone acetylation and inflammatory gene transcription in endothelium [#7]. PRKAA1 additionally signals through PINK1/Parkin-dependent mitophagy in stressed neurons [#10] and through JNK1 and Akt to promote proliferation and suppress apoptosis in gastric cancer [#6]. PRKAA1 abundance is set post-transcriptionally by FTO-mediated m6A demethylation of its 3'-UTR, which protects the transcript from YTHDF2-dependent degradation [#11], and by targeting miRNAs including miR-181a, which represses PRKAA1 to modulate hippocampal memory formation [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that PRKAA1/2 acts as a stress-responsive switch in trophoblast stem cells, distinguishing low-stress metabolic adaptation from high-stress differentiation.\",\n      \"evidence\": \"Pharmacological AMPK modulation, proteasome inhibition, and PRKAA1/2 knockdown with phospho-ACC and ID2 readouts in mouse TSCs, including benzo(a)pyrene exposure\",\n      \"pmids\": [\"20876741\", \"20422711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate relationship to ID2 loss not demonstrated\", \"α1 versus α2 contribution not separated\", \"single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"First indication that PRKAA1 activation confers cytoprotection against an environmental toxicant, hinting at a stress-survival role.\",\n      \"evidence\": \"siRNA knockdown and AICAR activation with viability readout in HEK293 cells under methylmercury exposure\",\n      \"pmids\": [\"20686348\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single pharmacological/RNAi approach with no defined downstream pathway\", \"AICAR is not PRKAA1-specific\", \"not validated in primary cells\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the molecular mechanism by which PRKAA1 drives mitophagy, showing it phosphorylates ULK1 Ser555 to assemble the autophagy-initiation complex required for clearing mitochondria during erythrocyte maturation.\",\n      \"evidence\": \"Prkaa1 knockout mice, ULK1 Ser555 phosphorylation assays, complex-formation and autophagic-flux measurement, ROS quantification, bone marrow transplantation, rapamycin/Mito-tempol rescue\",\n      \"pmids\": [\"24988326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser555 phosphorylation is direct versus indirect not formally resolved by in vitro kinase assay\", \"generalization beyond erythroid lineage untested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed PRKAA1 activation upstream of and independent from autophagy during exercise, dissociating its sensor function from its autophagic output in skeletal muscle.\",\n      \"evidence\": \"Inducible muscle-specific Atg7 knockout mice with exercise performance, PRKAA1 activity, and mitochondrial function assays\",\n      \"pmids\": [\"25483961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result regarding PRKAA1 dependence on autophagy\", \"does not address PRKAA1 substrates during exercise\", \"single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Ordered an upstream-to-downstream signaling cascade, showing PRKAA1 transmits CAMKK2 and P2RY6 receptor input to ULK1-dependent autophagy to drive human monocyte differentiation.\",\n      \"evidence\": \"siRNA knockdown, pharmacological inhibition, and epistasis in primary human monocytes and CMML patient cells with P2RY6 ligand rescue\",\n      \"pmids\": [\"26029847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between P2RY6/CAMKK2 and PRKAA1 activation not shown\", \"structural basis of pathway coupling unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PRKAA1 as a post-transcriptionally regulated node in memory, repressed by miR-181a in the hippocampus.\",\n      \"evidence\": \"Luciferase reporter validation, in vivo miR-181a agomir/antagomir injection with AICAR/compound C rescue, and behavioral memory assays in mouse dorsal hippocampus\",\n      \"pmids\": [\"28814760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream PRKAA1 substrates in neurons not defined\", \"AICAR/compound C are not PRKAA1-selective\", \"single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PRKAA1 restrains lipid storage and mTOR signaling in skeletal muscle under dietary lipid load.\",\n      \"evidence\": \"Muscle-specific Prkaa1 knockout mice on high-fat diet with lipid quantification, gene expression, and mTOR signaling assays\",\n      \"pmids\": [\"29288408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate driving lipid phenotype not identified\", \"redundancy with α2 not tested\", \"single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a protective metabolic role for endothelial PRKAA1, driving GLUT1-dependent glycolysis that preserves endothelial integrity and limits atherosclerosis under disturbed flow.\",\n      \"evidence\": \"Endothelial-specific Prkaa1 knockout in hyperlipidemic mice with Slc2a1 overexpression rescue, siRNA in human ECs, and in vitro disturbed-flow models\",\n      \"pmids\": [\"30405100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PRKAA1 upregulates GLUT1 not detailed\", \"flow-sensing input upstream of PRKAA1 unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated PRKAA1 as a pro-proliferative, anti-apoptotic kinase in gastric cancer acting through JNK1 and Akt.\",\n      \"evidence\": \"shRNA knockdown, compound C, JNK1/Akt inhibitors, overexpression rescue, and xenografts with Western blot\",\n      \"pmids\": [\"31558185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JNK1/Akt activation is direct is unresolved\", \"context-dependence versus tumor-suppressive AMPK roles not reconciled\", \"single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an unexpected pro-inflammatory, disease-promoting facet of PRKAA1 in endothelium and myeloid cells, linking its metabolic activity to acetyl-CoA-dependent epigenetic and recruitment programs.\",\n      \"evidence\": \"EC-specific and myeloid-specific Prkaa1 knockout mice on high-fat/Western diet, metabolic flux, gene expression, and flow cytometry with acetyl-CoA/ATP-citrate-lyase/p300 readouts\",\n      \"pmids\": [\"34796475\", \"33511118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent contradiction with the atheroprotective endothelial role (idx 0) not reconciled\", \"direct PRKAA1 substrate in the acetyl-CoA axis unknown\", \"single lab each\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined how PRKAA1 protein abundance is set post-transcriptionally, via FTO-mediated m6A demethylation that blocks YTHDF2-dependent transcript decay.\",\n      \"evidence\": \"m6A RNA immunoprecipitation, YTHDF2 interaction, FTO gain/loss, mRNA stability assays, and glycolysis measurement in gastric cancer cells\",\n      \"pmids\": [\"36305690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A site mapping resolution limited\", \"in vivo relevance of the FTO-PRKAA1 axis untested\", \"single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed PRKAA1 can drive maladaptive PINK1/Parkin mitophagy that promotes neuronal apoptosis under toxicant stress.\",\n      \"evidence\": \"Rat NaF model and SH-SY5Y cells with phosphoproteomics, Western blot, and dorsomorphin/3-MA pharmacological epistasis\",\n      \"pmids\": [\"36924562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from PRKAA1 to PINK1/Parkin upregulation not defined\", \"pharmacological inhibitors lack full specificity\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated PRKAA1-mediated autophagy as the effector enhancing amyloid-β clearance and dampening NF-κB inflammation in astrocytes when glucose uptake is restricted.\",\n      \"evidence\": \"Pharmacological glucose-transport inhibition in primary astrocytes with ATP/AMP measurement, PRKAA1 siRNA, autophagy flux, NF-κB translocation, and cytokine ELISA\",\n      \"pmids\": [\"40395536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRKAA1 substrates linking autophagy to NF-κB suppression not identified\", \"in vivo amyloid clearance not tested\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PRKAA1 function to tissue maintenance, showing its loss in tendon progenitors disrupts ECM organization, accelerates senescence, and causes mechanical decline and ectopic calcification.\",\n      \"evidence\": \"Conditional Prkaa1 knockout in tendon progenitors with RNA-seq, mechanical testing, senescence immunostaining, ECM adhesion assays, and exercise intervention (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"molecular substrate linking PRKAA1 to ECM/senescence programs unknown\", \"single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRKAA1 produces opposite outcomes in different contexts—atheroprotective glycolysis versus pro-inflammatory acetyl-CoA signaling, cytoprotective versus apoptotic mitophagy—remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying framework distinguishing context-specific substrate selection\", \"α1 versus α2 subunit-specific functions rarely separated\", \"direct in vitro kinase-substrate validation lacking for several reported targets\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 6, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 5, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ULK1\",\n      \"CAMKK2\",\n      \"P2RY6\",\n      \"BECN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}