{"id":"5d82805b-fb39-555e-8f99-162cb6be7927","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-pen2-null-ampk","predicate":"reduces","statement":"Knockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"ed1d77f9-8f5e-56fd-9bb3-5d6a03a63e30","mechanism_event_label":"Without that protein the switch is not thrown.","subject":{"id":"610c7f16-f6bd-58d5-a5d2-b799db8d052c","slug":"mouse-psenen-liver-null","display_name":"Liver-specific Pen2 knockout mice in the 2022 study","entity_type_key":"protein_state"},"object":{"id":"3f80c230-5a0c-5f09-8627-4dcd191a49f9","slug":"lysosomal-ampk-activation","display_name":"Lysosome-associated AMPK activation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"ed1d77f9-8f5e-56fd-9bb3-5d6a03a63e30","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-pen2-null-ampk-event","event_type":"biochemical_relationship","label":"Without that protein the switch is not thrown.","description":"Knockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"64798027-fbeb-5800-89f4-98929b748d1d","slug":"psenen","display_name":"Human presenilin enhancer gamma-secretase subunit / PEN2 / PSENEN","entity_type_key":"protein"},"role":"missing_protein","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"610c7f16-f6bd-58d5-a5d2-b799db8d052c","slug":"mouse-psenen-liver-null","display_name":"Liver-specific Pen2 knockout mice in the 2022 study","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3f80c230-5a0c-5f09-8627-4dcd191a49f9","slug":"lysosomal-ampk-activation","display_name":"Lysosome-associated AMPK activation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/metformin-research/35197629.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983\", \"start_char\": 0, \"end_char\": 1549, \"text_sha256\": \"587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Photoactive metformin probe, binding studies, knockouts in mice and C. elegans","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"metformin","display_name":"Metformin","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human cells, mouse and C. elegans","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Without that protein the switch is not thrown.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Lysosome, liver and intestine","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"3b164f16-ac17-5821-b34a-7f88bae5e008","evidence_kind":"source_excerpt","locator":"Lines 671-682","start_line":671,"end_line":682,"excerpt":"### metformin-pen2-null-ampk\nKnockout of PEN2, or re-introduction of a PEN2 mutant that does not bind ATP6AP1, blunted AMPK activation.\nCondition category: machinery_impairment\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: Without that protein the switch is not thrown.\norganism: Human cells, mouse and C. elegans\ntissue_or_cell_type: Lysosome, liver and intestine\nexperimental_model: Photoactive metformin probe, binding studies, knockouts in mice and C. elegans\nlimitations: A direct binding partner at low dose with a micromolar dissociation constant. Lifespan and fat-content endpoints are model endpoints, not clinical outcomes.\nexposure: Clinically relevant low metformin concentrations; PEN2 knockout and ATP6AP1-binding mutants\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/35197629.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983\", \"start_char\": 0, \"end_char\": 1549, \"text_sha256\": \"587594a8bbbf0a2baa7066264c0c46b26ded6231287176608885e736bee36983\"}\n[metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8","model_system":"Photoactive metformin probe, binding studies, knockouts in mice and C. elegans","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [metformin-p35197629] Low-dose metformin targets the lysosomal AMPK pathway through PEN2. (2022). https://pubmed.ncbi.nlm.nih.gov/35197629/ DOI: 10.1038/s41586-022-04431-8","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"d0474bd9-7cfd-5695-a152-12f3633a6813","stable_key":"import-8b3cf083-ea9c-54f5-b42b-bf1fef5b2978","title":"Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"0b51d0759aeeb88ac5b3a6277245a196b2bb024d7c32ec89379ed428fb06bfb5","revision_id":"0405c75e-f06e-5af7-a642-1777802f6004","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}