{"id":"8ac55fea-e0a1-5f3f-8995-c67ed6dcb667","stable_key":"09b23d0d-35e2-51ff-b1aa-b4f9227e4fa2:isoleucine-iars2-respiration","predicate":"supports","statement":"IARS2 knockdown and patient variants impaired respiratory complexes I and III; wild-type, but not tested mutant, IARS2 rescued respiration and ATP in knockdown cells.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"c66f893d-de5f-5b93-9296-eb732171178a","mechanism_event_label":"Mitochondria need their own isoleucine-charging machinery.","subject":{"id":"e36465cc-0273-5680-94cd-4111ee6675c0","slug":"iars2","display_name":"Human mitochondrial isoleucyl-tRNA synthetase / IARS2","entity_type_key":"protein"},"object":{"id":"4785c5d5-78e7-5530-b00a-36ca270c64e8","slug":"human-iars2-dependent-oxphos","display_name":"Mitochondrial respiratory function dependent on human IARS2","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"c66f893d-de5f-5b93-9296-eb732171178a","stable_key":"09b23d0d-35e2-51ff-b1aa-b4f9227e4fa2:isoleucine-iars2-respiration-event","event_type":"observed_relationship","label":"Mitochondria need their own isoleucine-charging machinery.","description":"IARS2 knockdown and patient variants impaired respiratory complexes I and III; wild-type, but not tested mutant, IARS2 rescued respiration and ATP in knockdown cells.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e36465cc-0273-5680-94cd-4111ee6675c0","slug":"iars2","display_name":"Human mitochondrial isoleucyl-tRNA synthetase / IARS2","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"4785c5d5-78e7-5530-b00a-36ca270c64e8","slug":"human-iars2-dependent-oxphos","display_name":"Mitochondrial respiratory function dependent on human IARS2","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c85b327e-f132-5d9a-8e4b-c2976fcc0373","slug":"isoleucine","display_name":"L-Isoleucine","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"58b974f1-d389-5bf6-81cd-889c44442c42","slug":"atp","display_name":"ATP","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_access","value_text":"Primary abstract","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"isoleucine","display_name":"L-Isoleucine","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"Mitochondria need their own isoleucine-charging machinery.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x","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":"c7fd03b5-db28-5c6d-81f4-99dd91c6c71c","evidence_kind":"source_excerpt","locator":"Lines 154-160","start_line":154,"end_line":160,"excerpt":"## isoleucine-iars2-respiration\nMitochondria need their own isoleucine-charging machinery.\nIARS2 knockdown and patient variants impaired respiratory complexes I and III; wild-type, but not tested mutant, IARS2 rescued respiration and ATP in knockdown cells.\nModel: Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue.\nLimitations: No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation.\nEvidence access: Primary abstract\nIARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x","model_system":"Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Original curation paraphrase; evidence access and experimental limitations specified.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"4b00f118-00fd-5cef-be97-13125eb958e9","stable_key":"import-09b23d0d-35e2-51ff-b1aa-b4f9227e4fa2","title":"L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted research curation; primary references, access levels and experimental limitations individually identified. 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