{"gene":"ATP5F1A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1994,"finding":"Crystal structure of bovine mitochondrial F1-ATPase at 2.8 Å resolution revealed that the three catalytic β-subunits differ in conformation and bound nucleotide, and that the α-subunit (ATP5F1A ortholog) participates in an α3β3 subassembly whose rotation relative to the γ-subunit drives the catalytic cycle, supporting a rotary mechanism for ATP synthesis.","method":"X-ray crystallography at 2.8 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution crystal structure of the functional complex, foundational mechanistic study replicated extensively","pmids":["8065448"],"is_preprint":false},{"year":1999,"finding":"The α-subunit of ATP synthase (ATP5F1A) is present on the surface of human umbilical vein endothelial cells, where it binds angiostatin (a proteolytic fragment of plasminogen) in a concentration-dependent, saturable, plasminogen-independent manner; antibody blockade of the α-subunit inhibited angiostatin's antiproliferative effect on endothelial cells by up to 90%, establishing cell-surface ATP5F1A as a functional mediator of angiostatin's antiangiogenic activity.","method":"Ligand blot of plasma membrane fractions, amino-terminal sequencing, peptide mass fingerprinting, binding assays with recombinant α-subunit, flow cytometry, immunofluorescence, anti-α-subunit antibody functional blockade","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (biochemical fractionation, recombinant protein binding, antibody inhibition of functional effect) in a single rigorous study","pmids":["10077593"],"is_preprint":false},{"year":2021,"finding":"A recurrent de novo heterozygous missense substitution c.620G>A [p.(Arg207His)] in ATP5F1A causes neonatal-onset complex V deficiency; patient-derived fibroblasts showed multiple deficits in complex V function and expression in vitro, and structural modelling predicts the substitution creates an abnormal negative-charge region on ATP5F1A's β-subunit-interacting surface adjacent to the active site, disrupting normal α–β subunit interaction.","method":"Exome sequencing, functional assays in patient-derived fibroblasts (complex V activity and expression), structural modelling","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — patient fibroblast biochemical validation plus structural modelling; single study","pmids":["34483339"],"is_preprint":false},{"year":2022,"finding":"The non-receptor tyrosine kinase TNK2/ACK1 directly phosphorylates ATP5F1A at Tyr243 and Tyr246 (Tyr200 and Tyr203 in the mature protein); this phosphorylation increases complex V stability and mitochondrial energy output in prostate cancer cells, and prevents ATP5F1A from binding its physiological inhibitor ATP5IF1, thereby sustaining mitochondrial activity to promote cancer cell growth. TNK2 inhibitor (R)-9b reversed this phosphorylation, induced mitophagy, and suppressed prostate tumor growth. Transgenic Tnk2 mice displayed increased p-Y-ATP5F1A and loss of mitophagy.","method":"Kinase assay, site-directed mutagenesis (Y243/246A mutant), Co-IP, mitochondrial function assays, Tnk2 transgenic mouse model, tumor xenograft experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — direct kinase assay with mutagenesis, Co-IP of ATP5F1A–ATP5IF1 interaction, in vivo transgenic validation; multiple orthogonal methods","pmids":["35895804"],"is_preprint":false},{"year":2022,"finding":"Fucoidan from Fucus vesiculosus (FvF) exerts neuroprotective effects in an MPTP-induced Parkinson's disease mouse model by targeting ATP5F1a as a key protein responsible for alleviating mitochondrial dysfunction, preventing neuronal apoptosis and dopaminergic neuron loss.","method":"MPTP mouse model, mechanistic investigation identifying ATP5F1a as FvF target (binding/functional assays), mitochondrial function assessment","journal":"Carbohydrate polymers","confidence":"Low","confidence_rationale":"Tier 3 — target identification described but mechanistic details of ATP5F1a–FvF interaction not fully characterized in the abstract; single study","pmids":["36657849"],"is_preprint":false},{"year":2023,"finding":"The HECT-type E3 ubiquitin ligase WWP2 ubiquitinates ATP5F1A (ATP synthase mitochondrial F1 complex subunit alpha), targeting it for proteasomal degradation; atorvastatin upregulates WWP2, leading to ATP5F1A degradation that stabilizes the Bcl-2/Bax ratio in the mitochondrial apoptosis pathway, thereby protecting vascular endothelial cells from angiotensin II-induced injury in hypertension.","method":"Ubiquitination assay, proteasome pathway inhibition, WWP2 overexpression/knockout (including endothelial cell-specific KO mice), Western blot, in vivo hypertension model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay plus in vivo conditional KO validation; single lab","pmids":["37557013"],"is_preprint":false},{"year":2024,"finding":"The chimeric RNA SFT2D2-TBX19 functions as a lncRNA that interacts with ATP5F1A and increases TNK2/ACK1-mediated phosphorylation of ATP5F1A, which stabilizes the interaction between ATP5F1A and ATP5F1B (β-subunit), thereby enhancing mitochondrial ATP synthase activity and ATP production to support prostate cancer cell proliferation. The region spanning 1801–2400 bp of SFT2D2-TBX19 and the intermediate structural domain of ATP5F1A are the key functional areas.","method":"RNA-protein interaction assays, Co-IP of ATP5F1A–ATP5F1B, phosphorylation assays, ATP synthase activity assay, domain mapping","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and functional activity assays with domain mapping; single lab, partially builds on prior TNK2 finding","pmids":["39540264"],"is_preprint":false},{"year":2024,"finding":"Overexpression of ATP5F1A specifically in cardiomyocytes (via adeno-associated virus 9) improved heart function and morphology, and reduced fibrosis and cardiomyocyte size in transverse aortic constriction and dilated cardiomyopathy heart failure mouse models, establishing ATP5F1A as a mediator of cardiac reverse remodeling.","method":"Single-nucleus RNA sequencing of human cardiac tissue, cardiomyocyte-specific AAV9 overexpression in mouse heart failure models, echocardiography, pathological staining","journal":"Circulation. Heart failure","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gene overexpression with defined cardiac phenotype; single study","pmids":["38910562"],"is_preprint":false},{"year":2025,"finding":"A de novo missense variant (c.1252G>A, p.Gly418Arg) in ATP5F1A reduces protein stability and expression without affecting mitochondrial localization. In zebrafish, atp5fa1 knockdown caused growth retardation, motor dysfunction, and impaired motor neuron axon development; rescue with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Knockdown increased P62 and decreased Lc3b-II expression, suggesting inhibition of autophagy as a pathomechanism.","method":"Whole-exome sequencing, HEK293T transfection (Western blot, immunofluorescence), morpholino knockdown in zebrafish, behavioral assays, RNA sequencing, qPCR, Western blot","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — zebrafish model with rescue experiment and autophagy pathway analysis; single study","pmids":["41053757"],"is_preprint":false},{"year":2025,"finding":"Six heterozygous de novo missense variants in ATP5F1A cause a dominant negative disruption of complex V: functional evaluation in C. elegans confirmed dominant negative mechanism; biochemical/proteomics studies in proband-derived blood cells and fibroblasts showed marked reduction in complex V abundance and activity; mitochondrial physiology studies revealed increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation as the pathophysiologic mechanism. This differs from the previously reported p.Arg207His variant mechanism.","method":"C. elegans dominant negative functional assay, quantitative proteomics, complex V activity assay, mitochondrial membrane potential and ATP measurement, oxygen consumption rate in fibroblasts","journal":"medRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods in patient-derived cells plus C. elegans in vivo validation; preprint not yet peer-reviewed","pmids":["40672495"],"is_preprint":true},{"year":2026,"finding":"SIRT3 (sirtuin 3) deacetylates ATP5F1A at lysine 498; LPS-induced acetylation of K498 on ATP5F1A impairs PRKN/parkin-dependent mitophagy. SIGMAR1 activation promotes SIRT3-mediated deacetylation of ATP5F1A at K498, which is required for SIGMAR1-mediated mitophagy and protection against endothelial ferroptosis and microvascular hyperpermeability in acute lung injury.","method":"Site-specific acetylation analysis (K498), SIRT3 KO and activation, siRNA knockdown of ATP5F1A, mitophagy assays (GFP-LC3, Western blot for P62/LC3), cell viability/ferroptosis assays, in vivo ALI mouse model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific PTM identification with genetic KO and siRNA validation in vitro and in vivo; single lab, not yet replicated","pmids":["41655128"],"is_preprint":false},{"year":2025,"finding":"DDIT4L (DNA damage-inducible transcript 4-like) is transported into mitochondria via TOM40 and directly interacts with the α-subunit of ATP synthase (ATP5F1A/ATP5A), inhibiting mitochondrial function and inducing tumor cell apoptosis in glioblastoma; a synthetic peptide DDIT4L V125–P132 recapitulated this tumor-suppressive effect.","method":"Lentiviral overexpression, PDX mouse model, co-immunoprecipitation of DDIT4L with ATP synthase α-subunit, mitochondrial function assays, apoptosis assays, synthetic peptide functional validation","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and functional assays in cancer model; preprint, single lab, not peer-reviewed","pmids":["bio_10.1101_2025.07.27.666981"],"is_preprint":true}],"current_model":"ATP5F1A (the α-subunit of mitochondrial complex V / F1-ATPase) forms the catalytic α3β3 core of ATP synthase whose rotation-driven conformational changes synthesize ATP; it is also present on the endothelial cell surface where it binds angiostatin to mediate antiangiogenic signaling. Its activity is regulated by multiple post-translational modifications: TNK2/ACK1-mediated phosphorylation at Tyr243/246 stabilizes complex V and blocks its inhibitor ATP5IF1, SIRT3-mediated deacetylation at Lys498 promotes mitophagy, and WWP2-mediated ubiquitination targets it for proteasomal degradation; pathogenic de novo missense variants cause complex V deficiency through dominant-negative disruption of oxidative phosphorylation or disruption of α–β subunit interactions, leading to developmental and neurological disorders."},"narrative":{"teleology":[{"year":1994,"claim":"Determination of how the α-subunit participates in catalysis: the 2.8 Å crystal structure of bovine F1-ATPase revealed that the α3β3 hexamer adopts asymmetric conformations around the central γ-shaft, establishing the rotary catalytic mechanism for ATP synthesis and defining the structural role of the α-subunit.","evidence":"X-ray crystallography of bovine mitochondrial F1-ATPase at 2.8 Å resolution","pmids":["8065448"],"confidence":"High","gaps":["Post-translational regulation of the α-subunit was not addressed","No information on potential non-mitochondrial localization or function"]},{"year":1999,"claim":"Discovery that ATP5F1A has an extramitochondrial role: identification of the α-subunit on the endothelial cell surface as the functional receptor for angiostatin established a moonlighting function independent of mitochondrial ATP synthesis.","evidence":"Ligand blot, mass spectrometry, flow cytometry, and antibody-blockade experiments in human endothelial cells","pmids":["10077593"],"confidence":"High","gaps":["Mechanism of ATP5F1A trafficking to the plasma membrane remains undefined","Whether cell-surface ATP synthase is catalytically active was not resolved"]},{"year":2021,"claim":"First genetic link of ATP5F1A to human disease: a recurrent de novo p.Arg207His variant was shown to cause neonatal complex V deficiency by disrupting the α–β subunit interface, demonstrating that single missense changes can dominantly impair oxidative phosphorylation.","evidence":"Exome sequencing, biochemical assays in patient-derived fibroblasts, and structural modelling","pmids":["34483339"],"confidence":"Medium","gaps":["Only one recurrent variant characterized; spectrum of pathogenic variants unknown","No rescue or complementation experiment performed"]},{"year":2022,"claim":"Identification of a kinase-mediated regulatory switch on ATP5F1A: TNK2/ACK1 phosphorylates Tyr243/Tyr246, stabilizing complex V and preventing ATP5IF1 binding, thereby linking tyrosine kinase signaling to mitochondrial energy output and mitophagy control in cancer.","evidence":"In vitro kinase assay, site-directed mutagenesis, Co-IP, transgenic mouse model, and xenograft experiments in prostate cancer","pmids":["35895804"],"confidence":"High","gaps":["Structural basis for how phosphorylation blocks ATP5IF1 binding not determined","Relevance of this phosphorylation outside prostate cancer cells not tested"]},{"year":2023,"claim":"Ubiquitin-dependent turnover of ATP5F1A was established: WWP2 ubiquitinates ATP5F1A for proteasomal degradation, connecting complex V abundance to an endothelial protective pathway in hypertension.","evidence":"Ubiquitination assay, proteasome inhibition, endothelial-specific WWP2 knockout mice, and in vivo hypertension model","pmids":["37557013"],"confidence":"Medium","gaps":["Specific ubiquitination sites on ATP5F1A not mapped","Whether WWP2-mediated regulation occurs in non-endothelial cell types is unknown"]},{"year":2024,"claim":"A chimeric lncRNA (SFT2D2-TBX19) was shown to scaffold the TNK2-ATP5F1A interaction, mapping the functional domain on ATP5F1A and demonstrating that RNA-protein complexes modulate ATP synthase phosphorylation and α–β subunit stability.","evidence":"RNA-protein interaction assays, Co-IP of ATP5F1A–ATP5F1B, phosphorylation assays, and domain mapping in prostate cancer cells","pmids":["39540264"],"confidence":"Medium","gaps":["Physiological relevance of SFT2D2-TBX19 outside prostate cancer is unclear","No structural data on the RNA–ATP5F1A interface"]},{"year":2024,"claim":"Cardiomyocyte-specific overexpression of ATP5F1A reversed cardiac remodeling in heart failure models, establishing ATP5F1A levels as limiting for cardiac bioenergetics and function.","evidence":"AAV9-mediated cardiomyocyte-specific overexpression in TAC and DCM mouse models, echocardiography, histology","pmids":["38910562"],"confidence":"Medium","gaps":["Mechanism linking ATP5F1A restoration to reduced fibrosis not delineated","Long-term effects and safety not evaluated"]},{"year":2025,"claim":"Expanded genetic evidence confirmed dominant-negative pathogenicity: six additional de novo ATP5F1A missense variants caused complex V deficiency with uncoupled oxidative phosphorylation, and zebrafish knockdown linked ATP5F1A loss to motor neuron axon defects and impaired autophagy.","evidence":"C. elegans dominant-negative assay, quantitative proteomics, patient fibroblast bioenergetics (preprint); zebrafish morpholino knockdown with mRNA rescue, autophagy marker analysis","pmids":["41053757","40672495"],"confidence":"Medium","gaps":["Preprint data (PMID:40672495) not yet peer-reviewed","Autophagy impairment mechanism downstream of ATP5F1A loss not fully characterized","Genotype–phenotype correlation across all known variants not systematically established"]},{"year":2026,"claim":"A deacetylation-dependent mitophagy switch was identified: SIRT3 deacetylates ATP5F1A at Lys498 to enable PRKN-dependent mitophagy, linking acetylation status of ATP5F1A to ferroptosis resistance and microvascular integrity in acute lung injury.","evidence":"Site-specific acetylation analysis, SIRT3 knockout and activation, siRNA knockdown, mitophagy and ferroptosis assays, in vivo acute lung injury mouse model","pmids":["41655128"],"confidence":"Medium","gaps":["How K498 deacetylation mechanistically activates PRKN recruitment is not defined","Not yet replicated independently"]},{"year":null,"claim":"Key unresolved questions include how ATP5F1A traffics to the plasma membrane, the structural basis for how individual post-translational modifications (phosphorylation, acetylation, ubiquitination) cooperate to regulate complex V assembly and turnover, and comprehensive genotype–phenotype maps for disease-causing variants.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural data showing how Tyr243/246 phosphorylation or K498 acetylation alter complex V conformation","Mechanism of ATP5F1A targeting to the cell surface is unknown","Crosstalk among phosphorylation, acetylation, and ubiquitination on ATP5F1A is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,3,6,7,8,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,8,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,8,9]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,3]}],"complexes":["F1-Fo ATP synthase (complex V)","F1-ATPase α3β3γ subcomplex"],"partners":["ATP5F1B","TNK2","ATP5IF1","WWP2","SIRT3","PRKN"],"other_free_text":[]},"mechanistic_narrative":"ATP5F1A encodes the α-subunit of the mitochondrial F1-Fo ATP synthase (complex V), forming the α3β3 catalytic hexamer whose rotation-driven conformational changes couple the proton-motive force to ATP synthesis [PMID:8065448]. Beyond oxidative phosphorylation, ATP5F1A resides on the endothelial cell surface where it serves as a functional receptor for angiostatin, mediating its antiproliferative, antiangiogenic activity [PMID:10077593]. Complex V stability and mitophagy are regulated through post-translational modifications of ATP5F1A: TNK2/ACK1-mediated phosphorylation at Tyr243/Tyr246 stabilizes the complex and blocks the inhibitor ATP5IF1 [PMID:35895804], SIRT3-mediated deacetylation at Lys498 promotes PRKN-dependent mitophagy [PMID:41655128], and WWP2-mediated ubiquitination targets ATP5F1A for proteasomal degradation [PMID:37557013]. De novo heterozygous missense variants in ATP5F1A cause complex V deficiency through dominant-negative disruption of oxidative phosphorylation, leading to neonatal-onset developmental and neurological disease [PMID:34483339, PMID:41053757]."},"prefetch_data":{"uniprot":{"accession":"P25705","full_name":"ATP synthase F(1) complex subunit alpha, mitochondrial","aliases":["ATP synthase F1 subunit alpha"],"length_aa":553,"mass_kda":59.8,"function":"Subunit alpha, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain (Probable). ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel (PubMed:37244256). These two domains are linked by a central stalk rotating inside the F(1) region and a stationary peripheral stalk (PubMed:37244256). During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation (Probable). In vivo, can only synthesize ATP although its ATP hydrolase activity can be activated artificially in vitro (By similarity). With the catalytic subunit beta (ATP5F1B), forms the catalytic core in the F(1) domain (PubMed:37244256). Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (Probable). Binds the bacterial siderophore enterobactin and can promote mitochondrial accumulation of enterobactin-derived iron ions (PubMed:30146159)","subcellular_location":"Mitochondrion; Mitochondrion inner membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25705/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP5F1A","classification":"Common Essential","n_dependent_lines":746,"n_total_lines":1208,"dependency_fraction":0.6175496688741722},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP5F1A","total_profiled":1310},"omim":[{"mim_id":"620358","title":"MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 4A; MC5DN4A","url":"https://www.omim.org/entry/620358"},{"mim_id":"620079","title":"LONG INTERGENIC NONCODING RNA 467; LINC00467","url":"https://www.omim.org/entry/620079"},{"mim_id":"617400","title":"EPOXIDE HYDROLASE 3; EPHX3","url":"https://www.omim.org/entry/617400"},{"mim_id":"616045","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 22; COXPD22","url":"https://www.omim.org/entry/616045"},{"mim_id":"615228","title":"MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 4B; MC5DN4B","url":"https://www.omim.org/entry/615228"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":1644.4}],"url":"https://www.proteinatlas.org/search/ATP5F1A"},"hgnc":{"alias_symbol":["ATP5A","hATP1","OMR","ORM"],"prev_symbol":["ATP5AL2","ATPM","ATP5A1"]},"alphafold":{"accession":"P25705","domains":[{"cath_id":"2.40.30.20","chopping":"53-138","consensus_level":"high","plddt":87.9401,"start":53,"end":138},{"cath_id":"3.40.50.300","chopping":"152-171_185-422","consensus_level":"high","plddt":96.0365,"start":152,"end":422},{"cath_id":"1.20.150.20","chopping":"426-549","consensus_level":"high","plddt":92.4126,"start":426,"end":549}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25705","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25705-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25705-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP5F1A","jax_strain_url":"https://www.jax.org/strain/search?query=ATP5F1A"},"sequence":{"accession":"P25705","fasta_url":"https://rest.uniprot.org/uniprotkb/P25705.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25705/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25705"}},"corpus_meta":[{"pmid":"20182505","id":"PMC_20182505","title":"Orm 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purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14744259","citation_count":372,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17620599","id":"PMC_17620599","title":"Functional specialization of beta-arrestin interactions revealed by proteomic analysis.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17620599","citation_count":360,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21575865","id":"PMC_21575865","title":"Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/21575865","citation_count":356,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36123,"output_tokens":2433,"usd":0.072432},"stage2":{"model":"claude-opus-4-6","input_tokens":5742,"output_tokens":2205,"usd":0.125752},"total_usd":0.462497,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":48954,"output_tokens":4335,"usd":0.105943},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7206,"output_tokens":2782,"usd":0.15837}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"TNK2/ACK1 (tyrosine kinase non-receptor 2) phosphorylates ATP5F1A at Tyr243 and Tyr246 (Tyr200 and Tyr203 in the mature protein), which increases stability of mitochondrial complex V and mitochondrial energy output in prostate cancer cells. Phospho-ATP5F1A also prevents binding of its physiological inhibitor ATP5IF1, causing sustained mitochondrial activity.\",\n      \"method\": \"In vitro kinase assays, site-directed mutagenesis (Y243,246A mutant), Co-IP, TNK2 inhibitor treatment, Tnk2 transgenic mouse model, mitophagy phenotype readout\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis, Co-IP, transgenic mouse model, and functional rescue; single lab but strong mechanistic depth\",\n      \"pmids\": [\"35895804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A recurrent de novo heterozygous substitution c.620G>A [p.(Arg207His)] in ATP5F1A causes neonatal-onset complex V deficiency. Patient-derived fibroblasts exhibited multiple deficits in complex V function and expression. Structural modelling predicts the substitution creates an abnormal region of negative charge on ATP5F1A's β-subunit-interacting surface, adjacent to the β-subunit's active site.\",\n      \"method\": \"Exome sequencing, patient-derived fibroblast functional assays (complex V activity and expression), structural modelling\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cell functional data with structural modelling, but single study without in vitro reconstitution or mutagenesis rescue\",\n      \"pmids\": [\"34483339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WWP2, a HECT-type E3 ubiquitin ligase, ubiquitinates ATP5F1A (ATP synthase mitochondrial F1 complex subunit alpha) leading to its degradation via the proteasome pathway, thereby stabilizing the Bcl-2/Bax ratio in the mitochondrial apoptosis pathway. Atorvastatin upregulates WWP2, promoting this degradation to protect vascular endothelial cells.\",\n      \"method\": \"Co-IP, WWP2 knockout mice (endothelial cell-specific), overexpression experiments, proteasome inhibitor treatment, in vivo vascular injury model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and tissue-specific KO with defined phenotype, single lab\",\n      \"pmids\": [\"37557013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chimeric RNA SFT2D2-TBX19 acts as a lncRNA that interacts with ATP5F1A and increases ATP5F1A phosphorylation mediated by TNK2/ACK1, stabilizing the interaction between ATP5F1A and ATP5F1B (β-subunit), thereby enhancing mitochondrial ATP synthase activity and ATP production in prostate cancer cells.\",\n      \"method\": \"RNA pulldown, Co-IP, phosphorylation assays, ATP synthase activity assays, domain deletion mapping\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, RNA-protein interaction assays, domain mapping, functional ATP production readout; single lab\",\n      \"pmids\": [\"39540264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Heterozygous de novo missense variants in ATP5F1A cause dominant negative disruption of complex V, with biochemical and proteomic studies showing marked reduction in complex V abundance and activity. Mitochondrial physiology studies in patient fibroblasts revealed increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation as the pathophysiologic mechanism.\",\n      \"method\": \"C. elegans dominant negative functional assays, patient-derived blood cell and fibroblast biochemistry, proteomics, mitochondrial membrane potential and oxygen consumption measurements\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (C. elegans genetics, biochemistry, proteomics, mitochondrial physiology), multi-proband study; preprint\",\n      \"pmids\": [\"40672495\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATP5F1A knockdown in zebrafish causes growth retardation, motor dysfunction, and impaired motor neuron axon development. A de novo missense mutation (p.Gly418Arg) reduces protein stability and expression. Rescue with wild-type human ATP5F1A mRNA partially restores motor neuron morphology. Transcriptomic analysis identified downregulation of autophagy-related genes (apln, becn1, map1lc3b) with increased P62 and decreased Lc3b-II, suggesting ATP5F1A dysfunction inhibits autophagy.\",\n      \"method\": \"Morpholino knockdown in zebrafish, wild-type mRNA rescue experiments, Western blot, immunofluorescence, RNA sequencing, qPCR\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — zebrafish KD with mRNA rescue, transcriptomic and protein-level mechanistic follow-up, single lab\",\n      \"pmids\": [\"41053757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP5F1A overexpression via cardiomyocyte-specific adeno-associated virus 9 in transverse aortic constriction and dilated cardiomyopathy heart failure mouse models improved heart function, reduced fibrosis, and reduced cardiomyocyte size, identifying ATP5F1A as a mediator of cardiac reverse remodeling.\",\n      \"method\": \"Single-nucleus RNA sequencing, cardiomyocyte-specific AAV9 overexpression, echocardiography, pathological staining in mouse heart failure models\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific overexpression with defined cardiac phenotype readout, corroborated by single-nucleus RNA-seq; single lab\",\n      \"pmids\": [\"38910562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT3 deacetylates ATP5F1A at lysine 498; acetylation of this site is induced by LPS. Deacetylation of ATP5F1A at K498 by SIRT3 is required for SIGMAR1-mediated PRKN/parkin-dependent mitophagy in endothelial cells, protecting against ferroptosis and microvascular hyperpermeability in acute lung injury.\",\n      \"method\": \"SIGMAR1 knockout mice, SIRT3 inhibition/activation, siRNA knockdown of ATP5F1A, co-immunoprecipitation, acetylation site-specific analysis, mitophagy assays (GFP-LC3, Western blot for P62/LC3), ferroptosis assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific acetylation at K498 identified, genetic and pharmacological manipulation of SIRT3 with functional mitophagy/ferroptosis readout; single lab\",\n      \"pmids\": [\"41655128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The functional ATP5F1A (ATP5A) gene maps to chromosome 18q12→q21 by FISH and CGH analysis. A pseudogene (ATP5AP1) maps to 9p12. The functional gene on 18q was identified as amplified in the retinoblastoma cell line Y79.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct FISH and CGH localization to specific chromosomal band; single study\",\n      \"pmids\": [\"9284928\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP5F1A encodes the α-subunit of mitochondrial complex V (ATP synthase), where it participates in ATP synthesis; its activity is regulated by TNK2/ACK1-mediated phosphorylation at Tyr243/246 (which enhances complex V stability and blocks inhibitor ATP5IF1 binding), by SIRT3-mediated deacetylation at Lys498 (which promotes mitophagy), and by WWP2-mediated ubiquitination and proteasomal degradation; pathogenic heterozygous missense mutations cause dominant negative complex V deficiency with uncoupled oxidative phosphorylation leading to neurodevelopmental disorders.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers about ORM/ORMDL (sphingolipid regulators), orosomucoid (alpha-1-acid glycoprotein), ORM pharmacological compounds (ORM-10921, ORM-13070, ORM-10103, ORM-10962, ORM-3819, ORM-15341), orchid mycorrhizal fungi, optomotor response (OMR), ormeloxifene (ORM), optical reflectance method (3D-ORM): **EXCLUDE** (alias collision)\n- Papers about ATP5F1A (ATP synthase F1 subunit alpha, the canonical protein): **KEEP**\n- Large proteomics/interactome surveys that incidentally list ATP5F1A: these are not mechanistic findings about ATP5F1A specifically → **EXCLUDE** (no mechanistic finding about the specific gene)\n- Papers about ATP5A/ATP5F1A structure, function, PTMs, disease variants: **KEEP**\n\n**KEEP list:**\n- PMID:35895804 (TNK2/ACK1 phosphorylation of ATP5F1A)\n- PMID:8065448 (F1-ATPase crystal structure — bovine ortholog, foundational)\n- PMID:10077593 (Angiostatin binds ATP synthase alpha-subunit on endothelial cell surface)\n- PMID:34483339 (de novo ATP5F1A variant, complex V deficiency)\n- PMID:40672495 (dominant negative ATP5F1A variants, neurological disorders — preprint)\n- PMID:41053757 (ATP5F1A deficiency, zebrafish model)\n- PMID:38910562 (Overexpression of ATP5F1A in cardiomyocytes)\n- PMID:37557013 (WWP2 ubiquitination of ATP5A)\n- PMID:36657849 (Fucoidan targets ATP5F1a)\n- PMID:39540264 (Chimeric SFT2D2-TBX19 / ATP5F1A phosphorylation)\n- PMID:41655128 (SIRT3 deacetylation of ATP5F1A at K498)\n- PMID:9284928 (ATP5A gene mapping — FISH/CGH, chromosomal localization, not mechanistic function) → **EXCLUDE** (no mechanistic finding)\n- PMID:30538797 (reduced ATP5F1A levels in prostate cancer — correlative/IHC) → **EXCLUDE**\n- PMID:38016997 (proteomics identifying ATP5A overexpressed in metastases — correlative) → **EXCLUDE**\n- bio_10.1101_2025.07.27.666981 (DDIT4L interacts with ATP synthase alpha subunit in GBM — preprint, mechanistic) → **KEEP**\n- PMID:42033056 (generative peptides targeting ATP5A — computational/therapeutic, no direct mechanistic experiment on ATP5F1A) → **EXCLUDE**\n- PMID:41743395 (case report, ATP5F1A mutation, no new mechanism) → **EXCLUDE**\n- Large interactome papers (BioPlex, etc.) — no specific mechanistic findings about ATP5F1A → **EXCLUDE**\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Crystal structure of bovine mitochondrial F1-ATPase at 2.8 Å resolution revealed that the three catalytic β-subunits differ in conformation and bound nucleotide, and that the α-subunit (ATP5F1A ortholog) participates in an α3β3 subassembly whose rotation relative to the γ-subunit drives the catalytic cycle, supporting a rotary mechanism for ATP synthesis.\",\n      \"method\": \"X-ray crystallography at 2.8 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure of the functional complex, foundational mechanistic study replicated extensively\",\n      \"pmids\": [\"8065448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The α-subunit of ATP synthase (ATP5F1A) is present on the surface of human umbilical vein endothelial cells, where it binds angiostatin (a proteolytic fragment of plasminogen) in a concentration-dependent, saturable, plasminogen-independent manner; antibody blockade of the α-subunit inhibited angiostatin's antiproliferative effect on endothelial cells by up to 90%, establishing cell-surface ATP5F1A as a functional mediator of angiostatin's antiangiogenic activity.\",\n      \"method\": \"Ligand blot of plasma membrane fractions, amino-terminal sequencing, peptide mass fingerprinting, binding assays with recombinant α-subunit, flow cytometry, immunofluorescence, anti-α-subunit antibody functional blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (biochemical fractionation, recombinant protein binding, antibody inhibition of functional effect) in a single rigorous study\",\n      \"pmids\": [\"10077593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A recurrent de novo heterozygous missense substitution c.620G>A [p.(Arg207His)] in ATP5F1A causes neonatal-onset complex V deficiency; patient-derived fibroblasts showed multiple deficits in complex V function and expression in vitro, and structural modelling predicts the substitution creates an abnormal negative-charge region on ATP5F1A's β-subunit-interacting surface adjacent to the active site, disrupting normal α–β subunit interaction.\",\n      \"method\": \"Exome sequencing, functional assays in patient-derived fibroblasts (complex V activity and expression), structural modelling\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient fibroblast biochemical validation plus structural modelling; single study\",\n      \"pmids\": [\"34483339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The non-receptor tyrosine kinase TNK2/ACK1 directly phosphorylates ATP5F1A at Tyr243 and Tyr246 (Tyr200 and Tyr203 in the mature protein); this phosphorylation increases complex V stability and mitochondrial energy output in prostate cancer cells, and prevents ATP5F1A from binding its physiological inhibitor ATP5IF1, thereby sustaining mitochondrial activity to promote cancer cell growth. TNK2 inhibitor (R)-9b reversed this phosphorylation, induced mitophagy, and suppressed prostate tumor growth. Transgenic Tnk2 mice displayed increased p-Y-ATP5F1A and loss of mitophagy.\",\n      \"method\": \"Kinase assay, site-directed mutagenesis (Y243/246A mutant), Co-IP, mitochondrial function assays, Tnk2 transgenic mouse model, tumor xenograft experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct kinase assay with mutagenesis, Co-IP of ATP5F1A–ATP5IF1 interaction, in vivo transgenic validation; multiple orthogonal methods\",\n      \"pmids\": [\"35895804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fucoidan from Fucus vesiculosus (FvF) exerts neuroprotective effects in an MPTP-induced Parkinson's disease mouse model by targeting ATP5F1a as a key protein responsible for alleviating mitochondrial dysfunction, preventing neuronal apoptosis and dopaminergic neuron loss.\",\n      \"method\": \"MPTP mouse model, mechanistic investigation identifying ATP5F1a as FvF target (binding/functional assays), mitochondrial function assessment\",\n      \"journal\": \"Carbohydrate polymers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — target identification described but mechanistic details of ATP5F1a–FvF interaction not fully characterized in the abstract; single study\",\n      \"pmids\": [\"36657849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The HECT-type E3 ubiquitin ligase WWP2 ubiquitinates ATP5F1A (ATP synthase mitochondrial F1 complex subunit alpha), targeting it for proteasomal degradation; atorvastatin upregulates WWP2, leading to ATP5F1A degradation that stabilizes the Bcl-2/Bax ratio in the mitochondrial apoptosis pathway, thereby protecting vascular endothelial cells from angiotensin II-induced injury in hypertension.\",\n      \"method\": \"Ubiquitination assay, proteasome pathway inhibition, WWP2 overexpression/knockout (including endothelial cell-specific KO mice), Western blot, in vivo hypertension model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay plus in vivo conditional KO validation; single lab\",\n      \"pmids\": [\"37557013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The chimeric RNA SFT2D2-TBX19 functions as a lncRNA that interacts with ATP5F1A and increases TNK2/ACK1-mediated phosphorylation of ATP5F1A, which stabilizes the interaction between ATP5F1A and ATP5F1B (β-subunit), thereby enhancing mitochondrial ATP synthase activity and ATP production to support prostate cancer cell proliferation. The region spanning 1801–2400 bp of SFT2D2-TBX19 and the intermediate structural domain of ATP5F1A are the key functional areas.\",\n      \"method\": \"RNA-protein interaction assays, Co-IP of ATP5F1A–ATP5F1B, phosphorylation assays, ATP synthase activity assay, domain mapping\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and functional activity assays with domain mapping; single lab, partially builds on prior TNK2 finding\",\n      \"pmids\": [\"39540264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of ATP5F1A specifically in cardiomyocytes (via adeno-associated virus 9) improved heart function and morphology, and reduced fibrosis and cardiomyocyte size in transverse aortic constriction and dilated cardiomyopathy heart failure mouse models, establishing ATP5F1A as a mediator of cardiac reverse remodeling.\",\n      \"method\": \"Single-nucleus RNA sequencing of human cardiac tissue, cardiomyocyte-specific AAV9 overexpression in mouse heart failure models, echocardiography, pathological staining\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gene overexpression with defined cardiac phenotype; single study\",\n      \"pmids\": [\"38910562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo missense variant (c.1252G>A, p.Gly418Arg) in ATP5F1A reduces protein stability and expression without affecting mitochondrial localization. In zebrafish, atp5fa1 knockdown caused growth retardation, motor dysfunction, and impaired motor neuron axon development; rescue with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Knockdown increased P62 and decreased Lc3b-II expression, suggesting inhibition of autophagy as a pathomechanism.\",\n      \"method\": \"Whole-exome sequencing, HEK293T transfection (Western blot, immunofluorescence), morpholino knockdown in zebrafish, behavioral assays, RNA sequencing, qPCR, Western blot\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — zebrafish model with rescue experiment and autophagy pathway analysis; single study\",\n      \"pmids\": [\"41053757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Six heterozygous de novo missense variants in ATP5F1A cause a dominant negative disruption of complex V: functional evaluation in C. elegans confirmed dominant negative mechanism; biochemical/proteomics studies in proband-derived blood cells and fibroblasts showed marked reduction in complex V abundance and activity; mitochondrial physiology studies revealed increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation as the pathophysiologic mechanism. This differs from the previously reported p.Arg207His variant mechanism.\",\n      \"method\": \"C. elegans dominant negative functional assay, quantitative proteomics, complex V activity assay, mitochondrial membrane potential and ATP measurement, oxygen consumption rate in fibroblasts\",\n      \"journal\": \"medRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods in patient-derived cells plus C. elegans in vivo validation; preprint not yet peer-reviewed\",\n      \"pmids\": [\"40672495\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT3 (sirtuin 3) deacetylates ATP5F1A at lysine 498; LPS-induced acetylation of K498 on ATP5F1A impairs PRKN/parkin-dependent mitophagy. SIGMAR1 activation promotes SIRT3-mediated deacetylation of ATP5F1A at K498, which is required for SIGMAR1-mediated mitophagy and protection against endothelial ferroptosis and microvascular hyperpermeability in acute lung injury.\",\n      \"method\": \"Site-specific acetylation analysis (K498), SIRT3 KO and activation, siRNA knockdown of ATP5F1A, mitophagy assays (GFP-LC3, Western blot for P62/LC3), cell viability/ferroptosis assays, in vivo ALI mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific PTM identification with genetic KO and siRNA validation in vitro and in vivo; single lab, not yet replicated\",\n      \"pmids\": [\"41655128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDIT4L (DNA damage-inducible transcript 4-like) is transported into mitochondria via TOM40 and directly interacts with the α-subunit of ATP synthase (ATP5F1A/ATP5A), inhibiting mitochondrial function and inducing tumor cell apoptosis in glioblastoma; a synthetic peptide DDIT4L V125–P132 recapitulated this tumor-suppressive effect.\",\n      \"method\": \"Lentiviral overexpression, PDX mouse model, co-immunoprecipitation of DDIT4L with ATP synthase α-subunit, mitochondrial function assays, apoptosis assays, synthetic peptide functional validation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional assays in cancer model; preprint, single lab, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.27.666981\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATP5F1A (the α-subunit of mitochondrial complex V / F1-ATPase) forms the catalytic α3β3 core of ATP synthase whose rotation-driven conformational changes synthesize ATP; it is also present on the endothelial cell surface where it binds angiostatin to mediate antiangiogenic signaling. Its activity is regulated by multiple post-translational modifications: TNK2/ACK1-mediated phosphorylation at Tyr243/246 stabilizes complex V and blocks its inhibitor ATP5IF1, SIRT3-mediated deacetylation at Lys498 promotes mitophagy, and WWP2-mediated ubiquitination targets it for proteasomal degradation; pathogenic de novo missense variants cause complex V deficiency through dominant-negative disruption of oxidative phosphorylation or disruption of α–β subunit interactions, leading to developmental and neurological disorders.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP5F1A encodes the α-subunit of mitochondrial F1-ATP synthase (complex V), functioning as an essential structural and catalytic component of oxidative phosphorylation-coupled ATP production. TNK2/ACK1-mediated phosphorylation of ATP5F1A at Tyr243/Tyr246 stabilizes complex V and prevents binding of the inhibitory subunit ATP5IF1, sustaining mitochondrial ATP output, while SIRT3-mediated deacetylation at Lys498 promotes PRKN-dependent mitophagy [PMID:35895804, PMID:41655128]. WWP2 ubiquitinates ATP5F1A for proteasomal degradation, linking ATP synthase turnover to mitochondrial apoptotic signaling [PMID:37557013]. Heterozygous de novo missense variants act through a dominant-negative mechanism to reduce complex V abundance and uncouple oxidative phosphorylation, causing neurodevelopmental disorders [PMID:34483339, PMID:41053757].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping the functional ATP5F1A locus to chromosome 18q12→q21 and distinguishing it from a pseudogene on 9p12 established the genomic context for all subsequent mechanistic studies.\",\n      \"evidence\": \"FISH and CGH in human cell lines including the retinoblastoma line Y79\",\n      \"pmids\": [\"9284928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data beyond chromosomal localization\", \"Amplification in Y79 not mechanistically explored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of a recurrent de novo heterozygous p.Arg207His substitution linked ATP5F1A to neonatal complex V deficiency, revealing that single-residue changes on the α/β-subunit interface can disrupt ATP synthase function.\",\n      \"evidence\": \"Exome sequencing, patient-derived fibroblast complex V activity and expression assays, structural modeling\",\n      \"pmids\": [\"34483339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment or in vitro reconstitution to confirm causality\", \"Dominant-negative versus haploinsufficiency mechanism not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that TNK2/ACK1 phosphorylates ATP5F1A at Tyr243/246 to stabilize complex V and block ATP5IF1 binding revealed the first post-translational regulatory switch controlling ATP synthase activity.\",\n      \"evidence\": \"In vitro kinase assays, Y243/246A mutagenesis, Co-IP, TNK2 inhibitor treatment, Tnk2 transgenic mouse model with mitophagy readout\",\n      \"pmids\": [\"35895804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how phospho-Tyr blocks ATP5IF1 binding not resolved\", \"Relevance outside prostate cancer cells not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of WWP2-mediated ubiquitination and proteasomal degradation of ATP5F1A established a proteostatic control point linking ATP synthase turnover to mitochondrial apoptotic regulation via Bcl-2/Bax ratio.\",\n      \"evidence\": \"Reciprocal Co-IP, endothelial cell-specific WWP2 knockout mice, proteasome inhibitor treatment, in vivo vascular injury model\",\n      \"pmids\": [\"37557013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on ATP5F1A not mapped\", \"How a cytosolic E3 ligase accesses a mitochondrial matrix protein not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A chimeric lncRNA (SFT2D2-TBX19) was shown to scaffold the TNK2–ATP5F1A interaction, enhancing Tyr phosphorylation and α/β-subunit stability, adding an RNA regulatory layer to the phosphorylation axis.\",\n      \"evidence\": \"RNA pulldown, Co-IP, phosphorylation assays, ATP synthase activity assays, domain deletion mapping in prostate cancer cells\",\n      \"pmids\": [\"39540264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding interface on ATP5F1A not defined\", \"Whether this lncRNA operates outside prostate cancer unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiomyocyte-specific ATP5F1A overexpression reversed pathological cardiac remodeling in heart failure models, establishing ATP5F1A as a functional bottleneck in failing cardiomyocyte bioenergetics.\",\n      \"evidence\": \"AAV9-mediated cardiomyocyte-specific overexpression, echocardiography, pathological staining in TAC and DCM mouse models\",\n      \"pmids\": [\"38910562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of reverse remodeling beyond bioenergetics not dissected\", \"No loss-of-function cardiac data provided\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multi-proband genetic and biochemical studies confirmed that heterozygous ATP5F1A missense variants act through a dominant-negative mechanism — reducing complex V abundance while uncoupling oxidative phosphorylation — establishing the disease mechanism for associated neurodevelopmental disorders.\",\n      \"evidence\": \"(preprint) C. elegans dominant-negative assays, patient fibroblast proteomics and mitochondrial physiology; complemented by zebrafish knockdown with mRNA rescue\",\n      \"pmids\": [\"40672495\", \"41053757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Allele-specific effects across different missense variants not fully catalogued\", \"Neuron-specific consequences not directly modeled in mammalian systems\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"SIRT3-mediated deacetylation of ATP5F1A at Lys498 was shown to be required for SIGMAR1-driven PRKN-dependent mitophagy, revealing an acetylation switch that connects ATP synthase to mitophagy and ferroptosis resistance.\",\n      \"evidence\": \"SIGMAR1 knockout mice, SIRT3 pharmacological and genetic manipulation, site-specific acetylation analysis, mitophagy and ferroptosis assays in endothelial cells\",\n      \"pmids\": [\"41655128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K498 acetylation state alters ATP5F1A conformation or protein interactions not structurally resolved\", \"Whether this acetylation switch operates in non-endothelial cell types unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An integrated structural understanding of how phosphorylation (Tyr243/246), acetylation (Lys498), and ubiquitination coordinately regulate ATP5F1A function, stability, and mitophagy signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data showing how each PTM alters complex V conformation or subunit interactions\", \"Crosstalk between the TNK2 phosphorylation, SIRT3 deacetylation, and WWP2 ubiquitination axes not tested\", \"Tissue-specific hierarchy of these regulatory mechanisms unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial F1-ATP synthase (complex V)\"\n    ],\n    \"partners\": [\n      \"TNK2\",\n      \"ATP5IF1\",\n      \"WWP2\",\n      \"SIRT3\",\n      \"PRKN\",\n      \"ATP5F1B\",\n      \"SIGMAR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP5F1A encodes the α-subunit of the mitochondrial F1-Fo ATP synthase (complex V), forming the α3β3 catalytic hexamer whose rotation-driven conformational changes couple the proton-motive force to ATP synthesis [PMID:8065448]. Beyond oxidative phosphorylation, ATP5F1A resides on the endothelial cell surface where it serves as a functional receptor for angiostatin, mediating its antiproliferative, antiangiogenic activity [PMID:10077593]. Complex V stability and mitophagy are regulated through post-translational modifications of ATP5F1A: TNK2/ACK1-mediated phosphorylation at Tyr243/Tyr246 stabilizes the complex and blocks the inhibitor ATP5IF1 [PMID:35895804], SIRT3-mediated deacetylation at Lys498 promotes PRKN-dependent mitophagy [PMID:41655128], and WWP2-mediated ubiquitination targets ATP5F1A for proteasomal degradation [PMID:37557013]. De novo heterozygous missense variants in ATP5F1A cause complex V deficiency through dominant-negative disruption of oxidative phosphorylation, leading to neonatal-onset developmental and neurological disease [PMID:34483339, PMID:41053757].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Determination of how the α-subunit participates in catalysis: the 2.8 Å crystal structure of bovine F1-ATPase revealed that the α3β3 hexamer adopts asymmetric conformations around the central γ-shaft, establishing the rotary catalytic mechanism for ATP synthesis and defining the structural role of the α-subunit.\",\n      \"evidence\": \"X-ray crystallography of bovine mitochondrial F1-ATPase at 2.8 Å resolution\",\n      \"pmids\": [\"8065448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Post-translational regulation of the α-subunit was not addressed\",\n        \"No information on potential non-mitochondrial localization or function\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery that ATP5F1A has an extramitochondrial role: identification of the α-subunit on the endothelial cell surface as the functional receptor for angiostatin established a moonlighting function independent of mitochondrial ATP synthesis.\",\n      \"evidence\": \"Ligand blot, mass spectrometry, flow cytometry, and antibody-blockade experiments in human endothelial cells\",\n      \"pmids\": [\"10077593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of ATP5F1A trafficking to the plasma membrane remains undefined\",\n        \"Whether cell-surface ATP synthase is catalytically active was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"First genetic link of ATP5F1A to human disease: a recurrent de novo p.Arg207His variant was shown to cause neonatal complex V deficiency by disrupting the α–β subunit interface, demonstrating that single missense changes can dominantly impair oxidative phosphorylation.\",\n      \"evidence\": \"Exome sequencing, biochemical assays in patient-derived fibroblasts, and structural modelling\",\n      \"pmids\": [\"34483339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only one recurrent variant characterized; spectrum of pathogenic variants unknown\",\n        \"No rescue or complementation experiment performed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a kinase-mediated regulatory switch on ATP5F1A: TNK2/ACK1 phosphorylates Tyr243/Tyr246, stabilizing complex V and preventing ATP5IF1 binding, thereby linking tyrosine kinase signaling to mitochondrial energy output and mitophagy control in cancer.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, Co-IP, transgenic mouse model, and xenograft experiments in prostate cancer\",\n      \"pmids\": [\"35895804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how phosphorylation blocks ATP5IF1 binding not determined\",\n        \"Relevance of this phosphorylation outside prostate cancer cells not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Ubiquitin-dependent turnover of ATP5F1A was established: WWP2 ubiquitinates ATP5F1A for proteasomal degradation, connecting complex V abundance to an endothelial protective pathway in hypertension.\",\n      \"evidence\": \"Ubiquitination assay, proteasome inhibition, endothelial-specific WWP2 knockout mice, and in vivo hypertension model\",\n      \"pmids\": [\"37557013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ubiquitination sites on ATP5F1A not mapped\",\n        \"Whether WWP2-mediated regulation occurs in non-endothelial cell types is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A chimeric lncRNA (SFT2D2-TBX19) was shown to scaffold the TNK2-ATP5F1A interaction, mapping the functional domain on ATP5F1A and demonstrating that RNA-protein complexes modulate ATP synthase phosphorylation and α–β subunit stability.\",\n      \"evidence\": \"RNA-protein interaction assays, Co-IP of ATP5F1A–ATP5F1B, phosphorylation assays, and domain mapping in prostate cancer cells\",\n      \"pmids\": [\"39540264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological relevance of SFT2D2-TBX19 outside prostate cancer is unclear\",\n        \"No structural data on the RNA–ATP5F1A interface\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiomyocyte-specific overexpression of ATP5F1A reversed cardiac remodeling in heart failure models, establishing ATP5F1A levels as limiting for cardiac bioenergetics and function.\",\n      \"evidence\": \"AAV9-mediated cardiomyocyte-specific overexpression in TAC and DCM mouse models, echocardiography, histology\",\n      \"pmids\": [\"38910562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking ATP5F1A restoration to reduced fibrosis not delineated\",\n        \"Long-term effects and safety not evaluated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded genetic evidence confirmed dominant-negative pathogenicity: six additional de novo ATP5F1A missense variants caused complex V deficiency with uncoupled oxidative phosphorylation, and zebrafish knockdown linked ATP5F1A loss to motor neuron axon defects and impaired autophagy.\",\n      \"evidence\": \"C. elegans dominant-negative assay, quantitative proteomics, patient fibroblast bioenergetics (preprint); zebrafish morpholino knockdown with mRNA rescue, autophagy marker analysis\",\n      \"pmids\": [\"41053757\", \"40672495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint data (PMID:40672495) not yet peer-reviewed\",\n        \"Autophagy impairment mechanism downstream of ATP5F1A loss not fully characterized\",\n        \"Genotype–phenotype correlation across all known variants not systematically established\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A deacetylation-dependent mitophagy switch was identified: SIRT3 deacetylates ATP5F1A at Lys498 to enable PRKN-dependent mitophagy, linking acetylation status of ATP5F1A to ferroptosis resistance and microvascular integrity in acute lung injury.\",\n      \"evidence\": \"Site-specific acetylation analysis, SIRT3 knockout and activation, siRNA knockdown, mitophagy and ferroptosis assays, in vivo acute lung injury mouse model\",\n      \"pmids\": [\"41655128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How K498 deacetylation mechanistically activates PRKN recruitment is not defined\",\n        \"Not yet replicated independently\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how ATP5F1A traffics to the plasma membrane, the structural basis for how individual post-translational modifications (phosphorylation, acetylation, ubiquitination) cooperate to regulate complex V assembly and turnover, and comprehensive genotype–phenotype maps for disease-causing variants.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural data showing how Tyr243/246 phosphorylation or K498 acetylation alter complex V conformation\",\n        \"Mechanism of ATP5F1A targeting to the cell surface is unknown\",\n        \"Crosstalk among phosphorylation, acetylation, and ubiquitination on ATP5F1A is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 8, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 8, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\n      \"F1-Fo ATP synthase (complex V)\",\n      \"F1-ATPase α3β3γ subcomplex\"\n    ],\n    \"partners\": [\n      \"ATP5F1B\",\n      \"TNK2\",\n      \"ATP5IF1\",\n      \"WWP2\",\n      \"SIRT3\",\n      \"PRKN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}