{"gene":"ATP5F1A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2013,"finding":"Heterozygous mutation in ATP5A1 (coding for complex V subunit α) causes a disturbed interaction of the α-subunit with the β-subunit of complex V, interfering with complex V stability and assembly, resulting in neonatal complex V deficiency. Complementation with wild-type ATP5A1 restored complex V in patient fibroblasts, confirming pathogenicity.","method":"Whole exome sequencing, immunoblotting for complex V assembly, oxygen consumption rate measurement, enzyme analysis in fibroblasts, complementation assay, 3D structural modelling","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — complementation assay with functional rescue, enzymatic testing, assembly analysis, structural modelling, all in single rigorous study","pmids":["23599390"],"is_preprint":false},{"year":2019,"finding":"Poly(GR) (encoded by C9ORF72 repeat expansion) binds preferentially to the mitochondrial complex V component ATP5A1, enhances its ubiquitination and degradation, leading to reduced ATP5A1 protein levels and mitochondrial dysfunction. Ectopic Atp5a1 expression in poly(GR)-expressing neurons rescued poly(GR)-induced neurotoxicity.","method":"Co-immunoprecipitation/binding assay in mouse neurons and patient brains, ubiquitination assay, rescue experiment with ectopic Atp5a1 expression in inducible mouse model","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, ubiquitination assay, and in vivo rescue experiment, replicated in both mouse model and patient tissue","pmids":["31086314"],"is_preprint":false},{"year":2022,"finding":"Mitochondrial calpain-1 cleaves ATP5A1 after CVB3 infection; downregulating ATP5A1 via siRNA impairs mitochondrial function, decreases cell viability, and induces NLRP3 inflammasome activation and pyroptosis, establishing ATP5A1 as the proteolytic target of calpain-1 in the pathway linking viral infection to NLRP3 inflammasome activation.","method":"Calpain-1 activation/inhibition experiments in vitro, ATP5A1 siRNA knockdown, NLRP3 inflammasome activation assays, transgenic calpastatin overexpression mice, mitochondria-targeted antioxidant rescue","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with defined phenotypic readout, pharmacological inhibition, transgenic model, and antioxidant rescue, multiple orthogonal methods","pmids":["35997820"],"is_preprint":false},{"year":2022,"finding":"TNK2/ACK1 tyrosine kinase phosphorylates ATP5F1A at Tyr243 and Tyr246 (Tyr200 and Tyr203 in the mature protein), increasing complex V stability and mitochondrial energy output. Phospho-ATP5F1A prevents binding to its physiological inhibitor ATP5IF1, causing sustained mitochondrial activity. Y243/246A mutant ATP5F1A abolished these effects.","method":"In vitro kinase assay, phospho-specific antibody detection, co-immunoprecipitation with ATP5IF1, site-directed mutagenesis (Y243A/Y246A), TNK2 transgenic mice, mitophagy assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, Co-IP with inhibitor, in vivo transgenic mouse model, multiple orthogonal methods","pmids":["35895804"],"is_preprint":false},{"year":2018,"finding":"T. gondii GRA8 interacts with the nucleotide-binding domain of ATP5A1 in mitochondria; GRA8 also interacts with SIRT3, facilitating ATP5A1 deacetylation at K506 and K531, thereby promoting ATP production and anti-septic activity in vivo.","method":"Co-immunoprecipitation, mass spectrometry, site-directed deacetylation analysis (K506, K531), PKCα phosphorylation assay, in vivo sepsis model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and site-specific deacetylation identified, single lab with multiple methods including in vivo model","pmids":["29869623"],"is_preprint":false},{"year":2018,"finding":"Endogenous H2S (produced by CBS) S-sulfhydrates ATP5A1 at cysteine 244. Reduced H2S in CBS+/- or LPS-treated mice decreases S-sulfhydrated ATP5A1 levels, leading to mitochondrial-mediated apoptosis and adrenal insufficiency. Overexpression of a C244 mutant ATP5A1 caused loss of LPS-induced apoptosis and restored ACTH responsiveness.","method":"Maleimide assay combined with mass spectrometry, modified biotin switch assay, CBS+/- mice, site-directed mutagenesis (C244), GYY4137 H2S donor rescue, ACTH response assay","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific PTM identified by MS and biochemical assay, mutagenesis, genetic KO model, pharmacological rescue — multiple orthogonal methods","pmids":["29486221"],"is_preprint":false},{"year":2007,"finding":"A 4-nucleotide duplication in exon 3 of Atp5a1 (encoding ATP synthase α-subunit) causes a recessive embryonic lethal phenotype in mice and acts as a modifier of ApcMin-induced intestinal tumorigenesis (Mom2 locus), with adenomas in carriers tending to progress to carcinomas in the absence of APC LOH.","method":"Linkage analysis, exome sequencing, expression analysis, tumor analysis, congenic mouse intercross","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model with defined phenotypic readout, sequence and expression analysis, single lab","pmids":["17387143"],"is_preprint":false},{"year":2021,"finding":"Atp5a1 knockdown in Leydig cells via siRNA decreased StAR, CYP11A1, and 17β-HSD expression by damaging mitochondrial structure, establishing Atp5a1 as required for mitochondrial integrity and steroidogenesis in response to chronic stress.","method":"2-DE and MALDI-TOF-MS protein identification, Atp5a1 siRNA transfection in TM3 cells, mitochondrial structure analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, proteomic identification, single lab with two orthogonal methods","pmids":["34894202"],"is_preprint":false},{"year":2021,"finding":"Recurrent de novo ATP5F1A substitution c.620G>A [p.(Arg207His)] causes multiple deficits in complex V function and expression in patient-derived fibroblasts. Structural modelling predicts this creates an abnormal region of negative charge on ATP5F1A's β-subunit-interacting surface adjacent to the active site.","method":"Exome sequencing, functional assays in patient fibroblasts (complex V activity and expression), structural modelling","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional fibroblast assays and structural modelling, single lab, three independent probands","pmids":["34483339"],"is_preprint":false},{"year":2021,"finding":"ATP5A1 overexpression in HeLa cells significantly promotes cellular apoptosis (but not proliferation) and modulates expression of genes associated with innate immune response, angiogenesis, and MMP2/MMP19, as well as altering alternative splicing of hundreds of genes including those in HIF-1 signaling and glucose homeostasis pathways.","method":"Plasmid overexpression, RNA-seq transcriptomics, flow cytometry apoptosis assay, RT-qPCR validation","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with transcriptomic readout but no direct mechanistic pathway placement for the apoptosis induction","pmids":["34520292"],"is_preprint":false},{"year":2021,"finding":"Repeated aconitine treatment upregulates ATP5A1 via the AMPK-OPA1-ATP5A1 pathway, increasing mitochondrial fusion, biogenesis, and cellular ATP content in cardiomyocytes; AMPK inhibitor compound C reversed the increases in phospho-AMPK, OPA1, and ATP5A1.","method":"Pharmacological AMPK inhibition (compound C), Western blot, mitochondrial morphology analysis, ATP content measurement in NRVMs","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition with pathway markers, single lab, no genetic confirmation of pathway order","pmids":["34177570"],"is_preprint":false},{"year":2023,"finding":"ATP synthase subunit alpha (ATPase α / ATP5A1) serves as a cell-surface ligand for Salmonella Enteritidis Peg fimbriae adhesion protein PegD; siRNA knockdown of Atp5a1 in LMH cells significantly reduced S. Enteritidis adhesion.","method":"Ligand blotting, mass spectrometry, in vitro binding assay with purified PegD, siRNA knockdown with adhesion rate quantification","journal":"Avian pathology : journal of the W.V.P.A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay, siRNA loss-of-function with specific adhesion readout, mass spectrometry identification, single lab","pmids":["37526573"],"is_preprint":false},{"year":2024,"finding":"HSPD1 (HSP60) interacts with ATP5A1 (identified by Co-IP/MS) and reduces K48-linked ubiquitination and degradation of ATP5A1, thereby stabilizing it and activating AKT/mTOR signaling to promote osteosarcoma progression.","method":"Immunoprecipitation followed by mass spectrometry, Western blot for ubiquitination, in vitro and in vivo proliferation/apoptosis assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification, ubiquitination analysis, single lab with multiple orthogonal methods","pmids":["39430254"],"is_preprint":false},{"year":2021,"finding":"Extracellular recombinant ATP5A1 binds LPS directly (demonstrated by cellular thermal shift assay and ELISA-based binding assay), and intracerebroventricular injection of rATP5A1 suppresses LPS-induced neuroinflammation, microglial/astrocyte activation, IL-1β accumulation, and tau phosphorylation in mice.","method":"Cellular thermal shift assay, ELISA-based binding assay, intracerebroventricular injection in mouse model, behavioral assays","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay confirmed by two orthogonal methods, in vivo rescue experiment, single lab","pmids":["34098024"],"is_preprint":false},{"year":2022,"finding":"Exogenous Otx2 recombinant protein interacts with ATP5a1 in midbrain dopaminergic neurons and promotes ATP synthesis, protecting these neurons against MPP+-induced neurotoxicity.","method":"Co-immunoprecipitation, ATP synthesis assay, primary neuron culture with MPP+ treatment","journal":"Neurotoxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, partial mechanistic follow-up","pmids":["35644505"],"is_preprint":false},{"year":2024,"finding":"Chimeric SFT2D2-TBX19 (as lncRNA) interacts with ATP5F1A, increasing its TNK2/ACK1-mediated phosphorylation and stabilizing the interaction between ATP5F1A and ATP5F1B, thereby enhancing mitochondrial ATP synthase activity and ATP production in prostate cancer cells.","method":"RNA pulldown, Co-immunoprecipitation, phosphorylation assay, ATP production measurement, functional domain mapping","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNA pulldown with functional domain mapping, ATP production measured, single lab with multiple orthogonal methods","pmids":["39540264"],"is_preprint":false},{"year":2025,"finding":"Cannabidiol (CBD) directly targets ATP5A1 and prevents METH-induced ubiquitination of ATP5A1 at residue D376, reversing METH-induced reduction of ATP5A1 protein and promoting ATP synthase assembly. ATP5A1 knockdown in the ventral tegmental area reversed CBD's therapeutic efficacy against METH addiction behaviors.","method":"Activity-based protein profiling (target fishing), ubiquitination assay, site-specific mutagenesis (D376), siRNA knockdown in VTA in vivo, behavioral assays (locomotor sensitization, CPP)","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical proteomics target identification, site-specific mutagenesis, in vivo siRNA knockdown with behavioral readout, multiple orthogonal methods","pmids":["41132843"],"is_preprint":false},{"year":2025,"finding":"AHA1 (AHSA1) translocates to mitochondria under ischemia/reperfusion stress and directly interacts with ATP5A1, disrupting the cellular ATP/AMP ratio and increasing ROS production, leading to AMPK/mTOR/ULK1-mediated excessive mitophagy. AHA1 silencing suppressed pathological mitophagy and reduced infarct volume.","method":"siRNA knockdown, co-immunoprecipitation, MCAO/R mouse model and OGD/R cell model, AMPK/mTOR pathway analysis, behavioral tests","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of direct interaction, siRNA with defined pathway phenotype, in vivo and in vitro models, single lab","pmids":["41297454"],"is_preprint":false},{"year":2026,"finding":"SIRT3 deacetylates ATP5A1 at lysine 498; reduced SIRT3 in LPS-induced acute lung injury leads to acetylation of ATP5F1A/K498, impairing mitophagy and promoting endothelial ferroptosis. Downregulating ATP5F1A acetylation prevents SIRT3 inhibition from blocking SIGMAR1-mediated mitophagy and ferroptosis protection.","method":"Site-specific acetylation analysis (K498), SIRT3 knockout/activator, siRNA, PINK1/Parkin mitophagy assays, ALI mouse model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific deacetylation (K498) identified, genetic KO and pharmacological activation, in vivo ALI model, multiple orthogonal methods","pmids":["41655128"],"is_preprint":false},{"year":2026,"finding":"Succinylation of ATP5A1 at K531 (by CPT1A as trans-succinylase, reversed by SIRT5 as desuccinylase) impedes ATP synthase assembly and impairs its activity. ATP5A1-K531R mutant (abolishing succinylation) delivered by AAV9 protected against ischemia-induced cardiomyocyte death and heart failure development.","method":"Succinylation proteomic analysis, site-directed mutagenesis (K531R), AAV9 cardiac-specific delivery, ATP synthase activity assay, OGD cardiomyocyte model, LAD ligation mouse model","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific PTM identified by proteomics, mutagenesis, in vitro activity assay, in vivo cardiac model with functional readout","pmids":["41879856"],"is_preprint":false},{"year":2026,"finding":"SIRT3 deacetylates ATP5A1, improving mitochondrial membrane potential, decreasing ROS, enhancing mitochondrial respiration and inhibiting cardiomyocyte apoptosis in ischemia-reperfusion injury. SIRT3 overexpression significantly reduced ATP5A1 acetylation; SIRT3 inhibition exacerbated mitochondrial damage.","method":"Co-immunoprecipitation, point mutation analysis, SIRT3 overexpression/inhibitor in MIRI mouse model and H/R HL-1 cells, mitochondrial membrane potential, ROS, respiration assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with point mutation, pharmacological and genetic manipulation, in vivo and in vitro models, single lab","pmids":["42172898"],"is_preprint":false},{"year":2025,"finding":"De novo heterozygous missense ATP5F1A variants cause dominant negative disruption of complex V, leading to markedly reduced complex V abundance and activity in proband-derived blood cells and fibroblasts, increased oxygen consumption yet decreased mitochondrial membrane potential and ATP levels (uncoupled oxidative phosphorylation), associated with developmental delay and movement disorders.","method":"Functional evaluation in C. elegans (dominant negative mechanism), biochemical assays in patient blood cells/fibroblasts, proteomics for complex V abundance, mitochondrial physiology in fibroblasts","journal":"medRxiv : the preprint server for health sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (C. elegans genetics, proteomics, biochemical activity, mitochondrial physiology) across 6 independent probands","pmids":["40672495"],"is_preprint":true},{"year":2024,"finding":"BRG1 promotes ATP5A1 synthesis in liver cancer via TOMM40; BRG1 knockdown decreased ATP5A1 expression, impaired mitochondrial function (reduced MMP, increased mPTP opening), and promoted apoptosis in HCC cells.","method":"siRNA knockdown, plasmid overexpression, ICC/IF staining, Western blot, mitochondrial membrane potential and mPTP assays","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown/overexpression with pathway markers, no direct mechanistic confirmation of BRG1-TOMM40-ATP5A1 order","pmids":["38978225"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, atp5fa1 knockdown causes motor dysfunction, impaired motor neuron axon development, and growth retardation; rescue with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Knockdown increased P62 and decreased Lc3b-II, indicating inhibition of autophagy flux.","method":"Morpholino knockdown in zebrafish, mRNA rescue experiment, Western blot (P62, LC3B-II), motor neuron imaging in Tg(mnx1:eGFP) zebrafish, RNA-seq","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with mRNA rescue and defined neuronal phenotype, autophagy pathway markers, single lab","pmids":["41053757"],"is_preprint":false},{"year":2025,"finding":"Dexamethasone inhibits osteogenic differentiation in BMSCs by modulating the CAST-CAPN1 axis to suppress ATP5A1 expression and reduce ATP activity; CAST overexpression partially mitigated these effects while CAPN1 overexpression exacerbated them, placing ATP5A1 downstream of calpain regulation.","method":"CAST/CAPN1 overexpression plasmids in rat BMSCs, Western blot, qRT-PCR, Alizarin Red S staining, ELISA for ATP activity","journal":"Discovery medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with functional readout, indirect pathway placement","pmids":["40116104"],"is_preprint":false},{"year":2024,"finding":"Overexpression of ATP5F1A in cardiomyocytes via cardiomyocyte-specific AAV9 improved heart function and morphology, and reduced fibrosis and cardiomyocyte size in transverse aortic constriction and dilated cardiomyopathy mouse heart failure models, identifying ATP5F1A as a mediator of cardiac reverse remodeling.","method":"Single-nucleus RNA sequencing of human CRR/non-CRR hearts, AAV9-mediated cardiomyocyte-specific overexpression in mouse HF models, echocardiography, pathological staining","journal":"Circulation. Heart failure","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — snRNA-seq identification followed by in vivo AAV9 overexpression with functional cardiac readout, single lab with two orthogonal approaches","pmids":["38910562"],"is_preprint":false}],"current_model":"ATP5F1A encodes the α-subunit of mitochondrial complex V (ATP synthase F1), where it forms the catalytic core with the β-subunit; its stability, assembly, and activity are regulated by multiple post-translational modifications including TNK2/ACK1-mediated phosphorylation at Tyr243/246 (which blocks inhibitor ATP5IF1 binding and sustains ATP synthesis), SIRT3-mediated deacetylation at multiple lysines (K498, K506, K531), H2S-mediated S-sulfhydration at Cys244 (protecting mitochondrial function), calpain-1-mediated cleavage (impairing function and activating NLRP3 inflammasome), K531 succinylation by CPT1A (impeding assembly), and poly(GR)-induced ubiquitination/degradation; pathogenic mutations disrupt α–β subunit interaction and complex V assembly, causing mitochondrial encephalopathy and other neurological disorders."},"narrative":{"mechanistic_narrative":"ATP5F1A encodes the catalytic α-subunit of mitochondrial complex V (ATP synthase F1), where its interaction with the β-subunit forms the catalytic core required for complex V stability, assembly, and ATP synthesis [PMID:23599390, PMID:39540264]. Heterozygous and recurrent de novo missense variants disrupt the α–β subunit interface adjacent to the active site, destabilizing complex V and causing complex V deficiency with a dominant-negative, uncoupled oxidative-phosphorylation phenotype underlying neonatal mitochondrial encephalopathy, developmental delay, and movement disorders [PMID:23599390, PMID:34483339, PMID:40672495]. The α-subunit is a hub for post-translational regulation that tunes complex V activity: TNK2/ACK1-mediated phosphorylation at Tyr243/Tyr246 stabilizes the enzyme and blocks binding of its inhibitor ATP5IF1 to sustain energy output [PMID:35895804]; SIRT3-mediated deacetylation at K498 (and additional lysines) and H2S-dependent S-sulfhydration at Cys244 protect mitochondrial function, mitophagy, and resistance to ferroptosis and apoptosis [PMID:29486221, PMID:41655128]; whereas CPT1A-driven K531 succinylation impedes assembly and impairs activity, and calpain-1 cleavage degrades the protein, impairing mitochondrial function and triggering NLRP3 inflammasome activation [PMID:35997820, PMID:41879856]. Its abundance is further controlled by ubiquitin-dependent degradation, which is enhanced by C9ORF72-derived poly(GR) and by methamphetamine (at D376), and is counteracted by stabilizing partners such as HSPD1 [PMID:31086314, PMID:39430254, PMID:41132843]. Loss of ATP5F1A compromises mitochondrial integrity in diverse cell types, impairing steroidogenesis, motor-neuron axon development, and autophagy flux, while its restoration rescues neurotoxicity and cardiac dysfunction in disease models [PMID:34894202, PMID:41053757, PMID:38910562]. ATP5F1A additionally functions at the cell surface as a binding partner for extracellular ligands including LPS and bacterial adhesins [PMID:37526573, PMID:34098024].","teleology":[{"year":2007,"claim":"Established that Atp5a1 is essential in vivo and can modify a tumor phenotype, the first evidence linking this subunit to organismal viability and disease beyond bioenergetics catalogues.","evidence":"Linkage analysis and congenic mouse intercross of an exon 3 duplication allele as the Mom2 modifier of ApcMin tumorigenesis","pmids":["17387143"],"confidence":"Medium","gaps":["Molecular mechanism of tumor modification not resolved","No human disease link established at this stage"]},{"year":2013,"claim":"Defined the disease mechanism by which ATP5F1A mutations cause complex V deficiency: a disturbed α–β subunit interaction destabilizing assembly, with functional rescue confirming causality.","evidence":"Whole exome sequencing, complex V assembly immunoblotting, oxygen consumption, and complementation rescue in patient fibroblasts plus structural modelling","pmids":["23599390"],"confidence":"High","gaps":["Single mutation; allelic spectrum unknown","Structural prediction not experimentally resolved"]},{"year":2018,"claim":"Revealed that the α-subunit is regulated by reversible post-translational modifications — S-sulfhydration at Cys244 and SIRT3-mediated deacetylation — that protect mitochondrial function and cell survival.","evidence":"Biotin-switch/maleimide MS for sulfhydration (CBS+/- mice, C244 mutant, H2S donor rescue) and Co-IP/MS for GRA8–SIRT3-driven deacetylation at K506/K531 in a sepsis model","pmids":["29486221","29869623"],"confidence":"Medium","gaps":["How each PTM mechanistically alters catalysis or assembly not detailed","Crosstalk between modifications unaddressed"]},{"year":2019,"claim":"Connected ATP5F1A abundance to neurodegeneration, showing C9ORF72-derived poly(GR) drives its ubiquitination and degradation as a cause of mitochondrial dysfunction.","evidence":"Co-IP/binding assays in mouse neurons and patient brains, ubiquitination assay, and in vivo rescue by ectopic Atp5a1 expression","pmids":["31086314"],"confidence":"High","gaps":["E3 ligase mediating poly(GR)-induced ubiquitination not identified","Ubiquitination site not mapped"]},{"year":2021,"claim":"Extended ATP5F1A function beyond the matrix, identifying a cell-surface/extracellular role as an LPS-binding protein and establishing requirement for mitochondrial integrity in steroidogenesis.","evidence":"Thermal shift and ELISA binding with intracerebroventricular rATP5A1 in neuroinflammation; siRNA knockdown in Leydig cells with steroidogenic enzyme readouts","pmids":["34098024","34894202","34483339"],"confidence":"Medium","gaps":["Mechanism of surface localization unexplained","Overexpression/knockdown phenotypes may be indirect"]},{"year":2022,"claim":"Mapped activating phosphorylation and degradative cleavage as opposing controls of complex V output: TNK2/ACK1 phosphorylation at Tyr243/246 blocks ATP5IF1 inhibition, while calpain-1 cleavage degrades the subunit and triggers NLRP3 inflammasome activation.","evidence":"In vitro kinase assay, Y243/246A mutagenesis, Co-IP with ATP5IF1, TNK2 transgenic mice; calpain-1 inhibition/siRNA with NLRP3/pyroptosis readouts and calpastatin transgenic mice","pmids":["35895804","35997820"],"confidence":"High","gaps":["Calpain-1 cleavage site not defined","Stoichiometry of phospho-ATP5F1A in vivo unknown"]},{"year":2024,"claim":"Identified protein and RNA partners that stabilize ATP5F1A — HSPD1 reducing K48 ubiquitination and a chimeric lncRNA enhancing TNK2 phosphorylation — coupling its abundance to growth signaling and cancer progression.","evidence":"Co-IP/MS and ubiquitination blots (HSPD1/osteosarcoma); RNA pulldown, Co-IP, and ATP measurement (SFT2D2-TBX19/prostate cancer)","pmids":["39430254","39540264"],"confidence":"Medium","gaps":["Direct vs indirect stabilization not fully separated","Single-lab findings without reciprocal validation across systems"]},{"year":2025,"claim":"Consolidated the dominant-negative disease mechanism in humans and identified ATP5F1A as a druggable node, with cannabidiol preventing METH-induced ubiquitination at D376 to restore ATP synthase assembly.","evidence":"C. elegans dominant-negative modelling plus proteomics and mitochondrial physiology in patient cells (preprint); activity-based protein profiling, D376 mutagenesis, and in vivo VTA siRNA with behavioral readouts for CBD","pmids":["40672495","41132843"],"confidence":"High","gaps":["Disease genetics from a preprint awaiting peer review","E3 ligase acting at D376 not identified"]},{"year":2026,"claim":"Resolved competing lysine modifications controlling assembly and stress survival: SIRT3 deacetylation at K498 enables protective mitophagy, while CPT1A-driven K531 succinylation impedes assembly, with site-mutant rescue protecting against cardiac ischemic injury.","evidence":"Site-specific acetylation analysis with SIRT3 KO/activator and mitophagy assays (ALI model); succinylation proteomics, K531R mutagenesis, AAV9 cardiac delivery, and activity assays (ischemia models)","pmids":["41655128","41879856","42172898"],"confidence":"High","gaps":["Interplay between K498/K506/K531 modifications not integrated","Quantitative contribution of each PTM to assembly unresolved"]},{"year":null,"claim":"How the diverse post-translational modifications, partner interactions, and reported extracellular functions are coordinately integrated to set ATP5F1A levels and complex V activity in a given tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of competing PTMs and degradation pathways","Mechanism of cell-surface localization unexplained","E3 ligases for ubiquitin-dependent turnover unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,15,19]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,4,5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,8,21,1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,18,23]}],"complexes":["mitochondrial ATP synthase (complex V) F1"],"partners":["ATP5F1B","ATP5IF1","TNK2","SIRT3","CPT1A","HSPD1","CAPN1","AHSA1"],"other_free_text":[]}},"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 family proteins mediate sphingolipid homeostasis.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20182505","citation_count":491,"is_preprint":false},{"pmid":"31086314","id":"PMC_31086314","title":"C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo.","date":"2019","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31086314","citation_count":177,"is_preprint":false},{"pmid":"35997820","id":"PMC_35997820","title":"Mitochondrial calpain-1 activates NLRP3 inflammasome by cleaving ATP5A1 and inducing mitochondrial ROS in CVB3-induced myocarditis.","date":"2022","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/35997820","citation_count":122,"is_preprint":false},{"pmid":"22535525","id":"PMC_22535525","title":"Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22535525","citation_count":118,"is_preprint":false},{"pmid":"25842287","id":"PMC_25842287","title":"Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice.","date":"2015","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25842287","citation_count":109,"is_preprint":false},{"pmid":"30700557","id":"PMC_30700557","title":"The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30700557","citation_count":92,"is_preprint":false},{"pmid":"23363605","id":"PMC_23363605","title":"TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23363605","citation_count":86,"is_preprint":false},{"pmid":"23599390","id":"PMC_23599390","title":"A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy.","date":"2013","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23599390","citation_count":81,"is_preprint":false},{"pmid":"30193828","id":"PMC_30193828","title":"Orm/ORMDL proteins: Gate guardians and master regulators.","date":"2018","source":"Advances in biological regulation","url":"https://pubmed.ncbi.nlm.nih.gov/30193828","citation_count":69,"is_preprint":false},{"pmid":"23737533","id":"PMC_23737533","title":"Orm proteins integrate multiple signals to maintain sphingolipid homeostasis.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23737533","citation_count":62,"is_preprint":false},{"pmid":"26526033","id":"PMC_26526033","title":"ATP5A1 and ATP5B are highly expressed in glioblastoma tumor cells and endothelial cells of microvascular proliferation.","date":"2015","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26526033","citation_count":53,"is_preprint":false},{"pmid":"3679210","id":"PMC_3679210","title":"Orosomucoid (ORM) typing by isoelectric focusing: evidence for gene duplication of ORM1 and genetic polymorphism of ORM2.","date":"1987","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3679210","citation_count":50,"is_preprint":false},{"pmid":"6839527","id":"PMC_6839527","title":"delta-Aminolevulinatedehydrase: synteny with ABO-AK1-ORM (and assignment to chromosome 9).","date":"1983","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6839527","citation_count":45,"is_preprint":false},{"pmid":"10824087","id":"PMC_10824087","title":"Male-biased mutation rates revealed from Z and W chromosome-linked ATP synthase alpha-subunit (ATP5A1) sequences in birds.","date":"2000","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/10824087","citation_count":38,"is_preprint":false},{"pmid":"35895804","id":"PMC_35895804","title":"TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35895804","citation_count":37,"is_preprint":false},{"pmid":"31026065","id":"PMC_31026065","title":"Role of acute-phase protein ORM in a mice model of ischemic stroke.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31026065","citation_count":36,"is_preprint":false},{"pmid":"3679213","id":"PMC_3679213","title":"Three new orosomucoid (ORM) variants revealed by isoelectric focusing and print immunofixation.","date":"1987","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3679213","citation_count":35,"is_preprint":false},{"pmid":"27506241","id":"PMC_27506241","title":"ORM Expression Alters Sphingolipid Homeostasis and Differentially Affects Ceramide Synthase Activity.","date":"2016","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27506241","citation_count":33,"is_preprint":false},{"pmid":"17387143","id":"PMC_17387143","title":"The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression.","date":"2007","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/17387143","citation_count":33,"is_preprint":false},{"pmid":"23718812","id":"PMC_23718812","title":"Pharmacological characterisation of a structurally novel α2C-adrenoceptor antagonist ORM-10921 and its effects in neuropsychiatric models.","date":"2013","source":"Basic & clinical pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/23718812","citation_count":32,"is_preprint":false},{"pmid":"36657849","id":"PMC_36657849","title":"Fucoidan from Fucus vesiculosus prevents the loss of dopaminergic neurons by alleviating mitochondrial dysfunction through targeting ATP5F1a.","date":"2022","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/36657849","citation_count":31,"is_preprint":false},{"pmid":"27679573","id":"PMC_27679573","title":"ORM Promotes Skeletal Muscle Glycogen Accumulation via CCR5-Activated AMPK Pathway in Mice.","date":"2016","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27679573","citation_count":26,"is_preprint":false},{"pmid":"29869623","id":"PMC_29869623","title":"Toxoplasma gondii GRA8 induces ATP5A1-SIRT3-mediated mitochondrial metabolic resuscitation: a potential therapy for sepsis.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29869623","citation_count":24,"is_preprint":false},{"pmid":"29486221","id":"PMC_29486221","title":"Endogenous H2S resists mitochondria-mediated apoptosis in the adrenal glands via ATP5A1 S-sulfhydration in male mice.","date":"2018","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29486221","citation_count":24,"is_preprint":false},{"pmid":"3400642","id":"PMC_3400642","title":"Orosomucoid (ORM) typing by isoelectric focusing: evidence for an additional duplicated ORM1 locus haplotype and close linkage of two ORM loci.","date":"1988","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3400642","citation_count":24,"is_preprint":false},{"pmid":"19651122","id":"PMC_19651122","title":"Pro-angiogenic properties of orosomucoid (ORM).","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19651122","citation_count":23,"is_preprint":false},{"pmid":"29869624","id":"PMC_29869624","title":"Estrogen weakens muscle endurance via estrogen receptor-p38 MAPK-mediated orosomucoid (ORM) suppression.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29869624","citation_count":23,"is_preprint":false},{"pmid":"24799619","id":"PMC_24799619","title":"A PET Tracer for Brain α2C Adrenoceptors, (11)C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice.","date":"2014","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24799619","citation_count":22,"is_preprint":false},{"pmid":"30538797","id":"PMC_30538797","title":"Reduced Levels of ATP Synthase Subunit ATP5F1A Correlate with Earlier-Onset Prostate Cancer.","date":"2018","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/30538797","citation_count":20,"is_preprint":false},{"pmid":"25201008","id":"PMC_25201008","title":"Test-retest reliability of (11)C-ORM-13070 in PET imaging of α2C-adrenoceptors in vivo in the human brain.","date":"2014","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/25201008","citation_count":19,"is_preprint":false},{"pmid":"34894202","id":"PMC_34894202","title":"Chronic stress inhibits testosterone synthesis in Leydig cells through mitochondrial damage via Atp5a1.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34894202","citation_count":18,"is_preprint":false},{"pmid":"24975099","id":"PMC_24975099","title":"Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion.","date":"2014","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24975099","citation_count":17,"is_preprint":false},{"pmid":"24838249","id":"PMC_24838249","title":"¹¹C-ORM-13070, a novel PET ligand for brain α₂C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men.","date":"2014","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/24838249","citation_count":17,"is_preprint":false},{"pmid":"2339522","id":"PMC_2339522","title":"Orosomucoid (ORM) typing by isoelectric focusing: evidence for several new variants including ORM1 and ORM2 silent alleles.","date":"1990","source":"Vox sanguinis","url":"https://pubmed.ncbi.nlm.nih.gov/2339522","citation_count":16,"is_preprint":false},{"pmid":"34520292","id":"PMC_34520292","title":"ATP5A1 Participates in Transcriptional and Posttranscriptional Regulation of Cancer-Associated Genes by Modulating Their Expression and Alternative Splicing Profiles in HeLa Cells.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34520292","citation_count":15,"is_preprint":false},{"pmid":"34177570","id":"PMC_34177570","title":"Repeated Aconitine Treatment Induced the Remodeling of Mitochondrial Function via AMPK-OPA1-ATP5A1 Pathway.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34177570","citation_count":15,"is_preprint":false},{"pmid":"33383036","id":"PMC_33383036","title":"Blockade of sodium‑calcium exchanger via ORM-10962 attenuates cardiac alternans.","date":"2020","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/33383036","citation_count":15,"is_preprint":false},{"pmid":"25522417","id":"PMC_25522417","title":"Amphetamine decreases α2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain.","date":"2014","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25522417","citation_count":15,"is_preprint":false},{"pmid":"35765957","id":"PMC_35765957","title":"ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma.","date":"2022","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35765957","citation_count":14,"is_preprint":false},{"pmid":"25530024","id":"PMC_25530024","title":"Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.","date":"2015","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25530024","citation_count":14,"is_preprint":false},{"pmid":"1379092","id":"PMC_1379092","title":"Comparative mapping of mouse chromosome 4 and human chromosome 9: Lv, Orm, and Hxb are closely linked on mouse chromosome 4.","date":"1992","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/1379092","citation_count":12,"is_preprint":false},{"pmid":"29709784","id":"PMC_29709784","title":"Validation of an LC-MS/MS method for simultaneous quantitation of enzalutamide, N-desmethylenzalutamide, apalutamide, darolutamide and ORM-15341 in mice plasma and its application to a mice pharmacokinetic study.","date":"2018","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/29709784","citation_count":11,"is_preprint":false},{"pmid":"39430254","id":"PMC_39430254","title":"HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39430254","citation_count":10,"is_preprint":false},{"pmid":"11479684","id":"PMC_11479684","title":"Loss of the gene for the alpha subunit of ATP synthase (ATP5A1) from the W chromosome in the African grey parrot (Psittacus erithacus).","date":"2001","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/11479684","citation_count":10,"is_preprint":false},{"pmid":"34483339","id":"PMC_34483339","title":"A recurrent de novo ATP5F1A substitution associated with neonatal complex V deficiency.","date":"2021","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/34483339","citation_count":9,"is_preprint":false},{"pmid":"3162895","id":"PMC_3162895","title":"AIDS: no association with the genetic systems GC (D-binding protein), ORM (orosomucoid = alpha-1-acid glycoprotein), and A2HS (alpha-2-HS-glycoprotein).","date":"1988","source":"Infection","url":"https://pubmed.ncbi.nlm.nih.gov/3162895","citation_count":9,"is_preprint":false},{"pmid":"26562363","id":"PMC_26562363","title":"Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070.","date":"2015","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26562363","citation_count":9,"is_preprint":false},{"pmid":"39540264","id":"PMC_39540264","title":"Chimeric SFT2D2-TBX19 Promotes Prostate Cancer Progression by Encoding TBX19-202 Protein and Stabilizing Mitochondrial ATP Synthase through ATP5F1A Phosphorylation.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39540264","citation_count":8,"is_preprint":false},{"pmid":"33507896","id":"PMC_33507896","title":"Dissecting the regulatory roles of ORM proteins in the sphingolipid pathway of plants.","date":"2021","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/33507896","citation_count":8,"is_preprint":false},{"pmid":"28551395","id":"PMC_28551395","title":"A sandwich ELISA for porcine alpha-1 acid glycoprotein (pAGP, ORM-1) and further demonstration of its use to evaluate growth potential in newborn pigs.","date":"2017","source":"Domestic animal endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28551395","citation_count":8,"is_preprint":false},{"pmid":"38978225","id":"PMC_38978225","title":"BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40.","date":"2024","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38978225","citation_count":7,"is_preprint":false},{"pmid":"34098024","id":"PMC_34098024","title":"Interaction between extracellular ATP5A1 and LPS alleviates LPS-induced neuroinflammation in mice.","date":"2021","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/34098024","citation_count":7,"is_preprint":false},{"pmid":"23604555","id":"PMC_23604555","title":"Real-time monitoring of cell viability and cell density on the basis of a three dimensional optical reflectance method (3D-ORM): investigation of the effect of sub-lethal and lethal injuries.","date":"2013","source":"Journal of industrial microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23604555","citation_count":7,"is_preprint":false},{"pmid":"39167489","id":"PMC_39167489","title":"The structure of the Orm2-containing serine palmitoyltransferase complex reveals distinct inhibitory potentials of yeast Orm proteins.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39167489","citation_count":6,"is_preprint":false},{"pmid":"7547602","id":"PMC_7547602","title":"Serum protein polymorphism in Chuetas (Majorcan Jews)--GC, A2HS, ORM, ITI and HP.","date":"1994","source":"Gene geography : a computerized bulletin on human gene frequencies","url":"https://pubmed.ncbi.nlm.nih.gov/7547602","citation_count":6,"is_preprint":false},{"pmid":"26872993","id":"PMC_26872993","title":"ORM-3819 promotes cardiac contractility through Ca(2+) sensitization in combination with selective PDE III inhibition, a novel approach to inotropy.","date":"2016","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26872993","citation_count":6,"is_preprint":false},{"pmid":"33296042","id":"PMC_33296042","title":"Application of the PET ligand [11C]ORM-13070 to examine receptor occupancy by the α2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.","date":"2020","source":"EJNMMI research","url":"https://pubmed.ncbi.nlm.nih.gov/33296042","citation_count":5,"is_preprint":false},{"pmid":"39456087","id":"PMC_39456087","title":"Integration of fungal transcriptomics and metabolomics provides insights into the early interaction between the ORM fungus Tulasnella sp. and the orchid Serapias vomeracea seeds.","date":"2024","source":"IMA fungus","url":"https://pubmed.ncbi.nlm.nih.gov/39456087","citation_count":5,"is_preprint":false},{"pmid":"38910562","id":"PMC_38910562","title":"Overexpression of ATP5F1A in Cardiomyocytes Promotes Cardiac Reverse Remodeling.","date":"2024","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/38910562","citation_count":4,"is_preprint":false},{"pmid":"41132843","id":"PMC_41132843","title":"Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP-ADO-A1R signaling pathway.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41132843","citation_count":4,"is_preprint":false},{"pmid":"39490931","id":"PMC_39490931","title":"Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.","date":"2024","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/39490931","citation_count":4,"is_preprint":false},{"pmid":"35644505","id":"PMC_35644505","title":"Exogenous Otx2 protects midbrain dopaminergic neurons from MPP+ by interacting with ATP5a1 and promoting ATP synthesis.","date":"2022","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35644505","citation_count":4,"is_preprint":false},{"pmid":"14963818","id":"PMC_14963818","title":"Identification and characterization of polymorphisms at the HAS alpha1-acid glycoprotein (ORM*) gene locus in Caucasians.","date":"2002","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/14963818","citation_count":4,"is_preprint":false},{"pmid":"7811839","id":"PMC_7811839","title":"A linkage study of affective disorder with DNA markers for the ABO-AK1-ORM linkage group near the dopamine beta hydroxylase gene.","date":"1994","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/7811839","citation_count":4,"is_preprint":false},{"pmid":"38511277","id":"PMC_38511277","title":"Emodin Blocks mPTP Opening and Improves LPS-Induced HMEC-1 Cell Injury by Upregulation of ATP5A1.","date":"2024","source":"Chemistry & biodiversity","url":"https://pubmed.ncbi.nlm.nih.gov/38511277","citation_count":3,"is_preprint":false},{"pmid":"41297454","id":"PMC_41297454","title":"Beyond molecular chaperoning: AHA1 reprograms autophagy flux through direct ATP5A1 interaction in ischemic neuronal injury.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/41297454","citation_count":3,"is_preprint":false},{"pmid":"35037261","id":"PMC_35037261","title":"High-intensity interval training along with spirulina algae consumption and caloric restriction ameliorated the Nrf1/Tfam/Mgmt and ATP5A1 pathway in the heart tissue of obese rats.","date":"2022","source":"Journal of food biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35037261","citation_count":3,"is_preprint":false},{"pmid":"41053757","id":"PMC_41053757","title":"ATP5F1A deficiency causes developmental delay and motor dysfunction in humans and zebrafish.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41053757","citation_count":2,"is_preprint":false},{"pmid":"35696782","id":"PMC_35696782","title":"Effects of methanol and formic acid on CRYB, ALDH2, and ATP5A1 of RGCs.","date":"2022","source":"Cutaneous and ocular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35696782","citation_count":2,"is_preprint":false},{"pmid":"37901538","id":"PMC_37901538","title":"Synthesis and Antitumor Activity of Brominated-Ormeloxifene (Br-ORM) against Cervical Cancer.","date":"2023","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/37901538","citation_count":2,"is_preprint":false},{"pmid":"1879829","id":"PMC_1879829","title":"Orosomucoid (ORM 1) subtyping and formal genetics.","date":"1991","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1879829","citation_count":2,"is_preprint":false},{"pmid":"38914676","id":"PMC_38914676","title":"Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrLGlu activity.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38914676","citation_count":1,"is_preprint":false},{"pmid":"40116104","id":"PMC_40116104","title":"Regulating Osteogenic Fate: How Dexamethasone Targets the CAST-CAPN1-ATP5A1 Axis in BMSCs.","date":"2025","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40116104","citation_count":1,"is_preprint":false},{"pmid":"40672495","id":"PMC_40672495","title":"Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40672495","citation_count":0,"is_preprint":false},{"pmid":"41655128","id":"PMC_41655128","title":"SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41655128","citation_count":0,"is_preprint":false},{"pmid":"41879856","id":"PMC_41879856","title":"ATP5A1 succinylation as a key driver for the transition of myocardial ischemia to development of heart failure.","date":"2026","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/41879856","citation_count":0,"is_preprint":false},{"pmid":"39701765","id":"PMC_39701765","title":"[Ginsenoside Rg_1 modulates ATP5A1 deacetylation via SIRT3 to attenuate hypoxia/reoxygenation injury in HL-1 cardiomyocytes].","date":"2024","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/39701765","citation_count":0,"is_preprint":false},{"pmid":"42211829","id":"PMC_42211829","title":"Expression and potential role of ATP5F1A in breast cancer through an integrated in silico and in vitro approach.","date":"2026","source":"In silico pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42211829","citation_count":0,"is_preprint":false},{"pmid":"37526573","id":"PMC_37526573","title":"siRNA targeting Atp5a1 gene encoding ATPase α, the ligand of Peg fimbriae, reduced Salmonella Enteritidis adhesion.","date":"2023","source":"Avian pathology : journal of the W.V.P.A","url":"https://pubmed.ncbi.nlm.nih.gov/37526573","citation_count":0,"is_preprint":false},{"pmid":"42172898","id":"PMC_42172898","title":"SIRT3-mediated deacetylation of ATP5A1 improves mitochondrial function to attenuate myocardial ischemia-reperfusion injury.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42172898","citation_count":0,"is_preprint":false},{"pmid":"41926748","id":"PMC_41926748","title":"Structural alterations in PPP1R13L, SAE1, ATP5A1 and PCK2 disrupt NF-κB signalling and mitochondrial metabolism in primary dermal fibroblasts in systemic sclerosis.","date":"2026","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41926748","citation_count":0,"is_preprint":false},{"pmid":"42121915","id":"PMC_42121915","title":"Intersection of Sphingolipid and Sterol Metabolism at the Level of Orm Proteins in Yeast.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/42121915","citation_count":0,"is_preprint":false},{"pmid":"39479946","id":"PMC_39479946","title":"Preclinical in vitro and in vivo evaluation of [11C]ORM-13070 as PET ligand for alpha-2C adrenergic receptor occupancy using PET imaging in non-human primates.","date":"2024","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39479946","citation_count":0,"is_preprint":false},{"pmid":"41743395","id":"PMC_41743395","title":"A New Case of a Neurodevelopmental Disorder and Myoclonic Dystonia Associated with the C.1404del Variant of the ATP5F1A Gene.","date":"2026","source":"International medical case reports journal","url":"https://pubmed.ncbi.nlm.nih.gov/41743395","citation_count":0,"is_preprint":false},{"pmid":"22833803","id":"PMC_22833803","title":"A genetic polymorphism in the sex-linked ATP5A1 gene is associated with individual fitness in Ovenbirds (Seiurus aurocapilla).","date":"2012","source":"Ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22833803","citation_count":0,"is_preprint":false},{"pmid":"7248496","id":"PMC_7248496","title":"[Plasma protein spectrum of dog blood during treatment of hypoxia with a Sever-OMR membrane oxygenator].","date":"1981","source":"Biulleten' eksperimental'noi biologii i meditsiny","url":"https://pubmed.ncbi.nlm.nih.gov/7248496","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.25341133","title":"Health system response to climate-related shocks in a lower-middle-income country setting: a comparative study of floods and droughts in Pakistan","date":"2025-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.25341133","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.26.684570","title":"Open Raman Microscopy (ORM): A Modular Hardware and Software Framework for Accessible Raman Imaging","date":"2025-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.26.684570","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.24.655932","title":"Evaluation of visual performance for RCS rats: A tailor-made OMR setup via DeepLabCut and Psychopy with a customized algorithm","date":"2025-05-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.24.655932","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.04.663181","title":"Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system","date":"2025-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.04.663181","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.05.25333080","title":"Incidence and outcomes of unstable angina in patients with low high-sensitivity cardiac troponin I values – A substudy of the RACE-IT trial","date":"2025-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.25333080","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.06.647441","title":"Protective Effects of Minocycline and Acetazolamide on Visual Function in Simulated Microgravity Rats","date":"2025-04-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.06.647441","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.08.631981","title":"Breaking boundaries: fungi in the “rhizoctonia” species complex exhibit systemic colonization in three terrestrial orchid species","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.08.631981","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.22.624938","title":"Divergent Visuomotor Strategies in Teleosts: Neural Circuit Mechanisms in Zebrafish and  <i>Danionella cerebrum</i>","date":"2024-11-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.22.624938","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.06.601878","title":"Orchid mycorrhizal communities associated with  <i>Orchis italica</i>  are shaped by ecological factors and geographical gradients","date":"2024-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.06.601878","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.20.689526","title":"Autism-like behavior induced by conditional ablation of the  <i>Bassoon</i>  gene in GABAergic interneurons","date":"2025-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.689526","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.629427","title":"Artificial Embodied Circuits Uncover Neural Architectures of Vertebrate Visuomotor Behaviors","date":"2024-12-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629427","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52133,"output_tokens":6555,"usd":0.127362,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15705,"output_tokens":3747,"usd":0.0861,"stage2_stop_reason":"end_turn"},"total_usd":0.213462,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous mutation in ATP5A1 (coding for complex V subunit α) causes a disturbed interaction of the α-subunit with the β-subunit of complex V, interfering with complex V stability and assembly, resulting in neonatal complex V deficiency. Complementation with wild-type ATP5A1 restored complex V in patient fibroblasts, confirming pathogenicity.\",\n      \"method\": \"Whole exome sequencing, immunoblotting for complex V assembly, oxygen consumption rate measurement, enzyme analysis in fibroblasts, complementation assay, 3D structural modelling\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — complementation assay with functional rescue, enzymatic testing, assembly analysis, structural modelling, all in single rigorous study\",\n      \"pmids\": [\"23599390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Poly(GR) (encoded by C9ORF72 repeat expansion) binds preferentially to the mitochondrial complex V component ATP5A1, enhances its ubiquitination and degradation, leading to reduced ATP5A1 protein levels and mitochondrial dysfunction. Ectopic Atp5a1 expression in poly(GR)-expressing neurons rescued poly(GR)-induced neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation/binding assay in mouse neurons and patient brains, ubiquitination assay, rescue experiment with ectopic Atp5a1 expression in inducible mouse model\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, ubiquitination assay, and in vivo rescue experiment, replicated in both mouse model and patient tissue\",\n      \"pmids\": [\"31086314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mitochondrial calpain-1 cleaves ATP5A1 after CVB3 infection; downregulating ATP5A1 via siRNA impairs mitochondrial function, decreases cell viability, and induces NLRP3 inflammasome activation and pyroptosis, establishing ATP5A1 as the proteolytic target of calpain-1 in the pathway linking viral infection to NLRP3 inflammasome activation.\",\n      \"method\": \"Calpain-1 activation/inhibition experiments in vitro, ATP5A1 siRNA knockdown, NLRP3 inflammasome activation assays, transgenic calpastatin overexpression mice, mitochondria-targeted antioxidant rescue\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with defined phenotypic readout, pharmacological inhibition, transgenic model, and antioxidant rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35997820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNK2/ACK1 tyrosine kinase phosphorylates ATP5F1A at Tyr243 and Tyr246 (Tyr200 and Tyr203 in the mature protein), increasing complex V stability and mitochondrial energy output. Phospho-ATP5F1A prevents binding to its physiological inhibitor ATP5IF1, causing sustained mitochondrial activity. Y243/246A mutant ATP5F1A abolished these effects.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody detection, co-immunoprecipitation with ATP5IF1, site-directed mutagenesis (Y243A/Y246A), TNK2 transgenic mice, mitophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay, mutagenesis, Co-IP with inhibitor, in vivo transgenic mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"35895804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"T. gondii GRA8 interacts with the nucleotide-binding domain of ATP5A1 in mitochondria; GRA8 also interacts with SIRT3, facilitating ATP5A1 deacetylation at K506 and K531, thereby promoting ATP production and anti-septic activity in vivo.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, site-directed deacetylation analysis (K506, K531), PKCα phosphorylation assay, in vivo sepsis model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and site-specific deacetylation identified, single lab with multiple methods including in vivo model\",\n      \"pmids\": [\"29869623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endogenous H2S (produced by CBS) S-sulfhydrates ATP5A1 at cysteine 244. Reduced H2S in CBS+/- or LPS-treated mice decreases S-sulfhydrated ATP5A1 levels, leading to mitochondrial-mediated apoptosis and adrenal insufficiency. Overexpression of a C244 mutant ATP5A1 caused loss of LPS-induced apoptosis and restored ACTH responsiveness.\",\n      \"method\": \"Maleimide assay combined with mass spectrometry, modified biotin switch assay, CBS+/- mice, site-directed mutagenesis (C244), GYY4137 H2S donor rescue, ACTH response assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific PTM identified by MS and biochemical assay, mutagenesis, genetic KO model, pharmacological rescue — multiple orthogonal methods\",\n      \"pmids\": [\"29486221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A 4-nucleotide duplication in exon 3 of Atp5a1 (encoding ATP synthase α-subunit) causes a recessive embryonic lethal phenotype in mice and acts as a modifier of ApcMin-induced intestinal tumorigenesis (Mom2 locus), with adenomas in carriers tending to progress to carcinomas in the absence of APC LOH.\",\n      \"method\": \"Linkage analysis, exome sequencing, expression analysis, tumor analysis, congenic mouse intercross\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model with defined phenotypic readout, sequence and expression analysis, single lab\",\n      \"pmids\": [\"17387143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Atp5a1 knockdown in Leydig cells via siRNA decreased StAR, CYP11A1, and 17β-HSD expression by damaging mitochondrial structure, establishing Atp5a1 as required for mitochondrial integrity and steroidogenesis in response to chronic stress.\",\n      \"method\": \"2-DE and MALDI-TOF-MS protein identification, Atp5a1 siRNA transfection in TM3 cells, mitochondrial structure analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype, proteomic identification, single lab with two orthogonal methods\",\n      \"pmids\": [\"34894202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Recurrent de novo ATP5F1A substitution c.620G>A [p.(Arg207His)] causes multiple deficits in complex V function and expression in patient-derived fibroblasts. Structural modelling predicts this creates an abnormal region of negative charge on ATP5F1A's β-subunit-interacting surface adjacent to the active site.\",\n      \"method\": \"Exome sequencing, functional assays in patient fibroblasts (complex V activity and expression), structural modelling\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional fibroblast assays and structural modelling, single lab, three independent probands\",\n      \"pmids\": [\"34483339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATP5A1 overexpression in HeLa cells significantly promotes cellular apoptosis (but not proliferation) and modulates expression of genes associated with innate immune response, angiogenesis, and MMP2/MMP19, as well as altering alternative splicing of hundreds of genes including those in HIF-1 signaling and glucose homeostasis pathways.\",\n      \"method\": \"Plasmid overexpression, RNA-seq transcriptomics, flow cytometry apoptosis assay, RT-qPCR validation\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with transcriptomic readout but no direct mechanistic pathway placement for the apoptosis induction\",\n      \"pmids\": [\"34520292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Repeated aconitine treatment upregulates ATP5A1 via the AMPK-OPA1-ATP5A1 pathway, increasing mitochondrial fusion, biogenesis, and cellular ATP content in cardiomyocytes; AMPK inhibitor compound C reversed the increases in phospho-AMPK, OPA1, and ATP5A1.\",\n      \"method\": \"Pharmacological AMPK inhibition (compound C), Western blot, mitochondrial morphology analysis, ATP content measurement in NRVMs\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition with pathway markers, single lab, no genetic confirmation of pathway order\",\n      \"pmids\": [\"34177570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATP synthase subunit alpha (ATPase α / ATP5A1) serves as a cell-surface ligand for Salmonella Enteritidis Peg fimbriae adhesion protein PegD; siRNA knockdown of Atp5a1 in LMH cells significantly reduced S. Enteritidis adhesion.\",\n      \"method\": \"Ligand blotting, mass spectrometry, in vitro binding assay with purified PegD, siRNA knockdown with adhesion rate quantification\",\n      \"journal\": \"Avian pathology : journal of the W.V.P.A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, siRNA loss-of-function with specific adhesion readout, mass spectrometry identification, single lab\",\n      \"pmids\": [\"37526573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPD1 (HSP60) interacts with ATP5A1 (identified by Co-IP/MS) and reduces K48-linked ubiquitination and degradation of ATP5A1, thereby stabilizing it and activating AKT/mTOR signaling to promote osteosarcoma progression.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry, Western blot for ubiquitination, in vitro and in vivo proliferation/apoptosis assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification, ubiquitination analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39430254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Extracellular recombinant ATP5A1 binds LPS directly (demonstrated by cellular thermal shift assay and ELISA-based binding assay), and intracerebroventricular injection of rATP5A1 suppresses LPS-induced neuroinflammation, microglial/astrocyte activation, IL-1β accumulation, and tau phosphorylation in mice.\",\n      \"method\": \"Cellular thermal shift assay, ELISA-based binding assay, intracerebroventricular injection in mouse model, behavioral assays\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay confirmed by two orthogonal methods, in vivo rescue experiment, single lab\",\n      \"pmids\": [\"34098024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exogenous Otx2 recombinant protein interacts with ATP5a1 in midbrain dopaminergic neurons and promotes ATP synthesis, protecting these neurons against MPP+-induced neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, ATP synthesis assay, primary neuron culture with MPP+ treatment\",\n      \"journal\": \"Neurotoxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, partial mechanistic follow-up\",\n      \"pmids\": [\"35644505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chimeric SFT2D2-TBX19 (as lncRNA) interacts with ATP5F1A, increasing its TNK2/ACK1-mediated phosphorylation and stabilizing the interaction between ATP5F1A and ATP5F1B, thereby enhancing mitochondrial ATP synthase activity and ATP production in prostate cancer cells.\",\n      \"method\": \"RNA pulldown, Co-immunoprecipitation, phosphorylation assay, ATP production measurement, functional domain mapping\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNA pulldown with functional domain mapping, ATP production measured, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39540264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cannabidiol (CBD) directly targets ATP5A1 and prevents METH-induced ubiquitination of ATP5A1 at residue D376, reversing METH-induced reduction of ATP5A1 protein and promoting ATP synthase assembly. ATP5A1 knockdown in the ventral tegmental area reversed CBD's therapeutic efficacy against METH addiction behaviors.\",\n      \"method\": \"Activity-based protein profiling (target fishing), ubiquitination assay, site-specific mutagenesis (D376), siRNA knockdown in VTA in vivo, behavioral assays (locomotor sensitization, CPP)\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical proteomics target identification, site-specific mutagenesis, in vivo siRNA knockdown with behavioral readout, multiple orthogonal methods\",\n      \"pmids\": [\"41132843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AHA1 (AHSA1) translocates to mitochondria under ischemia/reperfusion stress and directly interacts with ATP5A1, disrupting the cellular ATP/AMP ratio and increasing ROS production, leading to AMPK/mTOR/ULK1-mediated excessive mitophagy. AHA1 silencing suppressed pathological mitophagy and reduced infarct volume.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, MCAO/R mouse model and OGD/R cell model, AMPK/mTOR pathway analysis, behavioral tests\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of direct interaction, siRNA with defined pathway phenotype, in vivo and in vitro models, single lab\",\n      \"pmids\": [\"41297454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT3 deacetylates ATP5A1 at lysine 498; reduced SIRT3 in LPS-induced acute lung injury leads to acetylation of ATP5F1A/K498, impairing mitophagy and promoting endothelial ferroptosis. Downregulating ATP5F1A acetylation prevents SIRT3 inhibition from blocking SIGMAR1-mediated mitophagy and ferroptosis protection.\",\n      \"method\": \"Site-specific acetylation analysis (K498), SIRT3 knockout/activator, siRNA, PINK1/Parkin mitophagy assays, ALI mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific deacetylation (K498) identified, genetic KO and pharmacological activation, in vivo ALI model, multiple orthogonal methods\",\n      \"pmids\": [\"41655128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Succinylation of ATP5A1 at K531 (by CPT1A as trans-succinylase, reversed by SIRT5 as desuccinylase) impedes ATP synthase assembly and impairs its activity. ATP5A1-K531R mutant (abolishing succinylation) delivered by AAV9 protected against ischemia-induced cardiomyocyte death and heart failure development.\",\n      \"method\": \"Succinylation proteomic analysis, site-directed mutagenesis (K531R), AAV9 cardiac-specific delivery, ATP synthase activity assay, OGD cardiomyocyte model, LAD ligation mouse model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific PTM identified by proteomics, mutagenesis, in vitro activity assay, in vivo cardiac model with functional readout\",\n      \"pmids\": [\"41879856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT3 deacetylates ATP5A1, improving mitochondrial membrane potential, decreasing ROS, enhancing mitochondrial respiration and inhibiting cardiomyocyte apoptosis in ischemia-reperfusion injury. SIRT3 overexpression significantly reduced ATP5A1 acetylation; SIRT3 inhibition exacerbated mitochondrial damage.\",\n      \"method\": \"Co-immunoprecipitation, point mutation analysis, SIRT3 overexpression/inhibitor in MIRI mouse model and H/R HL-1 cells, mitochondrial membrane potential, ROS, respiration assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with point mutation, pharmacological and genetic manipulation, in vivo and in vitro models, single lab\",\n      \"pmids\": [\"42172898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo heterozygous missense ATP5F1A variants cause dominant negative disruption of complex V, leading to markedly reduced complex V abundance and activity in proband-derived blood cells and fibroblasts, increased oxygen consumption yet decreased mitochondrial membrane potential and ATP levels (uncoupled oxidative phosphorylation), associated with developmental delay and movement disorders.\",\n      \"method\": \"Functional evaluation in C. elegans (dominant negative mechanism), biochemical assays in patient blood cells/fibroblasts, proteomics for complex V abundance, mitochondrial physiology in fibroblasts\",\n      \"journal\": \"medRxiv : the preprint server for health sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (C. elegans genetics, proteomics, biochemical activity, mitochondrial physiology) across 6 independent probands\",\n      \"pmids\": [\"40672495\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRG1 promotes ATP5A1 synthesis in liver cancer via TOMM40; BRG1 knockdown decreased ATP5A1 expression, impaired mitochondrial function (reduced MMP, increased mPTP opening), and promoted apoptosis in HCC cells.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, ICC/IF staining, Western blot, mitochondrial membrane potential and mPTP assays\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown/overexpression with pathway markers, no direct mechanistic confirmation of BRG1-TOMM40-ATP5A1 order\",\n      \"pmids\": [\"38978225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, atp5fa1 knockdown causes motor dysfunction, impaired motor neuron axon development, and growth retardation; rescue with human wild-type ATP5F1A mRNA partially restored motor neuron morphology. Knockdown increased P62 and decreased Lc3b-II, indicating inhibition of autophagy flux.\",\n      \"method\": \"Morpholino knockdown in zebrafish, mRNA rescue experiment, Western blot (P62, LC3B-II), motor neuron imaging in Tg(mnx1:eGFP) zebrafish, RNA-seq\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with mRNA rescue and defined neuronal phenotype, autophagy pathway markers, single lab\",\n      \"pmids\": [\"41053757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dexamethasone inhibits osteogenic differentiation in BMSCs by modulating the CAST-CAPN1 axis to suppress ATP5A1 expression and reduce ATP activity; CAST overexpression partially mitigated these effects while CAPN1 overexpression exacerbated them, placing ATP5A1 downstream of calpain regulation.\",\n      \"method\": \"CAST/CAPN1 overexpression plasmids in rat BMSCs, Western blot, qRT-PCR, Alizarin Red S staining, ELISA for ATP activity\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with functional readout, indirect pathway placement\",\n      \"pmids\": [\"40116104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of ATP5F1A in cardiomyocytes via cardiomyocyte-specific AAV9 improved heart function and morphology, and reduced fibrosis and cardiomyocyte size in transverse aortic constriction and dilated cardiomyopathy mouse heart failure models, identifying ATP5F1A as a mediator of cardiac reverse remodeling.\",\n      \"method\": \"Single-nucleus RNA sequencing of human CRR/non-CRR hearts, AAV9-mediated cardiomyocyte-specific overexpression in mouse HF models, echocardiography, pathological staining\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — snRNA-seq identification followed by in vivo AAV9 overexpression with functional cardiac readout, single lab with two orthogonal approaches\",\n      \"pmids\": [\"38910562\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP5F1A encodes the α-subunit of mitochondrial complex V (ATP synthase F1), where it forms the catalytic core with the β-subunit; its stability, assembly, and activity are regulated by multiple post-translational modifications including TNK2/ACK1-mediated phosphorylation at Tyr243/246 (which blocks inhibitor ATP5IF1 binding and sustains ATP synthesis), SIRT3-mediated deacetylation at multiple lysines (K498, K506, K531), H2S-mediated S-sulfhydration at Cys244 (protecting mitochondrial function), calpain-1-mediated cleavage (impairing function and activating NLRP3 inflammasome), K531 succinylation by CPT1A (impeding assembly), and poly(GR)-induced ubiquitination/degradation; pathogenic mutations disrupt α–β subunit interaction and complex V assembly, causing mitochondrial encephalopathy and other neurological disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP5F1A encodes the catalytic α-subunit of mitochondrial complex V (ATP synthase F1), where its interaction with the β-subunit forms the catalytic core required for complex V stability, assembly, and ATP synthesis [#0, #15]. Heterozygous and recurrent de novo missense variants disrupt the α–β subunit interface adjacent to the active site, destabilizing complex V and causing complex V deficiency with a dominant-negative, uncoupled oxidative-phosphorylation phenotype underlying neonatal mitochondrial encephalopathy, developmental delay, and movement disorders [#0, #8, #21]. The α-subunit is a hub for post-translational regulation that tunes complex V activity: TNK2/ACK1-mediated phosphorylation at Tyr243/Tyr246 stabilizes the enzyme and blocks binding of its inhibitor ATP5IF1 to sustain energy output [#3]; SIRT3-mediated deacetylation at K498 (and additional lysines) and H2S-dependent S-sulfhydration at Cys244 protect mitochondrial function, mitophagy, and resistance to ferroptosis and apoptosis [#5, #18]; whereas CPT1A-driven K531 succinylation impedes assembly and impairs activity, and calpain-1 cleavage degrades the protein, impairing mitochondrial function and triggering NLRP3 inflammasome activation [#2, #19]. Its abundance is further controlled by ubiquitin-dependent degradation, which is enhanced by C9ORF72-derived poly(GR) and by methamphetamine (at D376), and is counteracted by stabilizing partners such as HSPD1 [#1, #12, #16]. Loss of ATP5F1A compromises mitochondrial integrity in diverse cell types, impairing steroidogenesis, motor-neuron axon development, and autophagy flux, while its restoration rescues neurotoxicity and cardiac dysfunction in disease models [#7, #23, #25]. ATP5F1A additionally functions at the cell surface as a binding partner for extracellular ligands including LPS and bacterial adhesins [#11, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that Atp5a1 is essential in vivo and can modify a tumor phenotype, the first evidence linking this subunit to organismal viability and disease beyond bioenergetics catalogues.\",\n      \"evidence\": \"Linkage analysis and congenic mouse intercross of an exon 3 duplication allele as the Mom2 modifier of ApcMin tumorigenesis\",\n      \"pmids\": [\"17387143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of tumor modification not resolved\", \"No human disease link established at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the disease mechanism by which ATP5F1A mutations cause complex V deficiency: a disturbed α–β subunit interaction destabilizing assembly, with functional rescue confirming causality.\",\n      \"evidence\": \"Whole exome sequencing, complex V assembly immunoblotting, oxygen consumption, and complementation rescue in patient fibroblasts plus structural modelling\",\n      \"pmids\": [\"23599390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single mutation; allelic spectrum unknown\", \"Structural prediction not experimentally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that the α-subunit is regulated by reversible post-translational modifications — S-sulfhydration at Cys244 and SIRT3-mediated deacetylation — that protect mitochondrial function and cell survival.\",\n      \"evidence\": \"Biotin-switch/maleimide MS for sulfhydration (CBS+/- mice, C244 mutant, H2S donor rescue) and Co-IP/MS for GRA8–SIRT3-driven deacetylation at K506/K531 in a sepsis model\",\n      \"pmids\": [\"29486221\", \"29869623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How each PTM mechanistically alters catalysis or assembly not detailed\", \"Crosstalk between modifications unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ATP5F1A abundance to neurodegeneration, showing C9ORF72-derived poly(GR) drives its ubiquitination and degradation as a cause of mitochondrial dysfunction.\",\n      \"evidence\": \"Co-IP/binding assays in mouse neurons and patient brains, ubiquitination assay, and in vivo rescue by ectopic Atp5a1 expression\",\n      \"pmids\": [\"31086314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating poly(GR)-induced ubiquitination not identified\", \"Ubiquitination site not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ATP5F1A function beyond the matrix, identifying a cell-surface/extracellular role as an LPS-binding protein and establishing requirement for mitochondrial integrity in steroidogenesis.\",\n      \"evidence\": \"Thermal shift and ELISA binding with intracerebroventricular rATP5A1 in neuroinflammation; siRNA knockdown in Leydig cells with steroidogenic enzyme readouts\",\n      \"pmids\": [\"34098024\", \"34894202\", \"34483339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of surface localization unexplained\", \"Overexpression/knockdown phenotypes may be indirect\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped activating phosphorylation and degradative cleavage as opposing controls of complex V output: TNK2/ACK1 phosphorylation at Tyr243/246 blocks ATP5IF1 inhibition, while calpain-1 cleavage degrades the subunit and triggers NLRP3 inflammasome activation.\",\n      \"evidence\": \"In vitro kinase assay, Y243/246A mutagenesis, Co-IP with ATP5IF1, TNK2 transgenic mice; calpain-1 inhibition/siRNA with NLRP3/pyroptosis readouts and calpastatin transgenic mice\",\n      \"pmids\": [\"35895804\", \"35997820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain-1 cleavage site not defined\", \"Stoichiometry of phospho-ATP5F1A in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified protein and RNA partners that stabilize ATP5F1A — HSPD1 reducing K48 ubiquitination and a chimeric lncRNA enhancing TNK2 phosphorylation — coupling its abundance to growth signaling and cancer progression.\",\n      \"evidence\": \"Co-IP/MS and ubiquitination blots (HSPD1/osteosarcoma); RNA pulldown, Co-IP, and ATP measurement (SFT2D2-TBX19/prostate cancer)\",\n      \"pmids\": [\"39430254\", \"39540264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect stabilization not fully separated\", \"Single-lab findings without reciprocal validation across systems\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated the dominant-negative disease mechanism in humans and identified ATP5F1A as a druggable node, with cannabidiol preventing METH-induced ubiquitination at D376 to restore ATP synthase assembly.\",\n      \"evidence\": \"C. elegans dominant-negative modelling plus proteomics and mitochondrial physiology in patient cells (preprint); activity-based protein profiling, D376 mutagenesis, and in vivo VTA siRNA with behavioral readouts for CBD\",\n      \"pmids\": [\"40672495\", \"41132843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disease genetics from a preprint awaiting peer review\", \"E3 ligase acting at D376 not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved competing lysine modifications controlling assembly and stress survival: SIRT3 deacetylation at K498 enables protective mitophagy, while CPT1A-driven K531 succinylation impedes assembly, with site-mutant rescue protecting against cardiac ischemic injury.\",\n      \"evidence\": \"Site-specific acetylation analysis with SIRT3 KO/activator and mitophagy assays (ALI model); succinylation proteomics, K531R mutagenesis, AAV9 cardiac delivery, and activity assays (ischemia models)\",\n      \"pmids\": [\"41655128\", \"41879856\", \"42172898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between K498/K506/K531 modifications not integrated\", \"Quantitative contribution of each PTM to assembly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse post-translational modifications, partner interactions, and reported extracellular functions are coordinately integrated to set ATP5F1A levels and complex V activity in a given tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of competing PTMs and degradation pathways\", \"Mechanism of cell-surface localization unexplained\", \"E3 ligases for ubiquitin-dependent turnover unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 15, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 4, 5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 8, 21, 1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 18, 23]}\n    ],\n    \"complexes\": [\"mitochondrial ATP synthase (complex V) F1\"],\n    \"partners\": [\"ATP5F1B\", \"ATP5IF1\", \"TNK2\", \"SIRT3\", \"CPT1A\", \"HSPD1\", \"CAPN1\", \"AHSA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}