{"gene":"ATP5PD","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2018,"finding":"Epigenetic loss of ATP5H (ATP synthase subunit d) in tumor cells leads to ROS accumulation and HIF-1α stabilization under normoxia, conferring a stem-like and invasive phenotype and cross-resistance to immunotherapy, chemotherapy, and radiotherapy. In vivo antioxidant delivery reversed these phenotypic changes and resensitized tumor cells to therapy.","method":"Sequential in vitro/in vivo immune selection of murine and human tumor cells, followed by molecular analysis of epigenetic changes, ROS measurement, HIF-1α stabilization assays, and in vivo antioxidant rescue experiments","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments in vitro and in vivo, multiple orthogonal methods (epigenetic analysis, ROS assay, HIF-1α stabilization, phenotypic rescue), replicated in murine and human tumor systems","pmids":["30124467"],"is_preprint":false},{"year":2013,"finding":"ATP5H (subunit d of the ATP synthase F0 complex) directly interacts with ATP5F1 (another F0 subunit), and both interactions are significantly decreased in interfibrillar mitochondria (IFM) of type 1 diabetic hearts, coinciding with decreased ATP synthase activity.","method":"Co-immunoprecipitation/pulldown to identify novel direct interactions between ATP synthase F0 subunits; Western blot quantification; ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin-induced diabetic FVB mice","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction identified by pulldown with functional activity assay, single lab, two orthogonal methods","pmids":["23872101"],"is_preprint":false},{"year":2015,"finding":"Knockdown of the d-subunit (ATP5H/ATP5PD) in human cells prevents formation of the ATP synthase holocomplex; instead, two separate subcomplexes accumulate: one containing the central rotor shaft plus catalytic subunits (F1-c-ring) and one containing stator stalk components (b-e-g complex), establishing that ATP5H is required for final assembly of the stator stalk with the rotor module.","method":"siRNA knockdown of d-subunit expression in human cells, followed by analysis of subcomplex accumulation by native PAGE and immunoblotting; additional knockdowns of mtDNA-encoded a-subunit and A6L to confirm F1-c-ring formation","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — clean knockdown with defined biochemical phenotype (subcomplex accumulation), multiple subunit knockdowns used as controls, clear mechanistic conclusion about assembly pathway","pmids":["26297831"],"is_preprint":false},{"year":2017,"finding":"Knockdown of C. elegans ortholog of ATP5H is associated with increased amyloid-β toxicity in a transgenic C. elegans Aβ proteotoxicity model, placing ATP5H in a pathway relevant to Aβ-mediated neurodegeneration.","method":"RNA interference (RNAi) knockdown of ATP5H C. elegans ortholog in a transgenic C. elegans Aβ proteotoxicity model; phenotypic readout of Aβ toxicity","journal":"Alzheimer's & Dementia","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with defined phenotypic readout in a model organism, single lab, single method","pmids":["28242297"],"is_preprint":false},{"year":2023,"finding":"Dihydroartemisinin (DHA) reduces ATP5H protein and mRNA expression in liver cancer cells via the CaMKK2/NCLX signaling pathway; knockdown of NCLX reproduced CaMKK2-mediated downregulation of ATP5H, placing ATP5H downstream of CaMKK2/NCLX in regulation of mitochondrial ATP production and cell migration/invasion.","method":"Western blotting and RT-qPCR for ATP5H expression; CaMKK2 overexpression and NCLX siRNA knockdown in HepG2 and HuH-7 cells; ATP fluorescent probe measurement; wound healing and Transwell invasion assays","journal":"Oncology Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by siRNA knockdown of upstream regulator, multiple orthogonal methods (expression, functional assays), single lab","pmids":["38020296"],"is_preprint":false},{"year":2021,"finding":"ATP5H (ATP5PD) protein abundance is elevated in spermatozoa from patients with repetitive fertilization failure after ICSI compared to controls with normal fertilization rates, suggesting altered mitochondrial function associated with fertilization failure.","method":"2D-LC-MS/MS quantitative proteomics of individual sperm samples; Western blot validation of selected proteins; JC-1 staining for mitochondrial membrane potential","journal":"Andrology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proteomics without functional manipulation of ATP5H specifically, only associative finding for this protein","pmids":["33615715"],"is_preprint":false},{"year":2012,"finding":"ATP5H is detected in both mitochondrial and nuclear fractions of MCF7 breast cancer cells, indicating dual subcellular localization of this oxidative phosphorylation subunit.","method":"Concurrent proteomics analysis of isolated nuclei and mitochondria from MCF7 cells; protein identification by mass spectrometry","journal":"Journal of Proteome Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proteomic identification without functional follow-up of the nuclear localization","pmids":["23051583"],"is_preprint":false},{"year":2021,"finding":"In a FACS-based workflow, ATP5H (nuclear-encoded mitochondrial protein) protein levels are used as a reference for mitochondrial content, and the ratio of MTCO1 (mtDNA-encoded) to ATP5H fluorescence intensity reports on mtDNA genomic stability, since MTCO1 is selectively depleted when mtDNA is damaged.","method":"FACS-based simultaneous measurement of ATP5H and MTCO1 protein levels by intracellular antibody staining; downstream qPCR for mtDNA copy number validation","journal":"BioChem","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, methodological application paper; establishes utility of ATP5H as stable nuclear-encoded mitochondrial reference but does not test ATP5H function directly","pmids":["35937039"],"is_preprint":false}],"current_model":"ATP5H (ATP5PD) is a peripheral stator stalk subunit (subunit d) of the mitochondrial F1Fo-ATP synthase that is required for holocomplex assembly — its loss causes accumulation of separate F1-c-ring and b-e-g stator sub-intermediates; it directly interacts with the F0 subunit ATP5F1 in a cardiolipin-dependent manner that is disrupted in diabetic heart; and epigenetic silencing of ATP5H in tumor cells triggers ROS accumulation and HIF-1α stabilization under normoxia, driving a stem-like, therapy-resistant phenotype that is reversed by antioxidant treatment."},"narrative":{"mechanistic_narrative":"ATP5PD (ATP5H, subunit d) is a stator stalk subunit of the mitochondrial F1Fo-ATP synthase that is required for assembly of the holocomplex: its depletion blocks joining of the stator stalk to the rotor module, causing accumulation of separate F1-c-ring and b-e-g stator sub-intermediates [PMID:26297831]. It directly contacts the F0 subunit ATP5F1, an interaction that is reduced in interfibrillar mitochondria of diabetic hearts in parallel with falling ATP synthase activity [PMID:23872101]. Beyond its structural role, epigenetic silencing of ATP5H in tumor cells drives ROS accumulation and normoxic HIF-1α stabilization, conferring a stem-like, invasive, therapy-resistant phenotype that is reversed by antioxidant treatment [PMID:30124467], and its expression is regulated downstream of CaMKK2/NCLX signaling in liver cancer cells where it controls mitochondrial ATP production and cell migration [PMID:38020296]. A model-organism study links loss of the ATP5H ortholog to enhanced amyloid-β proteotoxicity [PMID:28242297]. No structural model of how subunit d bridges the stator and rotor modules has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established that subunit d physically engages another F0 subunit and that this contact is functionally coupled to enzyme output, framing ATP5H as a structural node within the membrane sector.","evidence":"Co-IP/pulldown plus ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin diabetic mice","pmids":["23872101"],"confidence":"Medium","gaps":["Single lab, no reciprocal validation of the ATP5F1 interaction","Cardiolipin dependence of the interaction not directly tested here","Correlative link between reduced interaction and lower activity, not causal"]},{"year":2015,"claim":"Resolved the assembly role of ATP5H by showing its loss arrests holocomplex formation at defined sub-intermediates, establishing subunit d as the factor that joins the stator stalk to the rotor module.","evidence":"siRNA knockdown in human cells with native PAGE and immunoblotting, plus control knockdowns of mtDNA-encoded subunits","pmids":["26297831"],"confidence":"High","gaps":["No structural model of the bridging interface","Order of subunit addition during assembly not fully resolved","Whether residual holocomplex retains activity untested"]},{"year":2017,"claim":"Connected ATP5H to neurodegeneration-relevant proteostasis by showing ortholog loss aggravates amyloid-β toxicity.","evidence":"RNAi knockdown of the C. elegans ortholog in a transgenic Aβ proteotoxicity model with phenotypic readout","pmids":["28242297"],"confidence":"Medium","gaps":["Single method in a model organism","Mechanism linking ATP synthase function to Aβ toxicity unknown","No mammalian validation"]},{"year":2018,"claim":"Revealed a non-canonical consequence of ATP5H loss: epigenetic silencing triggers ROS-driven normoxic HIF-1α stabilization and a therapy-resistant stem-like state, reversible by antioxidants.","evidence":"Immune selection of murine and human tumor cells with epigenetic, ROS, HIF-1α assays and in vivo antioxidant rescue","pmids":["30124467"],"confidence":"High","gaps":["Mechanism linking ATP synthase deficiency to ROS rise not fully dissected","Direct test of whether assembly defect causes the ROS phenotype absent","Generalizability across tumor types beyond models tested"]},{"year":2023,"claim":"Placed ATP5H downstream of a defined signaling axis by showing CaMKK2/NCLX controls its expression and thereby mitochondrial ATP output and cell motility.","evidence":"CaMKK2 overexpression and NCLX siRNA in HepG2/HuH-7 cells with expression, ATP probe, and migration/invasion assays","pmids":["38020296"],"confidence":"Medium","gaps":["Single lab, mechanism of transcriptional/translational regulation unresolved","Direct binding of regulators to ATP5H locus not shown","Contribution of ATP5H specifically to migration vs. bystander effect"]},{"year":null,"claim":"How the assembly defect, ATP5F1/cardiolipin interaction, and the downstream ROS/HIF-1α and signaling phenotypes mechanistically connect into a single causal chain remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of subunit d at the stator-rotor interface","Causal link between assembly failure and ROS accumulation untested","Cardiolipin dependence of the ATP5F1 contact not directly demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,1]}],"complexes":["F1Fo-ATP synthase"],"partners":["ATP5F1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75947","full_name":"ATP synthase peripheral stalk subunit d, mitochondrial","aliases":["ATP synthase peripheral stalk subunit d"],"length_aa":161,"mass_kda":18.5,"function":"Subunit d, 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 (PubMed:37244256). 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). Part of the complex F(0) domain (PubMed:37244256). Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements (By similarity)","subcellular_location":"Mitochondrion; Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/O75947/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP5PD","classification":"Not Classified","n_dependent_lines":345,"n_total_lines":1208,"dependency_fraction":0.2855960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NVL","stoichiometry":10.0},{"gene":"STK4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATP5PD","total_profiled":1310},"omim":[{"mim_id":"618121","title":"ATP SYNTHASE PERIPHERAL STALK, SUBUNIT D; ATP5PD","url":"https://www.omim.org/entry/618121"},{"mim_id":"607196","title":"MICROCEPHALY, AMISH TYPE; MCPHA","url":"https://www.omim.org/entry/607196"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP5PD"},"hgnc":{"alias_symbol":["ATPQ","ATP5JD"],"prev_symbol":["ATP5H"]},"alphafold":{"accession":"O75947","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75947","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75947-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75947-F1-predicted_aligned_error_v6.png","plddt_mean":86.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP5PD","jax_strain_url":"https://www.jax.org/strain/search?query=ATP5PD"},"sequence":{"accession":"O75947","fasta_url":"https://rest.uniprot.org/uniprotkb/O75947.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75947/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75947"}},"corpus_meta":[{"pmid":"23857120","id":"PMC_23857120","title":"ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.","date":"2013","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23857120","citation_count":58,"is_preprint":false},{"pmid":"26913989","id":"PMC_26913989","title":"Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.","date":"2016","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26913989","citation_count":55,"is_preprint":false},{"pmid":"30342406","id":"PMC_30342406","title":"Mitochondrial respiratory chain complex abnormal expressions and fusion disorder are involved in fluoride-induced mitochondrial dysfunction in ovarian granulosa cells.","date":"2018","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/30342406","citation_count":52,"is_preprint":false},{"pmid":"20472544","id":"PMC_20472544","title":"Characterization of the N-ATPase, a distinct, laterally transferred Na+-translocating form of the bacterial F-type membrane ATPase.","date":"2010","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20472544","citation_count":51,"is_preprint":false},{"pmid":"23874806","id":"PMC_23874806","title":"Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23874806","citation_count":45,"is_preprint":false},{"pmid":"29843597","id":"PMC_29843597","title":"Understanding the regulatory mechanisms of milk production using integrative transcriptomic and proteomic analyses: improving inefficient utilization of crop by-products as forage in dairy industry.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29843597","citation_count":44,"is_preprint":false},{"pmid":"30124467","id":"PMC_30124467","title":"Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30124467","citation_count":41,"is_preprint":false},{"pmid":"27466200","id":"PMC_27466200","title":"Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3β-mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1).","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27466200","citation_count":40,"is_preprint":false},{"pmid":"20667664","id":"PMC_20667664","title":"Differentially expressed proteins during fat accumulation in bovine skeletal muscle.","date":"2010","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/20667664","citation_count":37,"is_preprint":false},{"pmid":"21060993","id":"PMC_21060993","title":"Quantitative proteomic analysis of dexamethasone-induced effects on osteoblast differentiation, proliferation, and apoptosis in MC3T3-E1 cells using SILAC.","date":"2011","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/21060993","citation_count":37,"is_preprint":false},{"pmid":"20440404","id":"PMC_20440404","title":"Analysis of differentially expressed mitochondrial proteins in chromophobe renal cell carcinomas and renal oncocytomas by 2-D gel electrophoresis.","date":"2010","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20440404","citation_count":35,"is_preprint":false},{"pmid":"28261761","id":"PMC_28261761","title":"ATP5J and ATP5H Proactive Expression Correlates with Cardiomyocyte Mitochondrial Dysfunction Induced by Fluoride.","date":"2017","source":"Biological trace element research","url":"https://pubmed.ncbi.nlm.nih.gov/28261761","citation_count":34,"is_preprint":false},{"pmid":"33173336","id":"PMC_33173336","title":"Circ-ATP5H Induces Hepatitis B Virus Replication and Expression by Regulating miR-138-5p/TNFAIP3 Axis.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33173336","citation_count":34,"is_preprint":false},{"pmid":"27847319","id":"PMC_27847319","title":"Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance, metabolic defects, apoptosis, and molecular signatures of immune activation in response to infections.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27847319","citation_count":34,"is_preprint":false},{"pmid":"28242297","id":"PMC_28242297","title":"Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.","date":"2017","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/28242297","citation_count":33,"is_preprint":false},{"pmid":"29593495","id":"PMC_29593495","title":"Mitochondrial Molecular Abnormalities Revealed by Proteomic Analysis of Hippocampal Organelles of Mice Triple Transgenic for Alzheimer Disease.","date":"2018","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29593495","citation_count":31,"is_preprint":false},{"pmid":"23051583","id":"PMC_23051583","title":"Spatial distribution of cellular function: the partitioning of proteins between mitochondria and the nucleus in MCF7 breast cancer cells.","date":"2012","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/23051583","citation_count":31,"is_preprint":false},{"pmid":"23872101","id":"PMC_23872101","title":"Evaluation of the cardiolipin biosynthetic pathway and its interactions in the diabetic heart.","date":"2013","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23872101","citation_count":30,"is_preprint":false},{"pmid":"26297831","id":"PMC_26297831","title":"Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26297831","citation_count":29,"is_preprint":false},{"pmid":"27338255","id":"PMC_27338255","title":"Fatal familial insomnia: mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus.","date":"2016","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/27338255","citation_count":22,"is_preprint":false},{"pmid":"29383422","id":"PMC_29383422","title":"Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.","date":"2018","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29383422","citation_count":19,"is_preprint":false},{"pmid":"34277444","id":"PMC_34277444","title":"Current Molecular Biology and Therapeutic Strategy Status and Prospects for circRNAs in HBV-Associated Hepatocellular Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34277444","citation_count":18,"is_preprint":false},{"pmid":"33053689","id":"PMC_33053689","title":"Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33053689","citation_count":18,"is_preprint":false},{"pmid":"26412427","id":"PMC_26412427","title":"Proteomic analysis of hepatocellular carcinoma HepG2 cells treated with platycodin D.","date":"2015","source":"Chinese journal of natural medicines","url":"https://pubmed.ncbi.nlm.nih.gov/26412427","citation_count":18,"is_preprint":false},{"pmid":"31291894","id":"PMC_31291894","title":"Comparative proteomic analysis of Tibetan pig spermatozoa at high and low altitudes.","date":"2019","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31291894","citation_count":18,"is_preprint":false},{"pmid":"25529766","id":"PMC_25529766","title":"Proteome alterations in cortex of mice exposed to fluoride and lead.","date":"2014","source":"Biological trace element research","url":"https://pubmed.ncbi.nlm.nih.gov/25529766","citation_count":17,"is_preprint":false},{"pmid":"29533806","id":"PMC_29533806","title":"Ca2+ metabolic disorder and abnormal expression of cardiac troponin involved in fluoride-induced cardiomyocyte damage.","date":"2018","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/29533806","citation_count":16,"is_preprint":false},{"pmid":"24633403","id":"PMC_24633403","title":"Bleomycin hydrolase and hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis.","date":"2014","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/24633403","citation_count":15,"is_preprint":false},{"pmid":"36640659","id":"PMC_36640659","title":"Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males.","date":"2023","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/36640659","citation_count":14,"is_preprint":false},{"pmid":"33615715","id":"PMC_33615715","title":"Altered mitochondrial function in spermatozoa from patients with repetitive fertilization failure after ICSI revealed by proteomics.","date":"2021","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/33615715","citation_count":14,"is_preprint":false},{"pmid":"26306689","id":"PMC_26306689","title":"Nicotine mediates expression of genes related to antioxidant capacity and oxidative stress response in HIV-1 transgenic rat brain.","date":"2015","source":"Journal of neurovirology","url":"https://pubmed.ncbi.nlm.nih.gov/26306689","citation_count":13,"is_preprint":false},{"pmid":"27242042","id":"PMC_27242042","title":"Insights into the potential of picoplanktonic marine cyanobacteria strains for cancer therapies - Cytotoxic mechanisms against the RKO colon cancer cell line.","date":"2016","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/27242042","citation_count":13,"is_preprint":false},{"pmid":"33909627","id":"PMC_33909627","title":"Sodium butyrate modulates chicken macrophage proteins essential for Salmonella Enteritidis invasion.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33909627","citation_count":12,"is_preprint":false},{"pmid":"38964153","id":"PMC_38964153","title":"Multi-omics revealed anti-fatigue property of polyphenol from areca nut.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38964153","citation_count":12,"is_preprint":false},{"pmid":"26813465","id":"PMC_26813465","title":"Mechanisms of propofol attenuation of ketamine-induced neonatal brain injury.","date":"2016","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26813465","citation_count":11,"is_preprint":false},{"pmid":"35034100","id":"PMC_35034100","title":"Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects.","date":"2022","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35034100","citation_count":10,"is_preprint":false},{"pmid":"33807173","id":"PMC_33807173","title":"Effects of Edible Insect Tenebrio molitor Larva Fermentation Extract as a Substitute Protein on Hepatosteatogenesis and Proteomic Changes in Obese Mice Induced by High-Fat Diet.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33807173","citation_count":9,"is_preprint":false},{"pmid":"39520298","id":"PMC_39520298","title":"Single-cell sequencing combined with transcriptomics and in vivo and in vitro analysis reveals the landscape of ferroptosis in myocardial ischemia-reperfusion injury.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39520298","citation_count":8,"is_preprint":false},{"pmid":"32283821","id":"PMC_32283821","title":"mPTP Proteins Regulated by Streptozotocin-Induced Diabetes Mellitus Are Effectively Involved in the Processes of Maintaining Myocardial Metabolic Adaptation.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32283821","citation_count":7,"is_preprint":false},{"pmid":"25347084","id":"PMC_25347084","title":"Paraoxonase 1 and dietary hyperhomocysteinemia modulate the expression of mouse proteins involved in liver homeostasis.","date":"2014","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/25347084","citation_count":7,"is_preprint":false},{"pmid":"30863671","id":"PMC_30863671","title":"Amorphous silica nanoparticles induce tumorigenesis via regulating ATP5H/SOD1-related oxidative stress, oxidative phosphorylation and EIF4G2/PABPC1-associated translational initiation.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30863671","citation_count":6,"is_preprint":false},{"pmid":"39164435","id":"PMC_39164435","title":"Proteomic analysis of laser captured tubular tissues reveals complement activation and mitochondrial dysfunction in autoimmune related kidney diseases.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39164435","citation_count":6,"is_preprint":false},{"pmid":"38130933","id":"PMC_38130933","title":"Particulate matter 10 induces oxidative stress and apoptosis in rhesus macaques skin fibroblast.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/38130933","citation_count":6,"is_preprint":false},{"pmid":"31514886","id":"PMC_31514886","title":"Ultrasonic-assisted extraction and digestion of proteins from solid biopsies followed by peptide sequential extraction hyphenated to MALDI-based profiling holds the promise of distinguishing renal oncocytoma from chromophobe renal cell carcinoma.","date":"2019","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/31514886","citation_count":6,"is_preprint":false},{"pmid":"30614852","id":"PMC_30614852","title":"Close association between abnormal expressed enzymes of energy metabolism and diarrhea-predominant irritable bowel syndrome.","date":"2019","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/30614852","citation_count":6,"is_preprint":false},{"pmid":"38020296","id":"PMC_38020296","title":"Dihydroartemisinin inhibits liver cancer cell migration and invasion by reducing ATP synthase production through CaMKK2/NCLX.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38020296","citation_count":5,"is_preprint":false},{"pmid":"23618392","id":"PMC_23618392","title":"Glucocorticoid receptor is involved in the breed-dependent transcriptional regulation of mtDNA- and nuclear-encoded mitochondria genes in the liver of newborn piglets.","date":"2013","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/23618392","citation_count":5,"is_preprint":false},{"pmid":"38259479","id":"PMC_38259479","title":"Gene crosstalk between COVID-19 and preeclampsia revealed by blood transcriptome analysis.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38259479","citation_count":4,"is_preprint":false},{"pmid":"38914933","id":"PMC_38914933","title":"Deregulation of oxidative phosphorylation pathways in embryos derived in vitro from prepubertal and pubertal heifers based on whole-transcriptome sequencing.","date":"2024","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38914933","citation_count":4,"is_preprint":false},{"pmid":"31478280","id":"PMC_31478280","title":"Candidate genes mediated by estrogen-related receptor γ in pancreatic β cells.","date":"2019","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31478280","citation_count":4,"is_preprint":false},{"pmid":"39161338","id":"PMC_39161338","title":"Dihydroartemisinin inhibits ATP6 activity, reduces energy metabolism of hepatocellular carcinoma cells, promotes apoptosis and inhibits metastasis via CANX.","date":"2024","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/39161338","citation_count":4,"is_preprint":false},{"pmid":"40333481","id":"PMC_40333481","title":"The chimeric gene orf610a reduces cotton pollen fertility by impairing the assembly of ATP synthase.","date":"2025","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/40333481","citation_count":3,"is_preprint":false},{"pmid":"32862779","id":"PMC_32862779","title":"Selection and validation of reference genes for RT-qPCR in adipose and longissimus dorsi muscle tissues of buffalo.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32862779","citation_count":3,"is_preprint":false},{"pmid":"40912539","id":"PMC_40912539","title":"Maternal polystyrene nanoplastics suppress zebrafish offspring development and locomotion through mitochondrial dysfunction.","date":"2025","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/40912539","citation_count":3,"is_preprint":false},{"pmid":"38736407","id":"PMC_38736407","title":"Upregulation of Oxidative Phosphorylation Genes in Cumulus Cells of The Polycystic Ovary Syndrome Patients with or without Insulin Resistance.","date":"2024","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/38736407","citation_count":3,"is_preprint":false},{"pmid":"39335448","id":"PMC_39335448","title":"Analysis of Sigma-1 Receptor Antagonist BD1047 Effect on Upregulating Proteins in HIV-1-Infected Macrophages Exposed to Cocaine Using Quantitative Proteomics.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39335448","citation_count":2,"is_preprint":false},{"pmid":"41151867","id":"PMC_41151867","title":"Differential Proteomic Analysis of DEN-induced Hepatocellular Carcinoma in Male and Female Balb/c Mice Reveals Novel Sex-Specific Markers.","date":"2025","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41151867","citation_count":2,"is_preprint":false},{"pmid":"39005664","id":"PMC_39005664","title":"Developing a comprehensive molecular subgrouping model for cervical cancer using machine learning.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39005664","citation_count":1,"is_preprint":false},{"pmid":"36230465","id":"PMC_36230465","title":"An Integrated Bioinformatics Approach to Identify Network-Derived Hub Genes in Starving Zebrafish.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36230465","citation_count":1,"is_preprint":false},{"pmid":"41331761","id":"PMC_41331761","title":"High-fructose diet induces depressive-like behaviors and short-term memory deficits through hippocampal neurogenesis impairment via neural stem cell dysfunction.","date":"2025","source":"Nutrition & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/41331761","citation_count":1,"is_preprint":false},{"pmid":"39919594","id":"PMC_39919594","title":"Auxin signaling related to H+-ATPase synthesis and antioxidant enzyme activities regulates fluoranthene uptake by ryegrass roots.","date":"2025","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/39919594","citation_count":1,"is_preprint":false},{"pmid":"22436252","id":"PMC_22436252","title":"An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3.","date":"2012","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22436252","citation_count":1,"is_preprint":false},{"pmid":"42254865","id":"PMC_42254865","title":"Mass spectrometry-based proteomic profiling of human tauopathy brains suggests mitochondria-associated alterations.","date":"2026","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/42254865","citation_count":0,"is_preprint":false},{"pmid":"42235782","id":"PMC_42235782","title":"Mitochondrial dysfunction in muscle cells induced by snoring vibrations.","date":"2026","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/42235782","citation_count":0,"is_preprint":false},{"pmid":"39466128","id":"PMC_39466128","title":"Consensus gene co-expression analysis across multiple intestinal tissues to identify key genes and pathways associated with abdominal fat deposition in broilers.","date":"2024","source":"British poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/39466128","citation_count":0,"is_preprint":false},{"pmid":"41009665","id":"PMC_41009665","title":"Proteomic Screening for Cellular Targets of the Duck Enteritis Virus Protein VP26 Reveals That the Host Actin-Myosin II Network Regulates the Proliferation of the Virus.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41009665","citation_count":0,"is_preprint":false},{"pmid":"35937039","id":"PMC_35937039","title":"A Novel FACS-Based Workflow for Simultaneous Assessment of RedOx Status, Cellular Phenotype, and Mitochondrial Genome Stability.","date":"2021","source":"BioChem","url":"https://pubmed.ncbi.nlm.nih.gov/35937039","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.15.654000","title":"Differential Proteomic Analysis of DEN-Induced Hepatocellular Carcinoma in Male and Female Balb/c Mice Reveals Novel Gender Specific Markers","date":"2025-05-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.15.654000","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40342,"output_tokens":2096,"usd":0.076233,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9236,"output_tokens":2250,"usd":0.051215,"stage2_stop_reason":"end_turn"},"total_usd":0.127448,"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\": 2018,\n      \"finding\": \"Epigenetic loss of ATP5H (ATP synthase subunit d) in tumor cells leads to ROS accumulation and HIF-1α stabilization under normoxia, conferring a stem-like and invasive phenotype and cross-resistance to immunotherapy, chemotherapy, and radiotherapy. In vivo antioxidant delivery reversed these phenotypic changes and resensitized tumor cells to therapy.\",\n      \"method\": \"Sequential in vitro/in vivo immune selection of murine and human tumor cells, followed by molecular analysis of epigenetic changes, ROS measurement, HIF-1α stabilization assays, and in vivo antioxidant rescue experiments\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments in vitro and in vivo, multiple orthogonal methods (epigenetic analysis, ROS assay, HIF-1α stabilization, phenotypic rescue), replicated in murine and human tumor systems\",\n      \"pmids\": [\"30124467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATP5H (subunit d of the ATP synthase F0 complex) directly interacts with ATP5F1 (another F0 subunit), and both interactions are significantly decreased in interfibrillar mitochondria (IFM) of type 1 diabetic hearts, coinciding with decreased ATP synthase activity.\",\n      \"method\": \"Co-immunoprecipitation/pulldown to identify novel direct interactions between ATP synthase F0 subunits; Western blot quantification; ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin-induced diabetic FVB mice\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction identified by pulldown with functional activity assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"23872101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of the d-subunit (ATP5H/ATP5PD) in human cells prevents formation of the ATP synthase holocomplex; instead, two separate subcomplexes accumulate: one containing the central rotor shaft plus catalytic subunits (F1-c-ring) and one containing stator stalk components (b-e-g complex), establishing that ATP5H is required for final assembly of the stator stalk with the rotor module.\",\n      \"method\": \"siRNA knockdown of d-subunit expression in human cells, followed by analysis of subcomplex accumulation by native PAGE and immunoblotting; additional knockdowns of mtDNA-encoded a-subunit and A6L to confirm F1-c-ring formation\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — clean knockdown with defined biochemical phenotype (subcomplex accumulation), multiple subunit knockdowns used as controls, clear mechanistic conclusion about assembly pathway\",\n      \"pmids\": [\"26297831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of C. elegans ortholog of ATP5H is associated with increased amyloid-β toxicity in a transgenic C. elegans Aβ proteotoxicity model, placing ATP5H in a pathway relevant to Aβ-mediated neurodegeneration.\",\n      \"method\": \"RNA interference (RNAi) knockdown of ATP5H C. elegans ortholog in a transgenic C. elegans Aβ proteotoxicity model; phenotypic readout of Aβ toxicity\",\n      \"journal\": \"Alzheimer's & Dementia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with defined phenotypic readout in a model organism, single lab, single method\",\n      \"pmids\": [\"28242297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dihydroartemisinin (DHA) reduces ATP5H protein and mRNA expression in liver cancer cells via the CaMKK2/NCLX signaling pathway; knockdown of NCLX reproduced CaMKK2-mediated downregulation of ATP5H, placing ATP5H downstream of CaMKK2/NCLX in regulation of mitochondrial ATP production and cell migration/invasion.\",\n      \"method\": \"Western blotting and RT-qPCR for ATP5H expression; CaMKK2 overexpression and NCLX siRNA knockdown in HepG2 and HuH-7 cells; ATP fluorescent probe measurement; wound healing and Transwell invasion assays\",\n      \"journal\": \"Oncology Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by siRNA knockdown of upstream regulator, multiple orthogonal methods (expression, functional assays), single lab\",\n      \"pmids\": [\"38020296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATP5H (ATP5PD) protein abundance is elevated in spermatozoa from patients with repetitive fertilization failure after ICSI compared to controls with normal fertilization rates, suggesting altered mitochondrial function associated with fertilization failure.\",\n      \"method\": \"2D-LC-MS/MS quantitative proteomics of individual sperm samples; Western blot validation of selected proteins; JC-1 staining for mitochondrial membrane potential\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proteomics without functional manipulation of ATP5H specifically, only associative finding for this protein\",\n      \"pmids\": [\"33615715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATP5H is detected in both mitochondrial and nuclear fractions of MCF7 breast cancer cells, indicating dual subcellular localization of this oxidative phosphorylation subunit.\",\n      \"method\": \"Concurrent proteomics analysis of isolated nuclei and mitochondria from MCF7 cells; protein identification by mass spectrometry\",\n      \"journal\": \"Journal of Proteome Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proteomic identification without functional follow-up of the nuclear localization\",\n      \"pmids\": [\"23051583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a FACS-based workflow, ATP5H (nuclear-encoded mitochondrial protein) protein levels are used as a reference for mitochondrial content, and the ratio of MTCO1 (mtDNA-encoded) to ATP5H fluorescence intensity reports on mtDNA genomic stability, since MTCO1 is selectively depleted when mtDNA is damaged.\",\n      \"method\": \"FACS-based simultaneous measurement of ATP5H and MTCO1 protein levels by intracellular antibody staining; downstream qPCR for mtDNA copy number validation\",\n      \"journal\": \"BioChem\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, methodological application paper; establishes utility of ATP5H as stable nuclear-encoded mitochondrial reference but does not test ATP5H function directly\",\n      \"pmids\": [\"35937039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP5H (ATP5PD) is a peripheral stator stalk subunit (subunit d) of the mitochondrial F1Fo-ATP synthase that is required for holocomplex assembly — its loss causes accumulation of separate F1-c-ring and b-e-g stator sub-intermediates; it directly interacts with the F0 subunit ATP5F1 in a cardiolipin-dependent manner that is disrupted in diabetic heart; and epigenetic silencing of ATP5H in tumor cells triggers ROS accumulation and HIF-1α stabilization under normoxia, driving a stem-like, therapy-resistant phenotype that is reversed by antioxidant treatment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP5PD (ATP5H, subunit d) is a stator stalk subunit of the mitochondrial F1Fo-ATP synthase that is required for assembly of the holocomplex: its depletion blocks joining of the stator stalk to the rotor module, causing accumulation of separate F1-c-ring and b-e-g stator sub-intermediates [#2]. It directly contacts the F0 subunit ATP5F1, an interaction that is reduced in interfibrillar mitochondria of diabetic hearts in parallel with falling ATP synthase activity [#1]. Beyond its structural role, epigenetic silencing of ATP5H in tumor cells drives ROS accumulation and normoxic HIF-1\\u03b1 stabilization, conferring a stem-like, invasive, therapy-resistant phenotype that is reversed by antioxidant treatment [#0], and its expression is regulated downstream of CaMKK2/NCLX signaling in liver cancer cells where it controls mitochondrial ATP production and cell migration [#4]. A model-organism study links loss of the ATP5H ortholog to enhanced amyloid-\\u03b2 proteotoxicity [#3]. No structural model of how subunit d bridges the stator and rotor modules has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that subunit d physically engages another F0 subunit and that this contact is functionally coupled to enzyme output, framing ATP5H as a structural node within the membrane sector.\",\n      \"evidence\": \"Co-IP/pulldown plus ATP synthase activity assay in cardiac mitochondrial subpopulations from streptozotocin diabetic mice\",\n      \"pmids\": [\"23872101\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab, no reciprocal validation of the ATP5F1 interaction\",\n        \"Cardiolipin dependence of the interaction not directly tested here\",\n        \"Correlative link between reduced interaction and lower activity, not causal\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the assembly role of ATP5H by showing its loss arrests holocomplex formation at defined sub-intermediates, establishing subunit d as the factor that joins the stator stalk to the rotor module.\",\n      \"evidence\": \"siRNA knockdown in human cells with native PAGE and immunoblotting, plus control knockdowns of mtDNA-encoded subunits\",\n      \"pmids\": [\"26297831\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model of the bridging interface\",\n        \"Order of subunit addition during assembly not fully resolved\",\n        \"Whether residual holocomplex retains activity untested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ATP5H to neurodegeneration-relevant proteostasis by showing ortholog loss aggravates amyloid-\\u03b2 toxicity.\",\n      \"evidence\": \"RNAi knockdown of the C. elegans ortholog in a transgenic A\\u03b2 proteotoxicity model with phenotypic readout\",\n      \"pmids\": [\"28242297\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single method in a model organism\",\n        \"Mechanism linking ATP synthase function to A\\u03b2 toxicity unknown\",\n        \"No mammalian validation\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a non-canonical consequence of ATP5H loss: epigenetic silencing triggers ROS-driven normoxic HIF-1\\u03b1 stabilization and a therapy-resistant stem-like state, reversible by antioxidants.\",\n      \"evidence\": \"Immune selection of murine and human tumor cells with epigenetic, ROS, HIF-1\\u03b1 assays and in vivo antioxidant rescue\",\n      \"pmids\": [\"30124467\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Mechanism linking ATP synthase deficiency to ROS rise not fully dissected\",\n        \"Direct test of whether assembly defect causes the ROS phenotype absent\",\n        \"Generalizability across tumor types beyond models tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ATP5H downstream of a defined signaling axis by showing CaMKK2/NCLX controls its expression and thereby mitochondrial ATP output and cell motility.\",\n      \"evidence\": \"CaMKK2 overexpression and NCLX siRNA in HepG2/HuH-7 cells with expression, ATP probe, and migration/invasion assays\",\n      \"pmids\": [\"38020296\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab, mechanism of transcriptional/translational regulation unresolved\",\n        \"Direct binding of regulators to ATP5H locus not shown\",\n        \"Contribution of ATP5H specifically to migration vs. bystander effect\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the assembly defect, ATP5F1/cardiolipin interaction, and the downstream ROS/HIF-1\\u03b1 and signaling phenotypes mechanistically connect into a single causal chain remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model of subunit d at the stator-rotor interface\",\n        \"Causal link between assembly failure and ROS accumulation untested\",\n        \"Cardiolipin dependence of the ATP5F1 contact not directly demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 1]}\n    ],\n    \"complexes\": [\n      \"F1Fo-ATP synthase\"\n    ],\n    \"partners\": [\n      \"ATP5F1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}