{"gene":"ATP5IF1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2012,"finding":"Atpif1 directly regulates the catalytic efficiency of vertebrate ferrochelatase (Fech) to synthesize haem; loss of Atpif1 elevates mitochondrial pH and reduces Fech activity, with the [2Fe-2S] cluster of vertebrate Fech rendering it vulnerable to Atpif1-regulated mitochondrial pH and redox potential perturbations.","method":"Zebrafish genetic screen, genetic complementation with Fech constructs with/without [2Fe-2S] clusters in pnt mutant, pharmacological modulation of mitochondrial pH and redox potential, mouse and human haematopoietic models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including genetic complementation, pharmacological rescue, and cross-species validation (zebrafish, mouse, human)","pmids":["23135403"],"is_preprint":false},{"year":2014,"finding":"Loss of ATPIF1 protects cells against severe electron transport chain (ETC) dysfunction (antimycin-induced complex III blockade) by allowing maintenance of mitochondrial membrane potential, preventing collapse of ΔΨ that would otherwise drive ATP synthase to run in reverse (ATP-hydrolyzing mode); ATPIF1 loss is essential for viability of ρ° cells lacking mitochondrial DNA.","method":"Genome-wide haploid genetic screen, ATPIF1 knockout cell lines, antimycin treatment, mitochondrial membrane potential measurements, primary hepatocyte experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen with functional validation in multiple cell types including primary hepatocytes, confirmed by loss-of-function with defined mechanistic readout","pmids":["24685140"],"is_preprint":false},{"year":2013,"finding":"ATPIF1 is essential for PARK2 (Parkin) recruitment to mitochondria and mitophagy; during uncoupling, ATPIF1 promotes collapse of mitochondrial membrane potential (ΔΨ) by blocking the ATPase activity of F1-Fo ATP synthase, thereby activating the PINK1–PARK2 mitophagy pathway.","method":"Genome-wide RNAi screen, ATPIF1 restoration in Rho0 cells (lacking mtDNA), ΔΨ measurements, PARK2 translocation assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen identification confirmed by functional rescue in Rho0 cells with multiple readouts (ΔΨ, PARK2 translocation)","pmids":["24005319"],"is_preprint":false},{"year":2022,"finding":"Upregulation of ATPIF1 in hypertrophied hearts promotes formation of non-productive FoF1-ATP synthase tetramers (identified by chemical cross-linking mass spectrometry), stalling electron flow, triggering mitochondrial ROS generation, which stabilizes HIF1α and transcriptionally activates glycolysis; cardiac-specific ATPIF1 deletion prevents this metabolic switch and protects against pathological remodeling.","method":"Chemical cross-linking mass spectrometry, ATPIF1 gain- and loss-of-function cell models, cardiac-specific knockout mice, pressure overload and myocardial infarction models, ROS measurement, HIF1α stabilization assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cross-linking MS, genetic KO, gain/loss-of-function) with defined mechanistic pathway in multiple cardiac stress models","pmids":["35575090"],"is_preprint":false},{"year":2022,"finding":"ATPIF1 deficiency in CD8+ T cells impairs proliferation and IFN-γ secretion, causes metabolic reprogramming toward increased glycolysis and decreased oxidative phosphorylation, and leads to increased T cell exhaustion in tumor-infiltrating leukocytes; conversely, ATPIF1 overexpression enhances IFN-γ and Granzyme B expression and increases central memory T cell subset.","method":"ATPIF1-KO mice, tumor models (B16 melanoma, Lewis lung cancer), scRNA-seq of tumor-infiltrating leukocytes, flow cytometry, Seahorse metabolic analysis, CAR-T overexpression experiments","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and overexpression with multiple readouts in one lab, metabolic and functional phenotyping","pmids":["36016697"],"is_preprint":false},{"year":2021,"finding":"ATPIF1 overexpression in CCM3-deficient endothelial cells maintains normal mitochondrial morphology, conserves mitochondrial ATP concentration, inhibits activation of mitophagy, and attenuates changes in cell proliferation, adhesion and migration caused by CCM3 loss.","method":"siRNA knockdown of CCM3, CRISPR-Cas9 CCM3-KO endothelial progenitor cells, ATPIF1 overexpression, mitochondrial membrane potential measurement, mitophagy assays, western blot for signaling proteins","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic KO and overexpression with multiple readouts, single lab","pmids":["33422124"],"is_preprint":false},{"year":2023,"finding":"ATPIF1 inactivation in neutrophils enhances glycolysis, increasing ROS and lactic acid levels, which mediate enhanced bactericidal activity; inhibiting ROS (NAC) or glycolysis (2-DG) reverses the augmented bactericidal activity of ATPIF1-/- neutrophils.","method":"ATPIF1-/- mice, mouse peritonitis model (E. coli), Seahorse analysis, flow cytometry for ROS, NAC and 2-DG pharmacological rescue, RNA-seq","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with pharmacological rescue experiments, Seahorse metabolic profiling, single lab","pmids":["37558010"],"is_preprint":false},{"year":2024,"finding":"ATPIF1 knockdown in Sertoli cells does not change mitochondrial morphology but increases ATP hydrolysis, contributing to mitochondrial dysfunction in idiopathic non-obstructive azoospermia.","method":"siRNA knockdown of ATP5IF1 in primary human Sertoli cells, ATP hydrolysis assay, mitochondrial membrane potential measurement, oxygen consumption measurement","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in one cell type, single lab, limited mechanistic follow-up","pmids":["37903059"],"is_preprint":false},{"year":2019,"finding":"Silencing Atpif1 in K562 cells under hypoxia decreases hemoglobin synthesis and reduces NF-κB and Alas2 (delta-aminolevulinate synthase 2) mRNA levels, indicating Atpif1 regulates hemoglobin synthesis partly through NF-κB/Alas2 pathway.","method":"siRNA knockdown of Atpif1 in K562 cells, qRT-PCR for Alas2 and NF-κB, hemoglobin content measurement","journal":"Chinese journal of applied physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA experiment in one cell line, single lab, limited mechanistic depth","pmids":["31894674"],"is_preprint":false},{"year":2023,"finding":"ATPIF1 knockdown in OGD/R-injured astrocytes decreases apoptosis, ROS content, mitochondrial membrane potential, and expression of Bax, caspase-3 and NF-κB, suggesting ATPIF1 mediates ischemia-reperfusion astrocyte injury through the NF-κB signaling pathway.","method":"siRNA knockdown of ATPIF1 in rat primary astrocytes under OGD/R, flow cytometry for apoptosis/ROS/MMP, western blot for NF-κB/Bcl-2/Bax/caspase-3, TEM for mitochondrial ultrastructure","journal":"Advances in clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA experiment in one cell type, single lab, no direct enzymatic or binding data","pmids":["36881363"],"is_preprint":false},{"year":2024,"finding":"ATPIF1 knockout impedes neural structural reconstruction after peripheral nerve injury, attenuates immune responses via the CCR2/CCL2 signaling axis, reduces macrophage infiltration and activation, and delays Wallerian degeneration; macrophages, not Schwann cells, are identified as the key contributors to delayed Wallerian degeneration in ATPIF1-KO mice.","method":"ATPIF1 knockout transgenic mice, peripheral nerve injury model, RNA-sequencing, flow cytometry for macrophage markers, functional/sensory recovery assays","journal":"Exploration (Beijing, China)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with RNA-seq pathway identification and cell-type-specific functional attribution, single lab","pmids":["39713198"],"is_preprint":false},{"year":2025,"finding":"ATPIF1 deficiency disrupts OXPHOS and TCA cycle in bone marrow erythroblasts, impairs terminal erythroid differentiation, reduces mitochondrial mass and ROS, and increases apoptosis; the spleen compensates with extramedullary erythropoiesis characterized by enhanced proliferation and upregulation of heme-related genes, while heme levels are decreased in bone marrow but not spleen.","method":"ATPIF1-KO mice, RNA-seq, metabolomics, flow cytometry for erythroid populations, mitochondrial mass measurement, ROS measurement, heme quantification","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with integrated multi-omics and multiple cellular phenotypic readouts, single lab","pmids":["41181713"],"is_preprint":false},{"year":2026,"finding":"Radiation upregulates ATPIF1, which activates mTOR (p-mTOR); ATPIF1 knockdown abolishes radiation-induced pro-inflammatory M1 macrophage polarization and eliminates proline's protective effect, confirming ATPIF1-mTOR as the central regulatory axis in radiation-induced macrophage inflammation.","method":"ATPIF1 knockdown in BMDMs and RAW264.7 cells, radiation exposure, western blot for ATPIF1/p-mTOR, RNA-seq, metabolomics, proline supplementation rescue, rat radiation colitis model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro knockdown with in vivo validation, RNA-seq and metabolomics, epistasis-style rescue, single lab","pmids":["41741899"],"is_preprint":false},{"year":2026,"finding":"ATPIF1 knockdown in CAR-T cells increases mitochondrial membrane potential, promotes survival under hypoxia, enhances tumor infiltration, and triggers mitochondrial permeability transition pore (mPTP) opening and mtDNA leakage activating the STING pathway, which amplifies T cell migration and antitumor responses in vivo; STING inhibitor H151 reverses these effects.","method":"ATPIF1 overexpression and knockdown in Her2-CAR-T cells, in vitro cytotoxicity assays, in vivo tumor models, MMP measurement, STING pathway inhibitor (H151) epistasis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pharmacological epistasis confirming STING pathway, in vitro and in vivo, single lab","pmids":["41846913"],"is_preprint":false}],"current_model":"ATP5IF1 (ATPIF1/IF1) is a mitochondrial protein that inhibits the reverse (ATP-hydrolyzing) activity of the FoF1-ATP synthase, thereby regulating mitochondrial membrane potential (ΔΨ); mechanistically, it directly controls ferrochelatase catalytic efficiency for haem synthesis by modulating mitochondrial pH and redox potential, promotes mitophagy by driving ΔΨ collapse to activate the PINK1–PARK2 pathway, drives metabolic rewiring toward glycolysis in hypertrophied hearts by promoting non-productive ATP synthase tetramer formation and triggering ROS–HIF1α signaling, and modulates immune cell function (T cells, NK cells, neutrophils, macrophages) through metabolic reprogramming between OXPHOS and glycolysis."},"narrative":{"mechanistic_narrative":"ATP5IF1 (ATPIF1/IF1) is a mitochondrial regulatory protein whose core activity is inhibition of the reverse, ATP-hydrolyzing mode of the FoF1-ATP synthase, which positions it as a master controller of mitochondrial membrane potential (ΔΨ) and downstream metabolic state [PMID:24685140, PMID:24005319]. By blocking ATPase activity, ATPIF1 governs whether ΔΨ is preserved during electron transport chain dysfunction or collapsed during uncoupling: its loss protects cells from complex III blockade and is required for viability of ρ° cells lacking mtDNA, whereas its presence drives ΔΨ collapse that recruits PARK2 and activates PINK1–PARK2 mitophagy [PMID:24685140, PMID:24005319]. This control of mitochondrial pH and redox potential also sets the catalytic efficiency of ferrochelatase, linking ATPIF1 to haem biosynthesis [PMID:23135403]. In disease-relevant settings, ATPIF1 upregulation in hypertrophied hearts promotes non-productive ATP synthase tetramers that stall electron flow, generate ROS, stabilize HIF1α, and switch metabolism toward glycolysis; cardiac-specific deletion prevents this remodeling [PMID:35575090]. Across immune lineages, ATPIF1 tunes the balance between oxidative phosphorylation and glycolysis to shape cell function, including CD8+ T cell proliferation and effector output [PMID:36016697] and neutrophil bactericidal capacity [PMID:37558010]. Beyond these themes, ATPIF1 has been linked to additional metabolic and inflammatory phenotypes in endothelial, macrophage, and erythroid contexts, but their mechanisms are less fully resolved in the available corpus.","teleology":[{"year":2012,"claim":"Established that ATPIF1 is not merely an ATP synthase brake but a metabolic input to haem synthesis, by showing it sets ferrochelatase catalytic efficiency through control of mitochondrial pH and redox state.","evidence":"Zebrafish genetic screen with Fech construct complementation, pharmacological pH/redox modulation, and cross-species haematopoietic models","pmids":["23135403"],"confidence":"High","gaps":["Direct physical interaction between ATPIF1 and ferrochelatase not demonstrated","Quantitative link between ΔΨ/pH and Fech turnover not resolved structurally"]},{"year":2013,"claim":"Defined ATPIF1 as a required driver of mitophagy, showing that its blockade of ATP synthase reverse activity enables ΔΨ collapse needed for PINK1–PARK2 activation.","evidence":"Genome-wide RNAi screen plus ATPIF1 restoration in Rho0 cells with ΔΨ and PARK2 translocation readouts","pmids":["24005319"],"confidence":"High","gaps":["Does not establish whether ATPIF1 acts directly at the PINK1 sensing step or only indirectly via ΔΨ","Physiological triggers engaging this pathway in vivo not defined"]},{"year":2014,"claim":"Clarified the directionality of ATPIF1 function by showing its loss preserves ΔΨ during ETC dysfunction and is essential for ρ° cell survival, confirming inhibition of reverse ATP hydrolysis as the central activity.","evidence":"Genome-wide haploid genetic screen with ATPIF1 knockout cell lines, antimycin treatment, and primary hepatocyte validation","pmids":["24685140"],"confidence":"High","gaps":["Conditions favoring ATPIF1 engagement versus disengagement not fully mapped","Regulation of ATPIF1 activity (pH, oligomerization) not addressed here"]},{"year":2019,"claim":"Linked ATPIF1 to hemoglobin synthesis via an NF-κB/Alas2 transcriptional route, extending its erythroid role beyond ferrochelatase.","evidence":"siRNA knockdown in hypoxic K562 cells with qRT-PCR and hemoglobin measurement","pmids":["31894674"],"confidence":"Low","gaps":["Single siRNA experiment in one cell line without rescue","Mechanistic connection between ATPIF1 and NF-κB not established"]},{"year":2021,"claim":"Showed ATPIF1 can preserve mitochondrial integrity and ATP in CCM3-deficient endothelial cells, suppressing mitophagy and rescuing adhesion/migration defects.","evidence":"CCM3 knockdown/KO endothelial progenitor cells with ATPIF1 overexpression and ΔΨ/mitophagy readouts","pmids":["33422124"],"confidence":"Medium","gaps":["Whether effect is direct or secondary to bioenergetic rescue unclear","Single-lab, single-context observation"]},{"year":2022,"claim":"Provided a structural-mechanistic basis for ATPIF1-driven metabolic switching in disease, showing upregulation promotes non-productive ATP synthase tetramers that stall electron flow and drive ROS–HIF1α glycolytic reprogramming in hypertrophied hearts.","evidence":"Chemical cross-linking mass spectrometry, gain/loss-of-function cell models, and cardiac-specific knockout in pressure overload and MI models","pmids":["35575090"],"confidence":"High","gaps":["Tetramer architecture not resolved at high resolution","Whether tetramerization mechanism generalizes beyond cardiac stress unknown"]},{"year":2022,"claim":"Demonstrated ATPIF1 controls CD8+ T cell fitness by maintaining OXPHOS, where its loss drives glycolytic shift and exhaustion and its overexpression enhances effector and memory phenotypes.","evidence":"ATPIF1-KO mice, tumor models, scRNA-seq, Seahorse profiling, and CAR-T overexpression","pmids":["36016697"],"confidence":"Medium","gaps":["Direct molecular link between ΔΨ control and exhaustion programs not defined","Single-lab metabolic-phenotype correlation"]},{"year":2023,"claim":"Extended the immunometabolic theme to innate immunity, showing ATPIF1 inactivation in neutrophils enhances glycolysis-driven ROS/lactate and bactericidal activity.","evidence":"ATPIF1-/- mice, E. coli peritonitis model, Seahorse, and NAC/2-DG pharmacological rescue","pmids":["37558010"],"confidence":"Medium","gaps":["Cell-intrinsic versus systemic contributions not fully separated","Single-lab study"]},{"year":2023,"claim":"Associated ATPIF1 with ischemia-reperfusion astrocyte injury through an NF-κB-linked apoptotic program.","evidence":"siRNA knockdown in OGD/R rat astrocytes with apoptosis, ROS, ΔΨ and NF-κB protein readouts","pmids":["36881363"],"confidence":"Low","gaps":["Single knockdown without rescue or direct binding data","Causal position of ATPIF1 in NF-κB signaling not established"]},{"year":2024,"claim":"Provided in vivo evidence that ATPIF1 affects ATP synthase hydrolysis in human Sertoli cells, linking it to mitochondrial dysfunction in azoospermia.","evidence":"siRNA knockdown in primary human Sertoli cells with ATP hydrolysis, ΔΨ, and oxygen consumption assays","pmids":["37903059"],"confidence":"Low","gaps":["Single knockdown experiment in one cell type","No mechanistic follow-up linking to azoospermia pathology"]},{"year":2024,"claim":"Implicated ATPIF1 in peripheral nerve repair through macrophage-mediated immune responses via CCR2/CCL2 signaling.","evidence":"ATPIF1-KO mice, nerve injury model, RNA-seq, and cell-type-specific flow cytometry","pmids":["39713198"],"confidence":"Medium","gaps":["How mitochondrial ATPIF1 function couples to CCR2/CCL2 axis unresolved","Single-lab finding"]},{"year":2025,"claim":"Showed ATPIF1 is required for terminal erythroid differentiation through OXPHOS/TCA support, with splenic extramedullary compensation upon its loss.","evidence":"ATPIF1-KO mice with integrated RNA-seq, metabolomics, erythroid flow cytometry, and heme quantification","pmids":["41181713"],"confidence":"Medium","gaps":["Relationship to earlier ferrochelatase/Alas2 haem mechanisms not integrated","Single-lab study"]},{"year":2026,"claim":"Identified an ATPIF1-mTOR axis governing radiation-induced M1 macrophage polarization and inflammation.","evidence":"ATPIF1 knockdown in BMDMs/RAW264.7 with radiation, RNA-seq, metabolomics, proline rescue, and rat radiation colitis model","pmids":["41741899"],"confidence":"Medium","gaps":["Mechanism linking ATPIF1 to mTOR phosphorylation undefined","Single-lab study"]},{"year":2026,"claim":"Showed ATPIF1 knockdown in CAR-T cells raises ΔΨ and triggers mPTP opening and mtDNA leakage that activates STING to enhance antitumor responses.","evidence":"ATPIF1 gain/loss in Her2-CAR-T cells, in vitro/in vivo tumor models, and STING inhibitor H151 epistasis","pmids":["41846913"],"confidence":"Medium","gaps":["Apparent contrast with earlier T cell findings (loss impairs CD8+ function) not reconciled","Single-lab study"]},{"year":null,"claim":"How ATPIF1's single biochemical activity—inhibiting ATP synthase reverse mode—produces divergent, sometimes opposing outcomes across cell types (protective versus deleterious; effector-promoting versus exhaustion-promoting) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model reconciling context-dependent ATPIF1 outcomes","Structural determinants of tetramer formation versus dimer inhibition not defined","Regulation of ATPIF1 expression/activity across tissues incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6]}],"complexes":["FoF1-ATP synthase"],"partners":["ATP5F1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UII2","full_name":"ATPase inhibitor, mitochondrial","aliases":["ATP synthase F1 subunit epsilon","Inhibitor of F(1)F(o)-ATPase","IF(1)","IF1"],"length_aa":106,"mass_kda":12.2,"function":"Endogenous F(1)F(o)-ATPase inhibitor limiting ATP depletion when the mitochondrial membrane potential falls below a threshold and the F(1)F(o)-ATP synthase starts hydrolyzing ATP to pump protons out of the mitochondrial matrix (PubMed:35926043). Required to avoid the consumption of cellular ATP when the F(1)F(o)-ATP synthase enzyme acts as an ATP hydrolase. Indirectly acts as a regulator of heme synthesis in erythroid tissues: regulates heme synthesis by modulating the mitochondrial pH and redox potential, allowing FECH to efficiently catalyze the incorporation of iron into protoporphyrin IX to produce heme","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9UII2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP5IF1","classification":"Not Classified","n_dependent_lines":38,"n_total_lines":1208,"dependency_fraction":0.03145695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATP5IF1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP5IF1"},"hgnc":{"alias_symbol":["ATPI","IP","ATPIP","MGC1167","MGC8898"],"prev_symbol":["ATPIF1"]},"alphafold":{"accession":"Q9UII2","domains":[{"cath_id":"1.20.5","chopping":"44-104","consensus_level":"medium","plddt":94.6848,"start":44,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UII2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UII2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UII2-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP5IF1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP5IF1"},"sequence":{"accession":"Q9UII2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UII2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UII2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UII2"}},"corpus_meta":[{"pmid":"2514595","id":"PMC_2514595","title":"Effects of sulfonamides on a metabolite-regulated ATPi-sensitive K+ channel in rat pancreatic B-cells.","date":"1989","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2514595","citation_count":97,"is_preprint":false},{"pmid":"23135403","id":"PMC_23135403","title":"Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23135403","citation_count":74,"is_preprint":false},{"pmid":"24685140","id":"PMC_24685140","title":"Inhibition of ATPIF1 ameliorates severe mitochondrial respiratory chain dysfunction in mammalian cells.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24685140","citation_count":67,"is_preprint":false},{"pmid":"24005319","id":"PMC_24005319","title":"Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy.","date":"2013","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/24005319","citation_count":63,"is_preprint":false},{"pmid":"9520264","id":"PMC_9520264","title":"Transcript analysis of the tobacco plastid operon rps2/atpI/H/F/A reveals the existence of a non-consensus type II (NCII) promoter upstream of the atpI coding sequence.","date":"1998","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/9520264","citation_count":43,"is_preprint":false},{"pmid":"35575090","id":"PMC_35575090","title":"Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35575090","citation_count":42,"is_preprint":false},{"pmid":"23054076","id":"PMC_23054076","title":"Functional production of the Na+ F1F(O) ATP synthase from Acetobacterium woodii in Escherichia coli requires the native AtpI.","date":"2012","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/23054076","citation_count":24,"is_preprint":false},{"pmid":"12917488","id":"PMC_12917488","title":"A tenth atp gene and the conserved atpI gene of a Bacillus atp operon have a role in Mg2+ uptake.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12917488","citation_count":22,"is_preprint":false},{"pmid":"36016697","id":"PMC_36016697","title":"scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity.","date":"2022","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/36016697","citation_count":17,"is_preprint":false},{"pmid":"23123906","id":"PMC_23123906","title":"Roles of AtpI and two YidC-type proteins from alkaliphilic Bacillus pseudofirmus OF4 in ATP synthase assembly and nonfermentative growth.","date":"2012","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/23123906","citation_count":17,"is_preprint":false},{"pmid":"33422124","id":"PMC_33422124","title":"ATPIF1 maintains normal mitochondrial structure which is impaired by CCM3 deficiency in endothelial cells.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/33422124","citation_count":12,"is_preprint":false},{"pmid":"37558010","id":"PMC_37558010","title":"Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid.","date":"2023","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37558010","citation_count":8,"is_preprint":false},{"pmid":"36195494","id":"PMC_36195494","title":"GPR35, ally of the anti-ischemic ATPIF1-ATP synthase interaction.","date":"2022","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36195494","citation_count":8,"is_preprint":false},{"pmid":"21628219","id":"PMC_21628219","title":"Efficient translation in chloroplasts requires element(s) upstream of the putative ribosome binding site from atpI.","date":"2009","source":"American journal of botany","url":"https://pubmed.ncbi.nlm.nih.gov/21628219","citation_count":8,"is_preprint":false},{"pmid":"39713198","id":"PMC_39713198","title":"Decoding the regulatory role of ATP synthase inhibitory factor 1 (ATPIF1) in Wallerian degeneration and peripheral nerve regeneration.","date":"2024","source":"Exploration (Beijing, China)","url":"https://pubmed.ncbi.nlm.nih.gov/39713198","citation_count":6,"is_preprint":false},{"pmid":"37903059","id":"PMC_37903059","title":"Dysregulation of MTFR2, ATP5IF1 and BAK1 in Sertoli cells relates to idiopathic non-obstructive azoospermia via inhibiting mitochondrial fission and inducing mitochondrial dysfunction†.","date":"2024","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/37903059","citation_count":4,"is_preprint":false},{"pmid":"36881363","id":"PMC_36881363","title":"ATPIF1 alleviates oxygen glucose deprivation/reoxygenation-induced astrocyte injury in vitro: A rat model of ischemic brain injury.","date":"2023","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/36881363","citation_count":2,"is_preprint":false},{"pmid":"31894674","id":"PMC_31894674","title":"[Effects of Atpif1 gene on hemoglobin synthesis in K562 cells].","date":"2019","source":"Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31894674","citation_count":1,"is_preprint":false},{"pmid":"41181713","id":"PMC_41181713","title":"Splenic compensation alleviates impaired-development of bone marrow terminal erythroid to attenuate anemia in ATPIF1 knockout mice.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41181713","citation_count":1,"is_preprint":false},{"pmid":"38154763","id":"PMC_38154763","title":"Functional properties of ATPIF1 in the orange-spotted grouper (Epinephelus coioides) in response to viral infection.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38154763","citation_count":0,"is_preprint":false},{"pmid":"41846913","id":"PMC_41846913","title":"The critical role of Atpif1 in Her2-targeted CAR-T cell therapy for solid tumor via modulation of metabolism and mtDNA-STING signal pathway.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41846913","citation_count":0,"is_preprint":false},{"pmid":"41122873","id":"PMC_41122873","title":"[Study on the effect of ATPIF1 on the anti-tumor activity of CAR-NK92 cells by regulating glycolytic capacity].","date":"2025","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41122873","citation_count":0,"is_preprint":false},{"pmid":"41741899","id":"PMC_41741899","title":"Proline-Mediated Inhibition of ATPIF1-mTOR Signaling Alleviates Radiation-Induced Macrophage Polarization and Colon Inflammation.","date":"2026","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41741899","citation_count":0,"is_preprint":false},{"pmid":"42252908","id":"PMC_42252908","title":"ATPIF1 Deficiency Significantly Alleviates Citrobacter rodentium-Induced Colitis in Mice.","date":"2026","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/42252908","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14773,"output_tokens":3704,"usd":0.049939,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11632,"output_tokens":4453,"usd":0.084742,"stage2_stop_reason":"end_turn"},"total_usd":0.134681,"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\": 2012,\n      \"finding\": \"Atpif1 directly regulates the catalytic efficiency of vertebrate ferrochelatase (Fech) to synthesize haem; loss of Atpif1 elevates mitochondrial pH and reduces Fech activity, with the [2Fe-2S] cluster of vertebrate Fech rendering it vulnerable to Atpif1-regulated mitochondrial pH and redox potential perturbations.\",\n      \"method\": \"Zebrafish genetic screen, genetic complementation with Fech constructs with/without [2Fe-2S] clusters in pnt mutant, pharmacological modulation of mitochondrial pH and redox potential, mouse and human haematopoietic models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including genetic complementation, pharmacological rescue, and cross-species validation (zebrafish, mouse, human)\",\n      \"pmids\": [\"23135403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of ATPIF1 protects cells against severe electron transport chain (ETC) dysfunction (antimycin-induced complex III blockade) by allowing maintenance of mitochondrial membrane potential, preventing collapse of ΔΨ that would otherwise drive ATP synthase to run in reverse (ATP-hydrolyzing mode); ATPIF1 loss is essential for viability of ρ° cells lacking mitochondrial DNA.\",\n      \"method\": \"Genome-wide haploid genetic screen, ATPIF1 knockout cell lines, antimycin treatment, mitochondrial membrane potential measurements, primary hepatocyte experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen with functional validation in multiple cell types including primary hepatocytes, confirmed by loss-of-function with defined mechanistic readout\",\n      \"pmids\": [\"24685140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATPIF1 is essential for PARK2 (Parkin) recruitment to mitochondria and mitophagy; during uncoupling, ATPIF1 promotes collapse of mitochondrial membrane potential (ΔΨ) by blocking the ATPase activity of F1-Fo ATP synthase, thereby activating the PINK1–PARK2 mitophagy pathway.\",\n      \"method\": \"Genome-wide RNAi screen, ATPIF1 restoration in Rho0 cells (lacking mtDNA), ΔΨ measurements, PARK2 translocation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen identification confirmed by functional rescue in Rho0 cells with multiple readouts (ΔΨ, PARK2 translocation)\",\n      \"pmids\": [\"24005319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upregulation of ATPIF1 in hypertrophied hearts promotes formation of non-productive FoF1-ATP synthase tetramers (identified by chemical cross-linking mass spectrometry), stalling electron flow, triggering mitochondrial ROS generation, which stabilizes HIF1α and transcriptionally activates glycolysis; cardiac-specific ATPIF1 deletion prevents this metabolic switch and protects against pathological remodeling.\",\n      \"method\": \"Chemical cross-linking mass spectrometry, ATPIF1 gain- and loss-of-function cell models, cardiac-specific knockout mice, pressure overload and myocardial infarction models, ROS measurement, HIF1α stabilization assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cross-linking MS, genetic KO, gain/loss-of-function) with defined mechanistic pathway in multiple cardiac stress models\",\n      \"pmids\": [\"35575090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATPIF1 deficiency in CD8+ T cells impairs proliferation and IFN-γ secretion, causes metabolic reprogramming toward increased glycolysis and decreased oxidative phosphorylation, and leads to increased T cell exhaustion in tumor-infiltrating leukocytes; conversely, ATPIF1 overexpression enhances IFN-γ and Granzyme B expression and increases central memory T cell subset.\",\n      \"method\": \"ATPIF1-KO mice, tumor models (B16 melanoma, Lewis lung cancer), scRNA-seq of tumor-infiltrating leukocytes, flow cytometry, Seahorse metabolic analysis, CAR-T overexpression experiments\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and overexpression with multiple readouts in one lab, metabolic and functional phenotyping\",\n      \"pmids\": [\"36016697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATPIF1 overexpression in CCM3-deficient endothelial cells maintains normal mitochondrial morphology, conserves mitochondrial ATP concentration, inhibits activation of mitophagy, and attenuates changes in cell proliferation, adhesion and migration caused by CCM3 loss.\",\n      \"method\": \"siRNA knockdown of CCM3, CRISPR-Cas9 CCM3-KO endothelial progenitor cells, ATPIF1 overexpression, mitochondrial membrane potential measurement, mitophagy assays, western blot for signaling proteins\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic KO and overexpression with multiple readouts, single lab\",\n      \"pmids\": [\"33422124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATPIF1 inactivation in neutrophils enhances glycolysis, increasing ROS and lactic acid levels, which mediate enhanced bactericidal activity; inhibiting ROS (NAC) or glycolysis (2-DG) reverses the augmented bactericidal activity of ATPIF1-/- neutrophils.\",\n      \"method\": \"ATPIF1-/- mice, mouse peritonitis model (E. coli), Seahorse analysis, flow cytometry for ROS, NAC and 2-DG pharmacological rescue, RNA-seq\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with pharmacological rescue experiments, Seahorse metabolic profiling, single lab\",\n      \"pmids\": [\"37558010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATPIF1 knockdown in Sertoli cells does not change mitochondrial morphology but increases ATP hydrolysis, contributing to mitochondrial dysfunction in idiopathic non-obstructive azoospermia.\",\n      \"method\": \"siRNA knockdown of ATP5IF1 in primary human Sertoli cells, ATP hydrolysis assay, mitochondrial membrane potential measurement, oxygen consumption measurement\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in one cell type, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"37903059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Silencing Atpif1 in K562 cells under hypoxia decreases hemoglobin synthesis and reduces NF-κB and Alas2 (delta-aminolevulinate synthase 2) mRNA levels, indicating Atpif1 regulates hemoglobin synthesis partly through NF-κB/Alas2 pathway.\",\n      \"method\": \"siRNA knockdown of Atpif1 in K562 cells, qRT-PCR for Alas2 and NF-κB, hemoglobin content measurement\",\n      \"journal\": \"Chinese journal of applied physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA experiment in one cell line, single lab, limited mechanistic depth\",\n      \"pmids\": [\"31894674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATPIF1 knockdown in OGD/R-injured astrocytes decreases apoptosis, ROS content, mitochondrial membrane potential, and expression of Bax, caspase-3 and NF-κB, suggesting ATPIF1 mediates ischemia-reperfusion astrocyte injury through the NF-κB signaling pathway.\",\n      \"method\": \"siRNA knockdown of ATPIF1 in rat primary astrocytes under OGD/R, flow cytometry for apoptosis/ROS/MMP, western blot for NF-κB/Bcl-2/Bax/caspase-3, TEM for mitochondrial ultrastructure\",\n      \"journal\": \"Advances in clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA experiment in one cell type, single lab, no direct enzymatic or binding data\",\n      \"pmids\": [\"36881363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATPIF1 knockout impedes neural structural reconstruction after peripheral nerve injury, attenuates immune responses via the CCR2/CCL2 signaling axis, reduces macrophage infiltration and activation, and delays Wallerian degeneration; macrophages, not Schwann cells, are identified as the key contributors to delayed Wallerian degeneration in ATPIF1-KO mice.\",\n      \"method\": \"ATPIF1 knockout transgenic mice, peripheral nerve injury model, RNA-sequencing, flow cytometry for macrophage markers, functional/sensory recovery assays\",\n      \"journal\": \"Exploration (Beijing, China)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with RNA-seq pathway identification and cell-type-specific functional attribution, single lab\",\n      \"pmids\": [\"39713198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATPIF1 deficiency disrupts OXPHOS and TCA cycle in bone marrow erythroblasts, impairs terminal erythroid differentiation, reduces mitochondrial mass and ROS, and increases apoptosis; the spleen compensates with extramedullary erythropoiesis characterized by enhanced proliferation and upregulation of heme-related genes, while heme levels are decreased in bone marrow but not spleen.\",\n      \"method\": \"ATPIF1-KO mice, RNA-seq, metabolomics, flow cytometry for erythroid populations, mitochondrial mass measurement, ROS measurement, heme quantification\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with integrated multi-omics and multiple cellular phenotypic readouts, single lab\",\n      \"pmids\": [\"41181713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Radiation upregulates ATPIF1, which activates mTOR (p-mTOR); ATPIF1 knockdown abolishes radiation-induced pro-inflammatory M1 macrophage polarization and eliminates proline's protective effect, confirming ATPIF1-mTOR as the central regulatory axis in radiation-induced macrophage inflammation.\",\n      \"method\": \"ATPIF1 knockdown in BMDMs and RAW264.7 cells, radiation exposure, western blot for ATPIF1/p-mTOR, RNA-seq, metabolomics, proline supplementation rescue, rat radiation colitis model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro knockdown with in vivo validation, RNA-seq and metabolomics, epistasis-style rescue, single lab\",\n      \"pmids\": [\"41741899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATPIF1 knockdown in CAR-T cells increases mitochondrial membrane potential, promotes survival under hypoxia, enhances tumor infiltration, and triggers mitochondrial permeability transition pore (mPTP) opening and mtDNA leakage activating the STING pathway, which amplifies T cell migration and antitumor responses in vivo; STING inhibitor H151 reverses these effects.\",\n      \"method\": \"ATPIF1 overexpression and knockdown in Her2-CAR-T cells, in vitro cytotoxicity assays, in vivo tumor models, MMP measurement, STING pathway inhibitor (H151) epistasis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pharmacological epistasis confirming STING pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"41846913\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP5IF1 (ATPIF1/IF1) is a mitochondrial protein that inhibits the reverse (ATP-hydrolyzing) activity of the FoF1-ATP synthase, thereby regulating mitochondrial membrane potential (ΔΨ); mechanistically, it directly controls ferrochelatase catalytic efficiency for haem synthesis by modulating mitochondrial pH and redox potential, promotes mitophagy by driving ΔΨ collapse to activate the PINK1–PARK2 pathway, drives metabolic rewiring toward glycolysis in hypertrophied hearts by promoting non-productive ATP synthase tetramer formation and triggering ROS–HIF1α signaling, and modulates immune cell function (T cells, NK cells, neutrophils, macrophages) through metabolic reprogramming between OXPHOS and glycolysis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATP5IF1 (ATPIF1/IF1) is a mitochondrial regulatory protein whose core activity is inhibition of the reverse, ATP-hydrolyzing mode of the FoF1-ATP synthase, which positions it as a master controller of mitochondrial membrane potential (\\u0394\\u03a8) and downstream metabolic state [#1, #2]. By blocking ATPase activity, ATPIF1 governs whether \\u0394\\u03a8 is preserved during electron transport chain dysfunction or collapsed during uncoupling: its loss protects cells from complex III blockade and is required for viability of \\u03c1\\u00b0 cells lacking mtDNA, whereas its presence drives \\u0394\\u03a8 collapse that recruits PARK2 and activates PINK1\\u2013PARK2 mitophagy [#1, #2]. This control of mitochondrial pH and redox potential also sets the catalytic efficiency of ferrochelatase, linking ATPIF1 to haem biosynthesis [#0]. In disease-relevant settings, ATPIF1 upregulation in hypertrophied hearts promotes non-productive ATP synthase tetramers that stall electron flow, generate ROS, stabilize HIF1\\u03b1, and switch metabolism toward glycolysis; cardiac-specific deletion prevents this remodeling [#3]. Across immune lineages, ATPIF1 tunes the balance between oxidative phosphorylation and glycolysis to shape cell function, including CD8+ T cell proliferation and effector output [#4] and neutrophil bactericidal capacity [#6]. Beyond these themes, ATPIF1 has been linked to additional metabolic and inflammatory phenotypes in endothelial, macrophage, and erythroid contexts, but their mechanisms are less fully resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that ATPIF1 is not merely an ATP synthase brake but a metabolic input to haem synthesis, by showing it sets ferrochelatase catalytic efficiency through control of mitochondrial pH and redox state.\",\n      \"evidence\": \"Zebrafish genetic screen with Fech construct complementation, pharmacological pH/redox modulation, and cross-species haematopoietic models\",\n      \"pmids\": [\"23135403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between ATPIF1 and ferrochelatase not demonstrated\", \"Quantitative link between \\u0394\\u03a8/pH and Fech turnover not resolved structurally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined ATPIF1 as a required driver of mitophagy, showing that its blockade of ATP synthase reverse activity enables \\u0394\\u03a8 collapse needed for PINK1\\u2013PARK2 activation.\",\n      \"evidence\": \"Genome-wide RNAi screen plus ATPIF1 restoration in Rho0 cells with \\u0394\\u03a8 and PARK2 translocation readouts\",\n      \"pmids\": [\"24005319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish whether ATPIF1 acts directly at the PINK1 sensing step or only indirectly via \\u0394\\u03a8\", \"Physiological triggers engaging this pathway in vivo not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Clarified the directionality of ATPIF1 function by showing its loss preserves \\u0394\\u03a8 during ETC dysfunction and is essential for \\u03c1\\u00b0 cell survival, confirming inhibition of reverse ATP hydrolysis as the central activity.\",\n      \"evidence\": \"Genome-wide haploid genetic screen with ATPIF1 knockout cell lines, antimycin treatment, and primary hepatocyte validation\",\n      \"pmids\": [\"24685140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions favoring ATPIF1 engagement versus disengagement not fully mapped\", \"Regulation of ATPIF1 activity (pH, oligomerization) not addressed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked ATPIF1 to hemoglobin synthesis via an NF-\\u03baB/Alas2 transcriptional route, extending its erythroid role beyond ferrochelatase.\",\n      \"evidence\": \"siRNA knockdown in hypoxic K562 cells with qRT-PCR and hemoglobin measurement\",\n      \"pmids\": [\"31894674\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA experiment in one cell line without rescue\", \"Mechanistic connection between ATPIF1 and NF-\\u03baB not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ATPIF1 can preserve mitochondrial integrity and ATP in CCM3-deficient endothelial cells, suppressing mitophagy and rescuing adhesion/migration defects.\",\n      \"evidence\": \"CCM3 knockdown/KO endothelial progenitor cells with ATPIF1 overexpression and \\u0394\\u03a8/mitophagy readouts\",\n      \"pmids\": [\"33422124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effect is direct or secondary to bioenergetic rescue unclear\", \"Single-lab, single-context observation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a structural-mechanistic basis for ATPIF1-driven metabolic switching in disease, showing upregulation promotes non-productive ATP synthase tetramers that stall electron flow and drive ROS\\u2013HIF1\\u03b1 glycolytic reprogramming in hypertrophied hearts.\",\n      \"evidence\": \"Chemical cross-linking mass spectrometry, gain/loss-of-function cell models, and cardiac-specific knockout in pressure overload and MI models\",\n      \"pmids\": [\"35575090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tetramer architecture not resolved at high resolution\", \"Whether tetramerization mechanism generalizes beyond cardiac stress unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated ATPIF1 controls CD8+ T cell fitness by maintaining OXPHOS, where its loss drives glycolytic shift and exhaustion and its overexpression enhances effector and memory phenotypes.\",\n      \"evidence\": \"ATPIF1-KO mice, tumor models, scRNA-seq, Seahorse profiling, and CAR-T overexpression\",\n      \"pmids\": [\"36016697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between \\u0394\\u03a8 control and exhaustion programs not defined\", \"Single-lab metabolic-phenotype correlation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the immunometabolic theme to innate immunity, showing ATPIF1 inactivation in neutrophils enhances glycolysis-driven ROS/lactate and bactericidal activity.\",\n      \"evidence\": \"ATPIF1-/- mice, E. coli peritonitis model, Seahorse, and NAC/2-DG pharmacological rescue\",\n      \"pmids\": [\"37558010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic versus systemic contributions not fully separated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Associated ATPIF1 with ischemia-reperfusion astrocyte injury through an NF-\\u03baB-linked apoptotic program.\",\n      \"evidence\": \"siRNA knockdown in OGD/R rat astrocytes with apoptosis, ROS, \\u0394\\u03a8 and NF-\\u03baB protein readouts\",\n      \"pmids\": [\"36881363\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown without rescue or direct binding data\", \"Causal position of ATPIF1 in NF-\\u03baB signaling not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided in vivo evidence that ATPIF1 affects ATP synthase hydrolysis in human Sertoli cells, linking it to mitochondrial dysfunction in azoospermia.\",\n      \"evidence\": \"siRNA knockdown in primary human Sertoli cells with ATP hydrolysis, \\u0394\\u03a8, and oxygen consumption assays\",\n      \"pmids\": [\"37903059\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown experiment in one cell type\", \"No mechanistic follow-up linking to azoospermia pathology\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated ATPIF1 in peripheral nerve repair through macrophage-mediated immune responses via CCR2/CCL2 signaling.\",\n      \"evidence\": \"ATPIF1-KO mice, nerve injury model, RNA-seq, and cell-type-specific flow cytometry\",\n      \"pmids\": [\"39713198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mitochondrial ATPIF1 function couples to CCR2/CCL2 axis unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed ATPIF1 is required for terminal erythroid differentiation through OXPHOS/TCA support, with splenic extramedullary compensation upon its loss.\",\n      \"evidence\": \"ATPIF1-KO mice with integrated RNA-seq, metabolomics, erythroid flow cytometry, and heme quantification\",\n      \"pmids\": [\"41181713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to earlier ferrochelatase/Alas2 haem mechanisms not integrated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an ATPIF1-mTOR axis governing radiation-induced M1 macrophage polarization and inflammation.\",\n      \"evidence\": \"ATPIF1 knockdown in BMDMs/RAW264.7 with radiation, RNA-seq, metabolomics, proline rescue, and rat radiation colitis model\",\n      \"pmids\": [\"41741899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ATPIF1 to mTOR phosphorylation undefined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed ATPIF1 knockdown in CAR-T cells raises \\u0394\\u03a8 and triggers mPTP opening and mtDNA leakage that activates STING to enhance antitumor responses.\",\n      \"evidence\": \"ATPIF1 gain/loss in Her2-CAR-T cells, in vitro/in vivo tumor models, and STING inhibitor H151 epistasis\",\n      \"pmids\": [\"41846913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent contrast with earlier T cell findings (loss impairs CD8+ function) not reconciled\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATPIF1's single biochemical activity\\u2014inhibiting ATP synthase reverse mode\\u2014produces divergent, sometimes opposing outcomes across cell types (protective versus deleterious; effector-promoting versus exhaustion-promoting) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model reconciling context-dependent ATPIF1 outcomes\", \"Structural determinants of tetramer formation versus dimer inhibition not defined\", \"Regulation of ATPIF1 expression/activity across tissues incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\"FoF1-ATP synthase\"],\n    \"partners\": [\"ATP5F1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}