{"gene":"ATAD3B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2021,"finding":"ATAD3B contains a LIR (LC3-interacting region) motif that directly binds LC3 and functions as a mitophagy receptor, promoting oxidative stress-induced mitophagy in a PINK1-independent manner to clear damaged mtDNA.","method":"Loss- and gain-of-function experiments, LIR motif identification, LC3 binding assay, mitophagy assay in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (LIR-LC3 binding, PINK1-independence, functional mitophagy rescue) in a single focused study with clear mechanistic pathway placement","pmids":["33665835"],"is_preprint":false},{"year":2021,"finding":"Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, which promotes targeting of the ATAD3B C-terminal region to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or depletion reduces this ATAD3B-ATAD3A hetero-oligomerization, leading to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent LC3 recruitment for mitophagy initiation.","method":"Co-immunoprecipitation, subcellular fractionation, oxidative stress treatment, mtDNA depletion, fluorescence microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and fractionation with functional mitophagy readout, multiple orthogonal methods in one focused study","pmids":["33665835"],"is_preprint":false},{"year":2012,"finding":"ATAD3B associates with ATAD3A (hetero-oligomerization), negatively regulates the interaction of ATAD3A with matrix nucleoid complexes, and contributes to a mitochondrial fragmentation phenotype. ATAD3B thus functions as a dominant negative regulator of ATAD3A.","method":"Loss- and gain-of-function approaches, Co-immunoprecipitation, mitochondrial morphology assays in hESCs and cancer cells","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional phenotype (nucleoid interaction, fragmentation), single lab with two orthogonal methods","pmids":["22664726"],"is_preprint":false},{"year":2006,"finding":"The ATAD3B gene encodes two distinct protein isoforms (AAA-TOB3s and AAA-TOB3l) generated from distinct transcription initiation sites, both localized to mitochondria. Both isoforms are early transcriptional targets of c-Myc. Knockdown of both isoforms results in polynuclear cells, decreased proliferation, dysfunctional cell division, and increased apoptosis, indicating a required role in cell division.","method":"RT-PCR, Western blot, siRNA knockdown, flow cytometry, immunofluorescence microscopy, c-Myc target validation","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined cellular phenotype (cell division defect) and mitochondrial localization confirmed; c-Myc regulation by single lab with multiple methods","pmids":["16909202"],"is_preprint":false},{"year":2026,"finding":"SEC62, an ER transmembrane protein at mitochondria-associated membranes (MAMs), directly interacts with ATAD3B and suppresses ATAD3B expression, leading to defective mitophagy, increased mitochondrial ROS, and amplified inflammatory responses in MASH.","method":"Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, Western blot, mitophagy assay, ROS measurement","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP demonstrating direct SEC62-ATAD3B interaction with functional downstream phenotype, single lab, single study","pmids":["42001994"],"is_preprint":false},{"year":2021,"finding":"ATAD3B re-expression in cells with m.3243A>G mutated mtDNA promotes clearance of the mutant mtDNA, demonstrating a functional role of ATAD3B-mediated mitophagy in eliminating pathogenic mtDNA variants.","method":"ATAD3B overexpression in MELAS patient fibroblasts and m.3243A>G mutated cells, mtDNA quantification","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with specific mtDNA clearance readout, part of broader mechanistic study with multiple supporting methods","pmids":["33665835"],"is_preprint":false}],"current_model":"ATAD3B is a primate-specific mitochondrial membrane protein that normally hetero-oligomerizes with ATAD3A (keeping its C-terminus in the intermembrane space and negatively regulating ATAD3A's nucleoid interactions), but upon oxidative stress-induced mtDNA damage this hetero-oligomerization is disrupted, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif recruits LC3 to initiate PINK1-independent mitophagy for selective clearance of damaged mtDNA; additionally, ATAD3B is transcriptionally regulated by c-Myc, is required for normal cell division, and its activity at MAMs can be suppressed by SEC62 interaction."},"narrative":{"mechanistic_narrative":"ATAD3B is a mitochondrial membrane protein that acts as a stress-responsive mitophagy receptor for selective clearance of damaged mitochondrial DNA [PMID:33665835]. Under basal conditions it hetero-oligomerizes with ATAD3A, which targets the ATAD3B C-terminus to the intermembrane space and negatively regulates ATAD3A's interaction with matrix nucleoid complexes, positioning ATAD3B as a dominant-negative modulator of ATAD3A whose loss perturbs mitochondrial morphology [PMID:33665835, PMID:22664726]. Oxidative stress-induced mtDNA damage or depletion disrupts the ATAD3B-ATAD3A hetero-oligomer, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif directly binds LC3 to initiate mitophagy independently of PINK1 [PMID:33665835]. This pathway is functionally consequential: ATAD3B re-expression promotes clearance of pathogenic m.3243A>G mutant mtDNA [PMID:33665835]. ATAD3B is encoded as two mitochondrially localized isoforms that are early transcriptional targets of c-Myc and are required for normal cell division, with knockdown producing polynuclear cells, reduced proliferation, and apoptosis [PMID:16909202]. At mitochondria-associated membranes, the ER protein SEC62 directly binds ATAD3B and suppresses its expression, dampening mitophagy and amplifying mitochondrial ROS and inflammation [PMID:42001994].","teleology":[{"year":2006,"claim":"Establishing that the ATAD3B locus produces mitochondrial protein isoforms under c-Myc control and is needed for faithful cell division placed the gene within mitochondrial biology and growth regulation rather than leaving it uncharacterized.","evidence":"RT-PCR, Western blot, siRNA knockdown, flow cytometry and c-Myc target validation in cultured cells","pmids":["16909202"],"confidence":"Medium","gaps":["Molecular basis of the cell-division requirement not defined","No mechanistic link drawn yet to mitophagy or ATAD3A","Functional difference between the two isoforms unresolved"]},{"year":2012,"claim":"Identifying ATAD3B as a hetero-oligomerization partner that antagonizes ATAD3A nucleoid interactions reframed it from a standalone protein to a dominant-negative regulator of ATAD3A and mitochondrial morphology.","evidence":"Co-immunoprecipitation and mitochondrial morphology assays in hESCs and cancer cells","pmids":["22664726"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of hetero-oligomerization unknown","Single-lab Co-IP with two methods","Physiological trigger that modulates the ATAD3A-ATAD3B balance not identified"]},{"year":2021,"claim":"Discovery of a functional LIR motif that binds LC3 and drives PINK1-independent mitophagy defined the core molecular activity of ATAD3B as a mitophagy receptor, and coupling this to stress-induced loss of ATAD3A oligomerization explained how the receptor is conditionally activated; rescue of mutant mtDNA clearance established physiological relevance.","evidence":"LIR identification, LC3 binding assay, PINK1-independence, reciprocal Co-IP, subcellular fractionation, and mtDNA clearance in m.3243A>G/MELAS cells","pmids":["33665835"],"confidence":"High","gaps":["Structural detail of LIR-LC3 engagement not resolved","How mtDNA damage is sensed upstream of oligomer disruption unknown","Selectivity for damaged versus healthy nucleoids not mechanistically defined"]},{"year":2026,"claim":"Identifying SEC62 as a direct MAM-resident binder that suppresses ATAD3B added a regulatory input controlling ATAD3B-dependent mitophagy and linked the pathway to ROS and inflammatory disease (MASH).","evidence":"Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, mitophagy and ROS assays","pmids":["42001994"],"confidence":"Medium","gaps":["Single-lab, single-study Co-IP without reciprocal/structural validation","Mechanism by which SEC62 suppresses ATAD3B expression unclear","Whether SEC62 acts on the oligomerization or LIR steps not determined"]},{"year":null,"claim":"How upstream mtDNA damage is sensed and transduced into ATAD3B-ATAD3A hetero-oligomer disruption, and the structural basis of the receptor's stress-dependent reorientation, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the ATAD3A-ATAD3B complex or its disassembly","Damage-sensing trigger upstream of oligomer disruption unidentified","Relationship between cell-division role and mitophagy role unintegrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ATAD3A","MAP1LC3B","SEC62"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T9A4","full_name":"ATPase family AAA domain-containing protein 3B","aliases":["AAA-TOB3"],"length_aa":648,"mass_kda":72.6,"function":"May play a role in a mitochondrial network organization typical for stem cells, characterized by reduced mitochondrial metabolism, low mtDNA copies and fragmentated mitochondrial network. May act by suppressing ATAD3A function, interfering with ATAD3A interaction with matrix nucleoid complexes","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q5T9A4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATAD3B","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATAD3B","total_profiled":1310},"omim":[{"mim_id":"618815","title":"CHROMOSOME 1p36.33 DUPLICATION SYNDROME, ATAD3 GENE CLUSTER, AUTOSOMAL DOMINANT","url":"https://www.omim.org/entry/618815"},{"mim_id":"618810","title":"PONTOCEREBELLAR HYPOPLASIA, HYPOTONIA, AND RESPIRATORY INSUFFICIENCY SYNDROME, NEONATAL LETHAL; PHRINL","url":"https://www.omim.org/entry/618810"},{"mim_id":"617227","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3C; ATAD3C","url":"https://www.omim.org/entry/617227"},{"mim_id":"612317","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3B; ATAD3B","url":"https://www.omim.org/entry/612317"},{"mim_id":"612316","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3A; ATAD3A","url":"https://www.omim.org/entry/612316"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Acrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATAD3B"},"hgnc":{"alias_symbol":["TOB3","KIAA1273"],"prev_symbol":[]},"alphafold":{"accession":"Q5T9A4","domains":[{"cath_id":"-","chopping":"67-239","consensus_level":"medium","plddt":84.9503,"start":67,"end":239},{"cath_id":"3.40.50.300","chopping":"286-475","consensus_level":"high","plddt":85.5526,"start":286,"end":475},{"cath_id":"1.10.8.60","chopping":"480-572","consensus_level":"high","plddt":90.283,"start":480,"end":572},{"cath_id":"1.20.5","chopping":"244-279","consensus_level":"medium","plddt":78.45,"start":244,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9A4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9A4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9A4-F1-predicted_aligned_error_v6.png","plddt_mean":76.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATAD3B","jax_strain_url":"https://www.jax.org/strain/search?query=ATAD3B"},"sequence":{"accession":"Q5T9A4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T9A4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T9A4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9A4"}},"corpus_meta":[{"pmid":"27640307","id":"PMC_27640307","title":"Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27640307","citation_count":144,"is_preprint":false},{"pmid":"33665835","id":"PMC_33665835","title":"ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33665835","citation_count":112,"is_preprint":false},{"pmid":"28549128","id":"PMC_28549128","title":"ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28549128","citation_count":109,"is_preprint":false},{"pmid":"20332122","id":"PMC_20332122","title":"ATPase family AAA domain-containing 3A is a novel anti-apoptotic factor in lung adenocarcinoma cells.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20332122","citation_count":80,"is_preprint":false},{"pmid":"28941010","id":"PMC_28941010","title":"ATAD3 proteins: brokers of a mitochondria-endoplasmic reticulum connection in mammalian cells.","date":"2017","source":"Biological reviews of the Cambridge Philosophical Society","url":"https://pubmed.ncbi.nlm.nih.gov/28941010","citation_count":76,"is_preprint":false},{"pmid":"15141305","id":"PMC_15141305","title":"Profile identification of disease-associated humoral antigens using AMIDA, a novel proteomics-based technology.","date":"2004","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/15141305","citation_count":57,"is_preprint":false},{"pmid":"28556940","id":"PMC_28556940","title":"Three TOB1-related YABBY genes are required to maintain proper function of the spikelet and branch meristems in rice.","date":"2017","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/28556940","citation_count":51,"is_preprint":false},{"pmid":"22318359","id":"PMC_22318359","title":"ATAD3, a vital membrane bound mitochondrial ATPase involved in tumor progression.","date":"2012","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/22318359","citation_count":48,"is_preprint":false},{"pmid":"28765560","id":"PMC_28765560","title":"Machine Learning-Assisted Network Inference Approach to Identify a New Class of Genes that Coordinate the Functionality of Cancer Networks.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28765560","citation_count":45,"is_preprint":false},{"pmid":"22664726","id":"PMC_22664726","title":"ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A.","date":"2012","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/22664726","citation_count":32,"is_preprint":false},{"pmid":"31727539","id":"PMC_31727539","title":"Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities.","date":"2019","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31727539","citation_count":27,"is_preprint":false},{"pmid":"16909202","id":"PMC_16909202","title":"Molecular characterization of the tumor-associated antigen AAA-TOB3.","date":"2006","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/16909202","citation_count":26,"is_preprint":false},{"pmid":"32368190","id":"PMC_32368190","title":"NEK10 interactome and depletion reveal new roles in mitochondria.","date":"2020","source":"Proteome science","url":"https://pubmed.ncbi.nlm.nih.gov/32368190","citation_count":26,"is_preprint":false},{"pmid":"24239551","id":"PMC_24239551","title":"Expression analysis of ATAD3 isoforms in rodent and human cell lines and tissues.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24239551","citation_count":23,"is_preprint":false},{"pmid":"35853630","id":"PMC_35853630","title":"Epigenome-wide DNA methylation study of whole blood in patients with sporadic amyotrophic lateral sclerosis.","date":"2022","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/35853630","citation_count":18,"is_preprint":false},{"pmid":"35136033","id":"PMC_35136033","title":"ATAD3B and SKIL polymorphisms associated with antipsychotic-induced QTc interval change in patients with schizophrenia: a genome-wide association study.","date":"2022","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35136033","citation_count":18,"is_preprint":false},{"pmid":"31248089","id":"PMC_31248089","title":"Differentially Expressed Mitochondrial Proteins in Human MCF7 Breast Cancer Cells Resistant to Paclitaxel.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31248089","citation_count":13,"is_preprint":false},{"pmid":"37286092","id":"PMC_37286092","title":"Circ_ATAD3B inhibits cell proliferation of breast cancer via mediating the miR-570-3p/MX2 axis.","date":"2023","source":"Preventive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37286092","citation_count":6,"is_preprint":false},{"pmid":"36061954","id":"PMC_36061954","title":"Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion.","date":"2022","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/36061954","citation_count":6,"is_preprint":false},{"pmid":"35199044","id":"PMC_35199044","title":"CRISPR/Cas9-induced gene conversion between ATAD3 paralogs.","date":"2022","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/35199044","citation_count":3,"is_preprint":false},{"pmid":"35525914","id":"PMC_35525914","title":"Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35525914","citation_count":3,"is_preprint":false},{"pmid":"28623644","id":"PMC_28623644","title":"Increased AAA-TOB3 correlates with lymph node metastasis and advanced stage of lung adenocarcinoma.","date":"2017","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/28623644","citation_count":2,"is_preprint":false},{"pmid":"38092275","id":"PMC_38092275","title":"\"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane\".","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38092275","citation_count":2,"is_preprint":false},{"pmid":"22192748","id":"PMC_22192748","title":"[ATAD3, a vital membrane-bound mitochondrial ATPase involved in tumor progression].","date":"2011","source":"Medecine sciences : M/S","url":"https://pubmed.ncbi.nlm.nih.gov/22192748","citation_count":2,"is_preprint":false},{"pmid":"40688112","id":"PMC_40688112","title":"Exploring potential therapeutic targets for colorectal tumors based on whole genome sequencing of colorectal tumors and paracancerous tissues.","date":"2025","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/40688112","citation_count":1,"is_preprint":false},{"pmid":"42001994","id":"PMC_42001994","title":"SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.","date":"2026","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/42001994","citation_count":0,"is_preprint":false},{"pmid":"41280066","id":"PMC_41280066","title":"Allele-specific correction of ATAD3A pathogenic variants via template-free CRISPR-Cas9 editing and gene conversion.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41280066","citation_count":0,"is_preprint":false},{"pmid":"41293266","id":"PMC_41293266","title":"Multiomics analyses of human colorectal cancer reveal changes in mitochondrial metabolism associated with chemotherapy resistance.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41293266","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16177,"output_tokens":1580,"usd":0.036116,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8387,"output_tokens":2235,"usd":0.048905,"stage2_stop_reason":"end_turn"},"total_usd":0.085021,"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\": 2021,\n      \"finding\": \"ATAD3B contains a LIR (LC3-interacting region) motif that directly binds LC3 and functions as a mitophagy receptor, promoting oxidative stress-induced mitophagy in a PINK1-independent manner to clear damaged mtDNA.\",\n      \"method\": \"Loss- and gain-of-function experiments, LIR motif identification, LC3 binding assay, mitophagy assay in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (LIR-LC3 binding, PINK1-independence, functional mitophagy rescue) in a single focused study with clear mechanistic pathway placement\",\n      \"pmids\": [\"33665835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, which promotes targeting of the ATAD3B C-terminal region to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or depletion reduces this ATAD3B-ATAD3A hetero-oligomerization, leading to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent LC3 recruitment for mitophagy initiation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, oxidative stress treatment, mtDNA depletion, fluorescence microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and fractionation with functional mitophagy readout, multiple orthogonal methods in one focused study\",\n      \"pmids\": [\"33665835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATAD3B associates with ATAD3A (hetero-oligomerization), negatively regulates the interaction of ATAD3A with matrix nucleoid complexes, and contributes to a mitochondrial fragmentation phenotype. ATAD3B thus functions as a dominant negative regulator of ATAD3A.\",\n      \"method\": \"Loss- and gain-of-function approaches, Co-immunoprecipitation, mitochondrial morphology assays in hESCs and cancer cells\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional phenotype (nucleoid interaction, fragmentation), single lab with two orthogonal methods\",\n      \"pmids\": [\"22664726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The ATAD3B gene encodes two distinct protein isoforms (AAA-TOB3s and AAA-TOB3l) generated from distinct transcription initiation sites, both localized to mitochondria. Both isoforms are early transcriptional targets of c-Myc. Knockdown of both isoforms results in polynuclear cells, decreased proliferation, dysfunctional cell division, and increased apoptosis, indicating a required role in cell division.\",\n      \"method\": \"RT-PCR, Western blot, siRNA knockdown, flow cytometry, immunofluorescence microscopy, c-Myc target validation\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined cellular phenotype (cell division defect) and mitochondrial localization confirmed; c-Myc regulation by single lab with multiple methods\",\n      \"pmids\": [\"16909202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC62, an ER transmembrane protein at mitochondria-associated membranes (MAMs), directly interacts with ATAD3B and suppresses ATAD3B expression, leading to defective mitophagy, increased mitochondrial ROS, and amplified inflammatory responses in MASH.\",\n      \"method\": \"Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, Western blot, mitophagy assay, ROS measurement\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP demonstrating direct SEC62-ATAD3B interaction with functional downstream phenotype, single lab, single study\",\n      \"pmids\": [\"42001994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATAD3B re-expression in cells with m.3243A>G mutated mtDNA promotes clearance of the mutant mtDNA, demonstrating a functional role of ATAD3B-mediated mitophagy in eliminating pathogenic mtDNA variants.\",\n      \"method\": \"ATAD3B overexpression in MELAS patient fibroblasts and m.3243A>G mutated cells, mtDNA quantification\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with specific mtDNA clearance readout, part of broader mechanistic study with multiple supporting methods\",\n      \"pmids\": [\"33665835\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATAD3B is a primate-specific mitochondrial membrane protein that normally hetero-oligomerizes with ATAD3A (keeping its C-terminus in the intermembrane space and negatively regulating ATAD3A's nucleoid interactions), but upon oxidative stress-induced mtDNA damage this hetero-oligomerization is disrupted, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif recruits LC3 to initiate PINK1-independent mitophagy for selective clearance of damaged mtDNA; additionally, ATAD3B is transcriptionally regulated by c-Myc, is required for normal cell division, and its activity at MAMs can be suppressed by SEC62 interaction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATAD3B is a mitochondrial membrane protein that acts as a stress-responsive mitophagy receptor for selective clearance of damaged mitochondrial DNA [#0]. Under basal conditions it hetero-oligomerizes with ATAD3A, which targets the ATAD3B C-terminus to the intermembrane space and negatively regulates ATAD3A's interaction with matrix nucleoid complexes, positioning ATAD3B as a dominant-negative modulator of ATAD3A whose loss perturbs mitochondrial morphology [#1, #2]. Oxidative stress-induced mtDNA damage or depletion disrupts the ATAD3B-ATAD3A hetero-oligomer, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif directly binds LC3 to initiate mitophagy independently of PINK1 [#0, #1]. This pathway is functionally consequential: ATAD3B re-expression promotes clearance of pathogenic m.3243A>G mutant mtDNA [#5]. ATAD3B is encoded as two mitochondrially localized isoforms that are early transcriptional targets of c-Myc and are required for normal cell division, with knockdown producing polynuclear cells, reduced proliferation, and apoptosis [#3]. At mitochondria-associated membranes, the ER protein SEC62 directly binds ATAD3B and suppresses its expression, dampening mitophagy and amplifying mitochondrial ROS and inflammation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that the ATAD3B locus produces mitochondrial protein isoforms under c-Myc control and is needed for faithful cell division placed the gene within mitochondrial biology and growth regulation rather than leaving it uncharacterized.\",\n      \"evidence\": \"RT-PCR, Western blot, siRNA knockdown, flow cytometry and c-Myc target validation in cultured cells\",\n      \"pmids\": [\"16909202\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular basis of the cell-division requirement not defined\",\n        \"No mechanistic link drawn yet to mitophagy or ATAD3A\",\n        \"Functional difference between the two isoforms unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying ATAD3B as a hetero-oligomerization partner that antagonizes ATAD3A nucleoid interactions reframed it from a standalone protein to a dominant-negative regulator of ATAD3A and mitochondrial morphology.\",\n      \"evidence\": \"Co-immunoprecipitation and mitochondrial morphology assays in hESCs and cancer cells\",\n      \"pmids\": [\"22664726\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of hetero-oligomerization unknown\",\n        \"Single-lab Co-IP with two methods\",\n        \"Physiological trigger that modulates the ATAD3A-ATAD3B balance not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of a functional LIR motif that binds LC3 and drives PINK1-independent mitophagy defined the core molecular activity of ATAD3B as a mitophagy receptor, and coupling this to stress-induced loss of ATAD3A oligomerization explained how the receptor is conditionally activated; rescue of mutant mtDNA clearance established physiological relevance.\",\n      \"evidence\": \"LIR identification, LC3 binding assay, PINK1-independence, reciprocal Co-IP, subcellular fractionation, and mtDNA clearance in m.3243A>G/MELAS cells\",\n      \"pmids\": [\"33665835\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Structural detail of LIR-LC3 engagement not resolved\",\n        \"How mtDNA damage is sensed upstream of oligomer disruption unknown\",\n        \"Selectivity for damaged versus healthy nucleoids not mechanistically defined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying SEC62 as a direct MAM-resident binder that suppresses ATAD3B added a regulatory input controlling ATAD3B-dependent mitophagy and linked the pathway to ROS and inflammatory disease (MASH).\",\n      \"evidence\": \"Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, mitophagy and ROS assays\",\n      \"pmids\": [\"42001994\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single-lab, single-study Co-IP without reciprocal/structural validation\",\n        \"Mechanism by which SEC62 suppresses ATAD3B expression unclear\",\n        \"Whether SEC62 acts on the oligomerization or LIR steps not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream mtDNA damage is sensed and transduced into ATAD3B-ATAD3A hetero-oligomer disruption, and the structural basis of the receptor's stress-dependent reorientation, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural model of the ATAD3A-ATAD3B complex or its disassembly\",\n        \"Damage-sensing trigger upstream of oligomer disruption unidentified\",\n        \"Relationship between cell-division role and mitophagy role unintegrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATAD3A\", \"MAP1LC3B\", \"SEC62\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}