{"gene":"ATAD3A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2010,"finding":"ATAD3A spans both mitochondrial membranes: its N-terminal domain interacts with the outer membrane (OM), a central transmembrane segment anchors it in the inner membrane (IM), and the C-terminal AAA+ ATPase domain resides in the matrix. Using dominant-negative mutants (defective ATP-binding and truncated N-terminus), ATAD3A was shown to regulate dynamic OM-IM interactions sensed by the fission machinery and is required for normal cell growth and cholesterol channeling at contact sites.","method":"Dominant-negative mutant expression, invalidation studies in Drosophila and human steroidogenic cell line, topology/fractionation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, genetic invalidation in two model systems, fractionation), replicated topology finding","pmids":["20154147"],"is_preprint":false},{"year":2010,"finding":"The N-terminal region of ATAD3A is accessible from outside the inner membrane (cytoplasm or intermembrane space) while the C-terminal region is located within the matrix, establishing the transmembrane topology of ATAD3A in purified human mitochondria.","method":"Back-titration ELISA and immunofluorescence on freshly purified human mitochondria using N-terminal and C-terminal specific anti-peptide antibodies","journal":"Journal of bioenergetics and biomembranes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical topology assay with two orthogonal immunological approaches on purified mitochondria, single lab","pmids":["20349121"],"is_preprint":false},{"year":2010,"finding":"ATAD3A is a high-affinity, calcium-dependent target of S100B in oligodendrocyte progenitor cells (OPCs). NMR spectroscopy defined the S100B binding motif on ATAD3A. S100B prevents cytoplasmic aggregation of a mitochondrial-import-deficient ATAD3A mutant and restores its mitochondrial localization, suggesting S100B assists in proper ATAD3A folding and subcellular targeting.","method":"NMR spectroscopy, Far-Western assay, cellular studies with truncated ATAD3A mutant deficient for mitochondrial import","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping plus functional cellular assay with mutant, single lab but multiple orthogonal methods","pmids":["20351179"],"is_preprint":false},{"year":2012,"finding":"ATAD3B associates with ATAD3A, negatively regulates ATAD3A interaction with matrix nucleoid complexes, and contributes to mitochondrial fragmentation, functioning as a dominant-negative paralog of ATAD3A.","method":"Loss- and gain-of-function approaches in human embryonic stem cells and cancer cells","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with nucleoid interaction and morphology readouts, single lab","pmids":["22664726"],"is_preprint":false},{"year":2015,"finding":"ATAD3A interacts with the WASF3 metastasis-promoting protein and GRP78 in a trimeric complex at the mitochondrial membrane. The N-terminal domain of WASF3 interacts with the N-terminal domain of ATAD3A. Knockdown of ATAD3A leads to decreased WASF3 protein levels and loss of its stability at the mitochondrial membrane; suppression of GRP78 destabilizes WASF3 in an ATAD3A-dependent manner. ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability.","method":"Mass spectrometry, co-immunoprecipitation, proteolysis of isolated mitochondria, knockdown experiments with invasion and tumor growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, domain mapping by proteolysis, functional knockdown with multiple cellular and in vivo readouts","pmids":["25823022"],"is_preprint":false},{"year":2016,"finding":"The dominant-negative ATAD3A p.Arg528Trp variant causes small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. Tissue-specific overexpression of the homologous Drosophila borR534W mutation dramatically decreased mitochondrial content, caused aberrant mitochondrial morphology, and increased autophagy. Homozygous null larvae showed decreased mitochondria; wild-type overexpression produced larger, elongated mitochondria. Patient fibroblasts exhibited increased mitophagy.","method":"Drosophila tissue-specific overexpression of dominant-negative mutant, patient fibroblast mitophagy assay, whole-exome sequencing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dominant-negative mechanism established in Drosophila model and patient fibroblasts, replicated across multiple individuals","pmids":["27640307"],"is_preprint":false},{"year":2017,"finding":"ATAD3A interacts with the mitochondrial channel components Tom40 and Tim23 and serves as a bridging factor to facilitate appropriate transportation and processing of the PINK1 mitophagy kinase. Loss of Atad3a causes PINK1 accumulation and hyperactivated mitophagy. Genetic deletion of Pink1 in Atad3a-deficient mice rescued hematopoietic progenitor and HSC pool defects, establishing epistasis: ATAD3A acts upstream of PINK1 to suppress mitophagy.","method":"Conditional knockout mice, co-immunoprecipitation with Tom40/Tim23/PINK1, genetic epistasis (double knockout rescue), flow cytometry of hematopoietic compartments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with channel components, clean conditional KO with defined cellular phenotype, genetic epistasis rescue in vivo","pmids":["29242539"],"is_preprint":false},{"year":2017,"finding":"A dominant-negative ATAD3A p.G355D mutation in the Walker A motif (responsible for ATP binding) markedly reduces ATPase activity of the recombinant protein. Overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass, and patient fibroblasts and iPSC-derived neurons show altered mitochondrial dynamics and increased lysosomes associated with upregulated autophagy via mTOR inactivation.","method":"In vitro ATPase activity assay of recombinant mutant protein, overexpression in cell lines, patient fibroblast and iPSC-neuron analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay demonstrating reduced ATPase activity, corroborated by cellular phenotypes in multiple human cell models","pmids":["28158749"],"is_preprint":false},{"year":2019,"finding":"ATAD3A dimerization (driven by deacetylation at K135) is required for Drp1-mediated mitochondrial fragmentation in Huntington's disease. ATAD3A interacts with the mitochondrial fission GTPase Drp1. Drp1/ATAD3A interaction promotes ATAD3A oligomerization, which impairs TFAM/mtDNA binding and leads to bioenergetic deficits. A blocking peptide (DA1) abolishing Drp1/ATAD3A interaction suppresses oligomerization, reduces mtDNA lesion, and reduces HD neuropathology in transgenic mice.","method":"Proteomic analysis, co-immunoprecipitation, acetylation site mutagenesis (K135), peptide-blocking experiments in HD mouse and patient-derived cells, behavioral/neuropathological readouts in transgenic mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of modification site, blocking peptide validation, in vivo rescue in HD mice, multiple orthogonal methods","pmids":["30914652"],"is_preprint":false},{"year":2021,"finding":"Upon mitochondrial depolarization, AMBRA1 is recruited to the outer mitochondrial membrane and interacts with both PINK1 and ATAD3A. AMBRA1 promotes PINK1 stability by counteracting ATAD3A-mediated PINK1 degradation by the mitochondrial protease LONP1. Silencing ATAD3A rescues defective PINK1 accumulation in AMBRA1-deficient cells, placing ATAD3A downstream of AMBRA1 in the PINK1-PARKIN mitophagy pathway.","method":"Co-immunoprecipitation, AMBRA1 knockdown, ATAD3A silencing rescue experiments, PINK1 ubiquitin phosphorylation assay, PRKN/PARKIN recruitment assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, epistasis rescue experiment, multiple functional readouts, single lab","pmids":["34798798"],"is_preprint":false},{"year":2021,"finding":"Knockdown of ATAD3A in THP-1 cells results in increased type I interferon signaling mediated by cGAS and STING. This enhanced interferon signaling is abrogated when cells are depleted of mitochondrial DNA, establishing that ATAD3A normally prevents mtDNA-driven cGAS-STING activation.","method":"ATAD3A knockdown in THP-1 cells, mtDNA depletion rescue, ISG expression measurement, patient fibroblast validation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KD with mechanistic rescue (mtDNA depletion), validated in patient fibroblasts and multiple patient samples","pmids":["34387651"],"is_preprint":false},{"year":2021,"finding":"ATAD3A associates with multiple components of the inner mitochondrial membrane including OXPHOS complex I, Letm1, and prohibitin complexes. Neuronal-specific Atad3 knockout mice develop severe encephalopathy with aberrant mitochondrial cristae morphogenesis preceding symptoms. STORM microscopy shows ATAD3A is regularly distributed along the inner mitochondrial membrane, supporting a structural scaffolding role in inner membrane organization.","method":"Conditional neuronal KO mouse, multi-omics, co-immunoprecipitation with inner membrane components, STORM super-resolution microscopy","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined ultrastructural phenotype, reciprocal Co-IP with multiple partners, super-resolution imaging, multi-omics","pmids":["34936866"],"is_preprint":false},{"year":2022,"finding":"ATAD3A oligomerization accumulates at mitochondria-associated ER membranes (MAMs) in Alzheimer's disease models and inhibits CYP46A1 gene expression, leading to cholesterol accumulation. Suppressing ATAD3A oligomerization (by heterozygous KO or peptide DA1) restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and reduces AD neuropathology and cognitive deficits in 5XFAD mice.","method":"5XFAD mouse model, heterozygous ATAD3A KO, DA1 peptide treatment, CYP46A1 expression analysis, cholesterol turnover assay, APP processing assay, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological intervention in vivo, multiple biochemical and behavioral readouts, multiple model systems","pmids":["35236834"],"is_preprint":false},{"year":2022,"finding":"ATAD3A mediates nucleoid trafficking inside mitochondria: its ATPase domain directly binds TFAM and mediates nucleoid movement along mitochondria via ATP hydrolysis. ATAD3A oligomerization via coiled-coil domains in the intermembrane space is also required for nucleoid trafficking. ATAD3A deficiency leads to dispersed small nucleoids and enhanced respiratory complex formation.","method":"Live imaging of nucleoid dynamics, in vitro binding assay of ATPase domain with TFAM, ATAD3A knockout/mutant analysis, respiratory complex assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assay, live imaging, ATPase-domain mutant analysis, functional respiratory complex readout, single lab with multiple methods","pmids":["36383603"],"is_preprint":false},{"year":2022,"finding":"MUC1 translocates to mitochondria and interacts with ATAD3A, inducing its degradation, which protects PINK1 from ATAD3A-mediated cleavage and thereby promotes PINK1-dependent mitophagy. This establishes a MUC1/ATAD3A/PINK1 axis in cancer cell mitophagy.","method":"Co-immunoprecipitation, knockdown/overexpression of MUC1 and ATAD3A, mitophagy flux assay, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, functional knockdown with mitophagy readout, in vivo validation, single lab","pmids":["36289190"],"is_preprint":false},{"year":2022,"finding":"ATAD3A binds to ERK1/2 in mitochondria in the presence of VDAC1, and this interaction is essential for activation of mitochondrial ERK1/2 signaling in a RAS-independent manner. Walker A dead mutant (K358) of ATAD3A produces a dominant-negative effect on HNSCC growth.","method":"Co-immunoprecipitation, CRISPR/Cas9 knockout, Walker A mutant overexpression, phospho-kinase profiling, orthotopic tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ERK1/2 and VDAC1, dominant-negative mutagenesis, in vivo rescue, single lab","pmids":["35093151"],"is_preprint":false},{"year":2023,"finding":"PINK1 recruits PD-L1 to mitochondria for degradation via mitophagy. ATAD3A suppresses PINK1-dependent mitophagy, preventing mitochondrial redistribution of PD-L1 and thereby maintaining PD-L1 on the tumor cell membrane. Paclitaxel increases ATAD3A expression to restrain PINK1-dependent mitophagy and PD-L1 degradation.","method":"Subcellular fractionation, knockdown/overexpression of ATAD3A and PINK1, mitophagy flux assay, PD-L1 localization analysis, patient tumor sample correlation","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with subcellular localization readout and defined pathway placement, single lab","pmids":["36627348"],"is_preprint":false},{"year":2023,"finding":"Sigma-1 receptor (σ1R) retains ATAD3A as a monomer at the MAM, inhibiting mitochondrial fragmentation. Loss of σ1R or SOD1-linked ALS conditions cause ATAD3A dimerization and mitochondrial fragmentation. σ1R-mediated MAM formation depends on ATAD3A.","method":"σ1R-deficient cells and SOD1-ALS mouse spinal cords, co-immunoprecipitation, native PAGE for ATAD3A oligomeric state, mitochondrial morphology analysis","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, native PAGE oligomeric state, in vivo ALS mouse model, single lab","pmids":["36736924"],"is_preprint":false},{"year":2023,"finding":"ATAD3C incorporates into the ATAD3A complex in the mitochondrial inner membrane as a monomer, reducing complex size and negatively regulating ATAD3A function. ATAD3C overexpression decreases cell proliferation and oxygen consumption and increases ROS, and increases dimeric CIII at the expense of respiratory supercomplexes.","method":"ATAD3C overexpression in fibroblasts, native PAGE of ATAD3A complexes, oxygen consumption rate, ROS measurement, respiratory complex analysis","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — native PAGE complex analysis, functional readouts (OCR, ROS, respiratory complexes), single lab with multiple methods","pmids":["38092275"],"is_preprint":false},{"year":2024,"finding":"ATAD3A interacts with PERK at mitochondria-ER contact sites. During ER stress, PERK-ATAD3A interactions increase, and ATAD3A competes with eIF2α for PERK binding, attenuating local PERK signaling and protecting mitochondria-localized translation from ER stress-induced repression. This protects expression of some mitochondrial proteins.","method":"Live-cell imaging of reporter mRNA translation, co-immunoprecipitation, ATAD3A knockdown, proximity ligation assay for MAM contact sites","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — live-cell translation imaging, Co-IP demonstrating competition with eIF2α, KD with functional translational readout, single rigorous study with multiple orthogonal methods","pmids":["39116259"],"is_preprint":false},{"year":2024,"finding":"SIRT3 deacetylates ATAD3A; acetylation at K134 disrupts ATAD3A self-oligomerization. The ATAD3A monomer (de-oligomerized form) closely interacts with the IP3R1-GRP75-VDAC1 complex at MAMs, leading to mitochondrial calcium overload and dysfunction. SIRT3 knockout mice show excessive MAM formation.","method":"Co-immunoprecipitation with IP3R1-GRP75-VDAC1, acetylation site mutagenesis (K134), SIRT3 KO mouse model, mitochondrial calcium measurement, cardiac hypertrophy model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetylation site mutagenesis, Co-IP with MAM complex, in vivo KO mouse model, single lab","pmids":["38250153"],"is_preprint":false},{"year":2024,"finding":"TBK1 is activated and localizes to mitochondria during cellular senescence, where it directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A suppresses PINK1-mediated mitophagy by facilitating PINK1 mitochondrial import. Blocking ATAD3A phosphorylation at Ser321 (by TBK1 deficiency or S321A mutation) rescues cellular senescence.","method":"In vitro kinase assay (TBK1 phosphorylating ATAD3A), phospho-site mutagenesis (S321A), TBK1 KO, blocking peptide (TAT-PEP), PINK1 import assay, senescence markers","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, mutagenesis of phospho-site with functional rescue, peptide validation, single lab with multiple orthogonal methods","pmids":["39520088"],"is_preprint":false},{"year":2024,"finding":"TRIM25 E3 ubiquitin ligase interacts with and ubiquitinates ATAD3A via the proteasome pathway, destabilizing ATAD3A and promoting PINK1/Parkin-dependent mitophagy during cerebral ischemia-reperfusion injury.","method":"Co-immunoprecipitation, ubiquitination assay, ATAD3A knockdown/overexpression, TRIM25 manipulation, in vivo MCAO model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrating direct ubiquitination, functional in vivo model, single lab","pmids":["39307194"],"is_preprint":false},{"year":2025,"finding":"ME2 (malic enzyme 2) competes with TRIM25 for binding to ATAD3A, disrupting TRIM25-ATAD3A interaction and thereby preventing ATAD3A ubiquitination and degradation. Loss of ME2 strengthens TRIM25-ATAD3A interaction, leading to ATAD3A ubiquitination, proteasomal degradation, PINK1 accumulation, and mitophagy activation.","method":"Co-immunoprecipitation, competitive binding assay, ubiquitination assay, ME2 knockdown with PINK1/mitophagy readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competition assay, ubiquitination readout, functional mitophagy phenotype, single lab","pmids":["41876455"],"is_preprint":false},{"year":2025,"finding":"FBXL6 E3 ubiquitin ligase directly targets ATAD3A and induces K63-linked polyubiquitination, which stabilizes ATAD3A (rather than degrading it) and activates aerobic glycolysis to promote TNBC malignancy.","method":"Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, ATAD3A knockdown, tumor growth assays in vitro and in vivo","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, functional tumor model, single lab","pmids":["40975350"],"is_preprint":false},{"year":2025,"finding":"ATAD3A directly interacts with complex I subunit NDUFS8 and is required for complex I assembly and activity. Knockdown of atad-3 reduces complex I activity and proton leakage, increases mitochondrial membrane potential, and thereby induces reverse electron transport (RET)-driven ROS production.","method":"Co-immunoprecipitation with NDUFS8, complex I activity assay, mitochondrial membrane potential measurement, ROS measurement in C. elegans and mammalian cells","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP with complex I subunit, enzymatic activity assay, functional RET-ROS measurement, single lab","pmids":["40961994"],"is_preprint":false},{"year":2025,"finding":"ATAD3A is an essential component of the mitochondrial permeability transition pore (mPTP). Genetic deletion of Atad3 in cardiomyocytes and hepatocytes abolishes Ca2+-induced mPTP-dependent swelling, and patch-clamp recordings of recombinant ATAD3A reconstituted in liposomes reveal intrinsic channel activity. Cardiac-specific Atad3 deletion markedly reduces infarct size following ischemia/reperfusion.","method":"Cardiomyocyte/hepatocyte-specific KO, Ca2+-induced mitochondrial swelling assay, patch-clamp of ATAD3A reconstituted in liposomes, I/R infarct size measurement","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in liposomes with patch-clamp channel recording, genetic KO with mPTP functional assay, in vivo cardiac I/R model; novel finding not covered by peer-reviewed work","pmids":["bio_10.1101_2025.06.13.658955"],"is_preprint":true},{"year":2025,"finding":"Thymoquinone (TQ) directly binds ATAD3A at its C-terminal L368 residue (validated by SPR and CETSA), stabilizes ATAD3A protein, and enhances ATAD3A-PERK interaction at MAMs. This preserves MAM integrity, attenuates PERK/eIF2α-mediated ER stress, and restores mitochondrial bioenergetics in myocardial ischemia-reperfusion models. ATAD3A-L368 mutant or PERK inhibition abolishes TQ's protective effects.","method":"Surface plasmon resonance (SPR), CETSA, co-immunoprecipitation-mass spectrometry, proximity ligation assay, MAM-SplitGFP system, ATAD3A-L368 mutant rescue experiment, in vivo MI/R mouse model","journal":"Phytomedicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding validated by SPR and CETSA, interaction mapped by IP-MS, functional site confirmed by mutant rescue, in vivo model","pmids":["40460607"],"is_preprint":false},{"year":2026,"finding":"ATAD3A overexpression reduces mitochondria-lysosome contacts, limits mitochondrial Ca2+ influx, and suppresses the FDXR/FDX1/LIAS lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis in vascular smooth muscle cells, thereby protecting against aortic aneurysm and dissection. ATAD3A interacts with DLST as identified by co-immunoprecipitation.","method":"VSMC-specific knockdown and systemic overexpression knock-in mice, co-immunoprecipitation of ATAD3A-DLST, mitochondria-lysosome contact quantification, Ca2+ imaging, lipoylation assay, in vivo AAD models","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, genetic KO and OE in vivo models with defined pathway (lipoylation/cuproptosis), multiple orthogonal methods, single lab","pmids":["42237912"],"is_preprint":false},{"year":2026,"finding":"PARK7 directly interacts with mitochondrial ATAD3A and downregulates its lactylation level, thereby suppressing expression of mitochondrial-related genes and promoting CD8+ T-cell exhaustion. T-cell-specific PARK7 deficiency enhances mitochondrial function in CD8+ T cells and alleviates exhaustion.","method":"Co-immunoprecipitation, lactylation modification assay, T-cell specific PARK7 KO, mitochondrial function assays, tumor growth assays","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct interaction, post-translational modification (delactylation) with functional gene expression readout, genetic KO with defined phenotype, single lab","pmids":["42162305"],"is_preprint":false}],"current_model":"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both membranes (N-terminus facing cytoplasm/IMS, C-terminal ATPase domain in matrix), functions as an essential structural scaffold for inner membrane cristae organization, directly binds TFAM to drive nucleoid trafficking via ATP hydrolysis, interacts with Tom40/Tim23 to mediate PINK1 import and proteolytic processing (thereby suppressing PINK1-dependent mitophagy), forms complexes with PERK at mitochondria-ER contact sites to locally attenuate ER-stress-induced translational repression, interacts with Drp1 via oligomerization-dependent mechanisms to couple mitochondrial fission with mtDNA maintenance and bioenergetics, and constitutes an essential pore-forming component of the mitochondrial permeability transition pore; its activity and oligomeric state are regulated by post-translational modifications including deacetylation (SIRT3 at K134/K135), phosphorylation (TBK1 at S321), K63-linked ubiquitination (FBXL6), and proteasomal ubiquitination (TRIM25), collectively controlling mitophagy flux, cholesterol metabolism, cGAS-STING-mediated interferon signaling, and cell survival."},"narrative":{"mechanistic_narrative":"ATAD3A is a mitochondrial AAA+ ATPase that spans both mitochondrial membranes—its N-terminus accessible from the cytoplasm/intermembrane space, a central transmembrane segment in the inner membrane, and the C-terminal ATPase domain in the matrix—where it serves as a structural scaffold coordinating membrane architecture, nucleoid organization, and mitochondria-ER crosstalk [PMID:20154147, PMID:20349121, PMID:34936866]. Distributed regularly along the inner membrane, it associates with OXPHOS complex I (directly binding NDUFS8), Letm1, and prohibitin complexes and is required for cristae morphogenesis and complex I assembly, such that its loss perturbs respiratory function and drives reverse-electron-transport ROS [PMID:34936866, PMID:40961994]. Through its ATPase domain, ATAD3A directly binds TFAM and powers trafficking of mtDNA nucleoids via ATP hydrolysis, a function further requiring intermembrane-space coiled-coil-mediated oligomerization [PMID:36383603]. A central regulatory theme is its control of PINK1-dependent mitophagy: ATAD3A bridges the Tom40/Tim23 import channels to facilitate PINK1 import and processing, thereby suppressing mitophagy, and it acts upstream of PINK1 in vivo, with PINK1 deletion rescuing ATAD3A-deficient hematopoietic defects [PMID:29242539]. This mitophagy-suppressive activity is tuned by post-translational modifications and competing partners—TBK1 phosphorylation at Ser321 promotes PINK1 import [PMID:39520088], AMBRA1, TRIM25-mediated proteasomal ubiquitination, and MUC1 destabilize ATAD3A to release PINK1 [PMID:34798798, PMID:39307194, PMID:36289190]. The protein's oligomeric state is itself a master regulatory switch: deacetylation at K135/K134 by SIRT3 governs dimerization, and Drp1-driven oligomerization couples mitochondrial fission to impaired TFAM/mtDNA binding and bioenergetic deficits in Huntington's disease, while at mitochondria-ER contact sites oligomerization controls CYP46A1-dependent cholesterol turnover in Alzheimer's models and competition with eIF2α attenuates PERK-mediated translational repression [PMID:30914652, PMID:35236834, PMID:39116259, PMID:38250153]. ATAD3A also restrains mtDNA-driven cGAS-STING type I interferon signaling [PMID:34387651] and functions as an essential pore-forming component of the mitochondrial permeability transition pore [PMID:bio_10.1101_2025.06.13.658955]. Dominant-negative ATAD3A mutations affecting ATP binding (p.G355D, p.R528W) cause human mitochondrial disease characterized by aberrant mitochondrial dynamics and hyperactivated mitophagy [PMID:27640307, PMID:28158749].","teleology":[{"year":2010,"claim":"Establishing ATAD3A's dual-membrane topology answered where this AAA+ ATPase sits and how it could physically bridge the two mitochondrial membranes to sense and regulate membrane contacts.","evidence":"Topology/fractionation and back-titration ELISA/immunofluorescence on purified human mitochondria, plus dominant-negative mutants in Drosophila and steroidogenic cells","pmids":["20154147","20349121"],"confidence":"High","gaps":["Structural basis of how a single protein anchors both membranes not resolved","Mechanism coupling topology to fission machinery sensing undefined"]},{"year":2010,"claim":"Identifying S100B as a calcium-dependent ATAD3A chaperone addressed how ATAD3A achieves proper folding and mitochondrial targeting.","evidence":"NMR mapping of the S100B binding motif and rescue of an import-deficient ATAD3A mutant in oligodendrocyte progenitors","pmids":["20351179"],"confidence":"High","gaps":["Physiological relevance of S100B chaperoning beyond OPCs unclear","Whether S100B affects endogenous ATAD3A import not tested"]},{"year":2012,"claim":"Discovery that the paralog ATAD3B antagonizes ATAD3A-nucleoid interactions introduced paralog-based regulation of ATAD3A function.","evidence":"Reciprocal gain/loss-of-function in human ES and cancer cells with nucleoid and morphology readouts","pmids":["22664726"],"confidence":"Medium","gaps":["Stoichiometry of ATAD3A/ATAD3B complexes unknown","Single lab; biochemical basis of dominant-negative effect not defined"]},{"year":2015,"claim":"Placing ATAD3A in a trimeric complex with WASF3 and GRP78 linked it to tumor cell stability of a metastasis driver and E-cadherin suppression.","evidence":"MS, Co-IP, mitochondrial proteolysis domain mapping, knockdown with invasion and tumor growth assays","pmids":["25823022"],"confidence":"High","gaps":["Whether ATAD3A's ATPase activity is required for WASF3 stabilization not shown","Mechanism connecting mitochondrial WASF3 to E-cadherin regulation incomplete"]},{"year":2016,"claim":"Dominant-negative ATAD3A disease variants established that perturbing ATAD3A triggers excess mitophagy and reduced mitochondrial content, defining a human disease mechanism.","evidence":"Whole-exome sequencing, Drosophila tissue-specific dominant-negative overexpression, patient fibroblast mitophagy assays","pmids":["27640307"],"confidence":"High","gaps":["Molecular trigger linking small mitochondria to mitophagy not yet defined","Tissue selectivity of phenotype unexplained"]},{"year":2017,"claim":"Two studies defined the upstream control of PINK1 by ATAD3A and demonstrated that ATP-binding-dead mutants are dominant-negative, mechanistically connecting ATPase activity to mitophagy suppression.","evidence":"Conditional KO mice with reciprocal Co-IP of Tom40/Tim23/PINK1 and PINK1 deletion epistasis rescue; in vitro ATPase assay of recombinant G355D mutant with patient fibroblast/iPSC-neuron phenotypes","pmids":["29242539","28158749"],"confidence":"High","gaps":["How ATAD3A physically presents PINK1 to the import channel not structurally resolved","Link between ATPase activity and bridging function not directly tested"]},{"year":2019,"claim":"Linking deacetylation-driven dimerization and Drp1 interaction to fission established ATAD3A oligomeric state as a switch coupling fission, TFAM/mtDNA binding, and bioenergetics in disease.","evidence":"Proteomics, Co-IP, K135 acetylation-site mutagenesis, DA1 blocking peptide, in vivo rescue in HD transgenic mice","pmids":["30914652"],"confidence":"High","gaps":["Direct deacetylase responsible not identified in this study","Structural model of oligomer-TFAM competition lacking"]},{"year":2021,"claim":"Multiple studies refined ATAD3A's mitophagy and immune roles—positioning it downstream of AMBRA1 in PINK1 stability and as a suppressor of mtDNA-driven cGAS-STING interferon signaling.","evidence":"Co-IP and epistasis rescue in AMBRA1-deficient cells; ATAD3A knockdown in THP-1 with mtDNA-depletion rescue and patient fibroblast validation","pmids":["34798798","34387651"],"confidence":"High","gaps":["How ATAD3A loss releases mtDNA to cGAS not mechanistically defined","Interplay between AMBRA1/LONP1 and ATAD3A-PINK1 import unresolved"]},{"year":2021,"claim":"Demonstrating ATAD3A association with complex I, Letm1, and prohibitins plus its regular IMM distribution established it as a structural scaffold for cristae morphogenesis.","evidence":"Neuronal conditional KO mice, multi-omics, Co-IP with inner membrane components, STORM super-resolution imaging","pmids":["34936866"],"confidence":"High","gaps":["Direct structural contribution to cristae versus indirect effects not separated","Whether scaffolding requires ATPase activity untested"]},{"year":2022,"claim":"A cluster of studies defined how ATAD3A oligomerization at MAMs and its ATPase-dependent TFAM binding govern nucleoid trafficking, cholesterol metabolism, and cancer mitophagy.","evidence":"In vitro ATPase-domain/TFAM binding and live nucleoid imaging; 5XFAD mice with CYP46A1/cholesterol readouts and DA1 peptide; MUC1/ATAD3A/PINK1 Co-IP and mitophagy flux","pmids":["36383603","35236834","36289190"],"confidence":"High","gaps":["How oligomeric state at MAMs controls CYP46A1 transcription mechanistically unclear","MUC1-ATAD3A axis validated in single lab"]},{"year":2022,"claim":"ATAD3A was shown to anchor RAS-independent mitochondrial ERK1/2 signaling, extending its scaffolding role to a growth-promoting kinase module.","evidence":"Co-IP with ERK1/2 and VDAC1, CRISPR KO, Walker A dead mutant (K358) dominant-negative, orthotopic HNSCC tumor model","pmids":["35093151"],"confidence":"Medium","gaps":["How ATAD3A activates mitochondrial ERK1/2 mechanistically unknown","Single lab; generality across tumor types untested"]},{"year":2023,"claim":"Studies connected ATAD3A monomer/oligomer balance at MAMs to PD-L1 trafficking, σ1R-controlled fragmentation, and showed its oligomeric state is the regulatory node across contexts.","evidence":"Subcellular fractionation and mitophagy flux for PINK1/PD-L1; σ1R-deficient cells and SOD1-ALS mouse spinal cords with native PAGE oligomeric state","pmids":["36627348","36736924"],"confidence":"Medium","gaps":["σ1R-ATAD3A regulation rests on single-lab Co-IP/native PAGE","Direct structural determinant of monomer-to-dimer transition undefined"]},{"year":2023,"claim":"Defining the ATAD3C paralog as a negative regulator that reduces complex size and shifts respiratory supercomplex assembly added a second paralog-based control of ATAD3A complexes.","evidence":"ATAD3C overexpression in fibroblasts, native PAGE complex analysis, OCR, ROS, and respiratory complex assays","pmids":["38092275"],"confidence":"Medium","gaps":["Endogenous stoichiometry of ATAD3A/ATAD3C complexes unknown","Single lab; physiological contexts of ATAD3C expression unclear"]},{"year":2024,"claim":"A set of studies established the post-translational and protein-protein code controlling ATAD3A's PERK competition, MAM calcium handling, mitophagy via phosphorylation, and proteasomal turnover.","evidence":"Live-cell translation imaging and Co-IP showing ATAD3A-eIF2α competition for PERK; SIRT3 deacetylation/K134 mutagenesis with IP3R1-GRP75-VDAC1 Co-IP; in vitro TBK1 kinase assay with S321A mutagenesis; TRIM25 ubiquitination assays","pmids":["39116259","38250153","39520088","39307194"],"confidence":"High","gaps":["How distinct modifications are integrated on the same molecule unresolved","Some axes (SIRT3, TRIM25) rest on single-lab Co-IP/ubiquitination assays"]},{"year":2025,"claim":"Multiple 2025 studies expanded the regulatory and functional network—competing E3/competitor inputs (FBXL6, ME2), direct complex I assembly via NDUFS8, and intrinsic mPTP channel activity.","evidence":"Linkage-specific K63 ubiquitination by FBXL6; ME2-TRIM25 competition assays; Co-IP with NDUFS8 and complex I activity/RET-ROS measurement; cardiomyocyte/hepatocyte KO with patch-clamp of liposome-reconstituted ATAD3A (preprint)","pmids":["40975350","41876455","40961994","bio_10.1101_2025.06.13.658955"],"confidence":"Medium","gaps":["Opposing K63-stabilizing versus proteasomal ubiquitination integration unclear","mPTP channel finding is a preprint awaiting peer review","Direct pore architecture and gating mechanism undefined"]},{"year":2025,"claim":"Identification of direct small-molecule binding at the C-terminal L368 residue showed ATAD3A is a druggable target whose stabilization enhances PERK interaction and protects against ischemia-reperfusion.","evidence":"SPR, CETSA, IP-MS, PLA, MAM-SplitGFP, L368 mutant rescue, in vivo MI/R model with thymoquinone","pmids":["40460607"],"confidence":"High","gaps":["Structure of the ligand-binding pocket not solved","Selectivity of thymoquinone for ATAD3A not fully characterized"]},{"year":2026,"claim":"New interactions placed ATAD3A within cuproptosis/lipoylation control via DLST and within CD8+ T-cell exhaustion via PARK7-regulated lactylation, broadening its roles into metabolic cell death and immune metabolism.","evidence":"VSMC-specific KD and overexpression knock-in mice with ATAD3A-DLST Co-IP and lipoylation assays; PARK7 Co-IP, lactylation assay, and T-cell-specific PARK7 KO","pmids":["42237912","42162305"],"confidence":"Medium","gaps":["How ATAD3A interaction modulates DLST lipoylation mechanistically unclear","PARK7-driven delactylation of ATAD3A rests on single-lab Co-IP/PTM assays"]},{"year":null,"claim":"How the multiple, sometimes opposing, post-translational modifications and competing partners are integrated to set ATAD3A's oligomeric state and select among its many functions in a context-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the monomer-to-oligomer transition","Hierarchy among acetylation, phosphorylation, and ubiquitination inputs unknown","Whether a single ATAD3A pool serves all functions or distinct subpopulations exist is unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,7,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11,13]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[26]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12,19,20]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,9,14,21]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[11,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[26,28]}],"complexes":["ATAD3A/ATAD3B/ATAD3C inner membrane complex","mitochondrial permeability transition pore","ATAD3A-WASF3-GRP78 complex"],"partners":["TFAM","PINK1","DRP1","PERK","NDUFS8","TOMM40","TIMM23","TRIM25"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVI7","full_name":"ATPase family AAA domain-containing protein 3A","aliases":[],"length_aa":586,"mass_kda":66.2,"function":"Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level (PubMed:17210950, PubMed:20154147, PubMed:22453275, PubMed:31522117, PubMed:37832546, PubMed:39116259). May play an important role in mitochondrial protein synthesis (PubMed:22453275). May also participate in mitochondrial DNA replication (PubMed:17210950). May bind to mitochondrial DNA D-loops and contribute to nucleoid stability (PubMed:17210950). Required for enhanced channeling of cholesterol for hormone-dependent steroidogenesis (PubMed:22453275). Involved in mitochondrial-mediated antiviral innate immunity (PubMed:31522117). Required to protect mitochondria from the PERK-mediated unfolded protein response: specifically inhibits the activity of EIF2AK3/PERK at mitochondria-endoplasmic reticulum contact sites, thereby providing a safe haven for mitochondrial protein translation during endoplasmic reticulum stress (PubMed:39116259). Ability to inhibit EIF2AK3/PERK is independent of its ATPase activity (PubMed:39116259). Also involved in the mitochondrial DNA damage response by promoting signaling between damaged genomes and the mitochondrial membrane, leading to activation of the integrated stress response (ISR) (PubMed:37832546)","subcellular_location":"Mitochondrion inner membrane; Mitochondrion matrix, mitochondrion nucleoid","url":"https://www.uniprot.org/uniprotkb/Q9NVI7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATAD3A","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATAD3A","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":"617183","title":"HAREL-YOON SYNDROME; HAYOS","url":"https://www.omim.org/entry/617183"},{"mim_id":"612317","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 3B; ATAD3B","url":"https://www.omim.org/entry/612317"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"},{"location":"Acrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATAD3A"},"hgnc":{"alias_symbol":["FLJ10709"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVI7","domains":[{"cath_id":"3.40.50.300","chopping":"334-521","consensus_level":"high","plddt":86.7367,"start":334,"end":521},{"cath_id":"1.10.8.60","chopping":"527-621","consensus_level":"high","plddt":91.9624,"start":527,"end":621},{"cath_id":"1.20.5","chopping":"292-327","consensus_level":"medium","plddt":78.845,"start":292,"end":327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVI7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVI7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVI7-F1-predicted_aligned_error_v6.png","plddt_mean":81.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATAD3A","jax_strain_url":"https://www.jax.org/strain/search?query=ATAD3A"},"sequence":{"accession":"Q9NVI7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVI7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVI7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVI7"}},"corpus_meta":[{"pmid":"27640307","id":"PMC_27640307","title":"Recurrent 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redirecting PD-L1 to mitochondria.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36627348","citation_count":102,"is_preprint":false},{"pmid":"25823022","id":"PMC_25823022","title":"Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25823022","citation_count":85,"is_preprint":false},{"pmid":"30914652","id":"PMC_30914652","title":"ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30914652","citation_count":83,"is_preprint":false},{"pmid":"33280610","id":"PMC_33280610","title":"Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis.","date":"2020","source":"Journal of experimental & clinical cancer research : 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mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28158749","citation_count":66,"is_preprint":false},{"pmid":"34936866","id":"PMC_34936866","title":"ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34936866","citation_count":59,"is_preprint":false},{"pmid":"36289190","id":"PMC_36289190","title":"The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36289190","citation_count":55,"is_preprint":false},{"pmid":"20351179","id":"PMC_20351179","title":"The calcium-dependent interaction between S100B and the mitochondrial AAA ATPase ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20351179","citation_count":41,"is_preprint":false},{"pmid":"20349121","id":"PMC_20349121","title":"Topological analysis of ATAD3A insertion in purified human mitochondria.","date":"2010","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/20349121","citation_count":40,"is_preprint":false},{"pmid":"39116259","id":"PMC_39116259","title":"PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39116259","citation_count":38,"is_preprint":false},{"pmid":"33580514","id":"PMC_33580514","title":"ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.","date":"2021","source":"Journal of cellular 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ATAD3A.","date":"2012","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/22664726","citation_count":32,"is_preprint":false},{"pmid":"38250153","id":"PMC_38250153","title":"The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy.","date":"2024","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38250153","citation_count":30,"is_preprint":false},{"pmid":"35093151","id":"PMC_35093151","title":"ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35093151","citation_count":30,"is_preprint":false},{"pmid":"32933822","id":"PMC_32933822","title":"Mitochondrial dysfunction caused by novel ATAD3A mutations.","date":"2020","source":"Molecular genetics and 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Yi xue ban = Journal of Zhejiang University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38105692","citation_count":2,"is_preprint":false},{"pmid":"38173481","id":"PMC_38173481","title":"Harel-Yoon syndrome caused by a novel variant in ATAD3A: A case report.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38173481","citation_count":2,"is_preprint":false},{"pmid":"40975350","id":"PMC_40975350","title":"Elevated FBXL6 activates ATAD3A through K63-linked polyubiquitination and promotes the malignant progression of TNBC via metabolic reprogramming.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40975350","citation_count":1,"is_preprint":false},{"pmid":"40961994","id":"PMC_40961994","title":"ATAD3A deficiency induces oxidative eustress via the complex I reverse electron transport.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40961994","citation_count":1,"is_preprint":false},{"pmid":"41876455","id":"PMC_41876455","title":"Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41876455","citation_count":1,"is_preprint":false},{"pmid":"32219745","id":"PMC_32219745","title":"Using Genome-Editing Tools to Develop a Novel In Situ Coincidence Reporter Assay for Screening ATAD3A Transcriptional Inhibitors.","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32219745","citation_count":1,"is_preprint":false},{"pmid":"41715136","id":"PMC_41715136","title":"Single-cell transcriptomic analysis and machine learning identify ATAD3A as a key gene that stabilizes mitochondrial-endoplasmic reticulum membranes, promoting bladder cancer progression.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41715136","citation_count":0,"is_preprint":false},{"pmid":"40246775","id":"PMC_40246775","title":"Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants.","date":"2025","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/40246775","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":"42001122","id":"PMC_42001122","title":"ATAD3A promotes bladder cancer progression by regulating glycolysis through MYC stabilization.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42001122","citation_count":0,"is_preprint":false},{"pmid":"42237912","id":"PMC_42237912","title":"ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation.","date":"2026","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/42237912","citation_count":0,"is_preprint":false},{"pmid":"42162305","id":"PMC_42162305","title":"PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells.","date":"2026","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42162305","citation_count":0,"is_preprint":false},{"pmid":"41401963","id":"PMC_41401963","title":"[A case of Harel-Yoon syndrome with seizures caused by an ATAD3A variant].","date":"2025","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41401963","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.06.680775","title":"ATAD3 megadalton complex in  <i>Plasmodium falciparum</i>  is essential for mitochondrial and cellular viability","date":"2025-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.680775","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.13.658955","title":"Atad3 is Essential for Mitochondrial Permeability Transition Pore Opening and Cardiac Ischemia Reperfusion Injury","date":"2025-06-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.658955","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.02.621207","title":"Transcriptome analysis of  <i>atad3-</i>  null zebrafish embryos elucidates possible disease mechanisms","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.02.621207","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.09.622805","title":"Reprogramming the neuronal secretory and metabolic machinery using correctors for Alzheimer therapy","date":"2024-11-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.09.622805","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33584,"output_tokens":8102,"usd":0.111141,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17836,"output_tokens":6257,"usd":0.122802,"stage2_stop_reason":"end_turn"},"total_usd":0.233943,"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\": 2010,\n      \"finding\": \"ATAD3A spans both mitochondrial membranes: its N-terminal domain interacts with the outer membrane (OM), a central transmembrane segment anchors it in the inner membrane (IM), and the C-terminal AAA+ ATPase domain resides in the matrix. Using dominant-negative mutants (defective ATP-binding and truncated N-terminus), ATAD3A was shown to regulate dynamic OM-IM interactions sensed by the fission machinery and is required for normal cell growth and cholesterol channeling at contact sites.\",\n      \"method\": \"Dominant-negative mutant expression, invalidation studies in Drosophila and human steroidogenic cell line, topology/fractionation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, genetic invalidation in two model systems, fractionation), replicated topology finding\",\n      \"pmids\": [\"20154147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminal region of ATAD3A is accessible from outside the inner membrane (cytoplasm or intermembrane space) while the C-terminal region is located within the matrix, establishing the transmembrane topology of ATAD3A in purified human mitochondria.\",\n      \"method\": \"Back-titration ELISA and immunofluorescence on freshly purified human mitochondria using N-terminal and C-terminal specific anti-peptide antibodies\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical topology assay with two orthogonal immunological approaches on purified mitochondria, single lab\",\n      \"pmids\": [\"20349121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATAD3A is a high-affinity, calcium-dependent target of S100B in oligodendrocyte progenitor cells (OPCs). NMR spectroscopy defined the S100B binding motif on ATAD3A. S100B prevents cytoplasmic aggregation of a mitochondrial-import-deficient ATAD3A mutant and restores its mitochondrial localization, suggesting S100B assists in proper ATAD3A folding and subcellular targeting.\",\n      \"method\": \"NMR spectroscopy, Far-Western assay, cellular studies with truncated ATAD3A mutant deficient for mitochondrial import\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping plus functional cellular assay with mutant, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20351179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATAD3B associates with ATAD3A, negatively regulates ATAD3A interaction with matrix nucleoid complexes, and contributes to mitochondrial fragmentation, functioning as a dominant-negative paralog of ATAD3A.\",\n      \"method\": \"Loss- and gain-of-function approaches in human embryonic stem cells and cancer cells\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with nucleoid interaction and morphology readouts, single lab\",\n      \"pmids\": [\"22664726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATAD3A interacts with the WASF3 metastasis-promoting protein and GRP78 in a trimeric complex at the mitochondrial membrane. The N-terminal domain of WASF3 interacts with the N-terminal domain of ATAD3A. Knockdown of ATAD3A leads to decreased WASF3 protein levels and loss of its stability at the mitochondrial membrane; suppression of GRP78 destabilizes WASF3 in an ATAD3A-dependent manner. ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, proteolysis of isolated mitochondria, knockdown experiments with invasion and tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, domain mapping by proteolysis, functional knockdown with multiple cellular and in vivo readouts\",\n      \"pmids\": [\"25823022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The dominant-negative ATAD3A p.Arg528Trp variant causes small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. Tissue-specific overexpression of the homologous Drosophila borR534W mutation dramatically decreased mitochondrial content, caused aberrant mitochondrial morphology, and increased autophagy. Homozygous null larvae showed decreased mitochondria; wild-type overexpression produced larger, elongated mitochondria. Patient fibroblasts exhibited increased mitophagy.\",\n      \"method\": \"Drosophila tissue-specific overexpression of dominant-negative mutant, patient fibroblast mitophagy assay, whole-exome sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dominant-negative mechanism established in Drosophila model and patient fibroblasts, replicated across multiple individuals\",\n      \"pmids\": [\"27640307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATAD3A interacts with the mitochondrial channel components Tom40 and Tim23 and serves as a bridging factor to facilitate appropriate transportation and processing of the PINK1 mitophagy kinase. Loss of Atad3a causes PINK1 accumulation and hyperactivated mitophagy. Genetic deletion of Pink1 in Atad3a-deficient mice rescued hematopoietic progenitor and HSC pool defects, establishing epistasis: ATAD3A acts upstream of PINK1 to suppress mitophagy.\",\n      \"method\": \"Conditional knockout mice, co-immunoprecipitation with Tom40/Tim23/PINK1, genetic epistasis (double knockout rescue), flow cytometry of hematopoietic compartments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with channel components, clean conditional KO with defined cellular phenotype, genetic epistasis rescue in vivo\",\n      \"pmids\": [\"29242539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A dominant-negative ATAD3A p.G355D mutation in the Walker A motif (responsible for ATP binding) markedly reduces ATPase activity of the recombinant protein. Overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass, and patient fibroblasts and iPSC-derived neurons show altered mitochondrial dynamics and increased lysosomes associated with upregulated autophagy via mTOR inactivation.\",\n      \"method\": \"In vitro ATPase activity assay of recombinant mutant protein, overexpression in cell lines, patient fibroblast and iPSC-neuron analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay demonstrating reduced ATPase activity, corroborated by cellular phenotypes in multiple human cell models\",\n      \"pmids\": [\"28158749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATAD3A dimerization (driven by deacetylation at K135) is required for Drp1-mediated mitochondrial fragmentation in Huntington's disease. ATAD3A interacts with the mitochondrial fission GTPase Drp1. Drp1/ATAD3A interaction promotes ATAD3A oligomerization, which impairs TFAM/mtDNA binding and leads to bioenergetic deficits. A blocking peptide (DA1) abolishing Drp1/ATAD3A interaction suppresses oligomerization, reduces mtDNA lesion, and reduces HD neuropathology in transgenic mice.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, acetylation site mutagenesis (K135), peptide-blocking experiments in HD mouse and patient-derived cells, behavioral/neuropathological readouts in transgenic mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of modification site, blocking peptide validation, in vivo rescue in HD mice, multiple orthogonal methods\",\n      \"pmids\": [\"30914652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon mitochondrial depolarization, AMBRA1 is recruited to the outer mitochondrial membrane and interacts with both PINK1 and ATAD3A. AMBRA1 promotes PINK1 stability by counteracting ATAD3A-mediated PINK1 degradation by the mitochondrial protease LONP1. Silencing ATAD3A rescues defective PINK1 accumulation in AMBRA1-deficient cells, placing ATAD3A downstream of AMBRA1 in the PINK1-PARKIN mitophagy pathway.\",\n      \"method\": \"Co-immunoprecipitation, AMBRA1 knockdown, ATAD3A silencing rescue experiments, PINK1 ubiquitin phosphorylation assay, PRKN/PARKIN recruitment assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, epistasis rescue experiment, multiple functional readouts, single lab\",\n      \"pmids\": [\"34798798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of ATAD3A in THP-1 cells results in increased type I interferon signaling mediated by cGAS and STING. This enhanced interferon signaling is abrogated when cells are depleted of mitochondrial DNA, establishing that ATAD3A normally prevents mtDNA-driven cGAS-STING activation.\",\n      \"method\": \"ATAD3A knockdown in THP-1 cells, mtDNA depletion rescue, ISG expression measurement, patient fibroblast validation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with mechanistic rescue (mtDNA depletion), validated in patient fibroblasts and multiple patient samples\",\n      \"pmids\": [\"34387651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATAD3A associates with multiple components of the inner mitochondrial membrane including OXPHOS complex I, Letm1, and prohibitin complexes. Neuronal-specific Atad3 knockout mice develop severe encephalopathy with aberrant mitochondrial cristae morphogenesis preceding symptoms. STORM microscopy shows ATAD3A is regularly distributed along the inner mitochondrial membrane, supporting a structural scaffolding role in inner membrane organization.\",\n      \"method\": \"Conditional neuronal KO mouse, multi-omics, co-immunoprecipitation with inner membrane components, STORM super-resolution microscopy\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined ultrastructural phenotype, reciprocal Co-IP with multiple partners, super-resolution imaging, multi-omics\",\n      \"pmids\": [\"34936866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A oligomerization accumulates at mitochondria-associated ER membranes (MAMs) in Alzheimer's disease models and inhibits CYP46A1 gene expression, leading to cholesterol accumulation. Suppressing ATAD3A oligomerization (by heterozygous KO or peptide DA1) restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and reduces AD neuropathology and cognitive deficits in 5XFAD mice.\",\n      \"method\": \"5XFAD mouse model, heterozygous ATAD3A KO, DA1 peptide treatment, CYP46A1 expression analysis, cholesterol turnover assay, APP processing assay, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological intervention in vivo, multiple biochemical and behavioral readouts, multiple model systems\",\n      \"pmids\": [\"35236834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A mediates nucleoid trafficking inside mitochondria: its ATPase domain directly binds TFAM and mediates nucleoid movement along mitochondria via ATP hydrolysis. ATAD3A oligomerization via coiled-coil domains in the intermembrane space is also required for nucleoid trafficking. ATAD3A deficiency leads to dispersed small nucleoids and enhanced respiratory complex formation.\",\n      \"method\": \"Live imaging of nucleoid dynamics, in vitro binding assay of ATPase domain with TFAM, ATAD3A knockout/mutant analysis, respiratory complex assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay, live imaging, ATPase-domain mutant analysis, functional respiratory complex readout, single lab with multiple methods\",\n      \"pmids\": [\"36383603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MUC1 translocates to mitochondria and interacts with ATAD3A, inducing its degradation, which protects PINK1 from ATAD3A-mediated cleavage and thereby promotes PINK1-dependent mitophagy. This establishes a MUC1/ATAD3A/PINK1 axis in cancer cell mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression of MUC1 and ATAD3A, mitophagy flux assay, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, functional knockdown with mitophagy readout, in vivo validation, single lab\",\n      \"pmids\": [\"36289190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A binds to ERK1/2 in mitochondria in the presence of VDAC1, and this interaction is essential for activation of mitochondrial ERK1/2 signaling in a RAS-independent manner. Walker A dead mutant (K358) of ATAD3A produces a dominant-negative effect on HNSCC growth.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR/Cas9 knockout, Walker A mutant overexpression, phospho-kinase profiling, orthotopic tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ERK1/2 and VDAC1, dominant-negative mutagenesis, in vivo rescue, single lab\",\n      \"pmids\": [\"35093151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PINK1 recruits PD-L1 to mitochondria for degradation via mitophagy. ATAD3A suppresses PINK1-dependent mitophagy, preventing mitochondrial redistribution of PD-L1 and thereby maintaining PD-L1 on the tumor cell membrane. Paclitaxel increases ATAD3A expression to restrain PINK1-dependent mitophagy and PD-L1 degradation.\",\n      \"method\": \"Subcellular fractionation, knockdown/overexpression of ATAD3A and PINK1, mitophagy flux assay, PD-L1 localization analysis, patient tumor sample correlation\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with subcellular localization readout and defined pathway placement, single lab\",\n      \"pmids\": [\"36627348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sigma-1 receptor (σ1R) retains ATAD3A as a monomer at the MAM, inhibiting mitochondrial fragmentation. Loss of σ1R or SOD1-linked ALS conditions cause ATAD3A dimerization and mitochondrial fragmentation. σ1R-mediated MAM formation depends on ATAD3A.\",\n      \"method\": \"σ1R-deficient cells and SOD1-ALS mouse spinal cords, co-immunoprecipitation, native PAGE for ATAD3A oligomeric state, mitochondrial morphology analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, native PAGE oligomeric state, in vivo ALS mouse model, single lab\",\n      \"pmids\": [\"36736924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATAD3C incorporates into the ATAD3A complex in the mitochondrial inner membrane as a monomer, reducing complex size and negatively regulating ATAD3A function. ATAD3C overexpression decreases cell proliferation and oxygen consumption and increases ROS, and increases dimeric CIII at the expense of respiratory supercomplexes.\",\n      \"method\": \"ATAD3C overexpression in fibroblasts, native PAGE of ATAD3A complexes, oxygen consumption rate, ROS measurement, respiratory complex analysis\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — native PAGE complex analysis, functional readouts (OCR, ROS, respiratory complexes), single lab with multiple methods\",\n      \"pmids\": [\"38092275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATAD3A interacts with PERK at mitochondria-ER contact sites. During ER stress, PERK-ATAD3A interactions increase, and ATAD3A competes with eIF2α for PERK binding, attenuating local PERK signaling and protecting mitochondria-localized translation from ER stress-induced repression. This protects expression of some mitochondrial proteins.\",\n      \"method\": \"Live-cell imaging of reporter mRNA translation, co-immunoprecipitation, ATAD3A knockdown, proximity ligation assay for MAM contact sites\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — live-cell translation imaging, Co-IP demonstrating competition with eIF2α, KD with functional translational readout, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"39116259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT3 deacetylates ATAD3A; acetylation at K134 disrupts ATAD3A self-oligomerization. The ATAD3A monomer (de-oligomerized form) closely interacts with the IP3R1-GRP75-VDAC1 complex at MAMs, leading to mitochondrial calcium overload and dysfunction. SIRT3 knockout mice show excessive MAM formation.\",\n      \"method\": \"Co-immunoprecipitation with IP3R1-GRP75-VDAC1, acetylation site mutagenesis (K134), SIRT3 KO mouse model, mitochondrial calcium measurement, cardiac hypertrophy model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetylation site mutagenesis, Co-IP with MAM complex, in vivo KO mouse model, single lab\",\n      \"pmids\": [\"38250153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBK1 is activated and localizes to mitochondria during cellular senescence, where it directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A suppresses PINK1-mediated mitophagy by facilitating PINK1 mitochondrial import. Blocking ATAD3A phosphorylation at Ser321 (by TBK1 deficiency or S321A mutation) rescues cellular senescence.\",\n      \"method\": \"In vitro kinase assay (TBK1 phosphorylating ATAD3A), phospho-site mutagenesis (S321A), TBK1 KO, blocking peptide (TAT-PEP), PINK1 import assay, senescence markers\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, mutagenesis of phospho-site with functional rescue, peptide validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39520088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM25 E3 ubiquitin ligase interacts with and ubiquitinates ATAD3A via the proteasome pathway, destabilizing ATAD3A and promoting PINK1/Parkin-dependent mitophagy during cerebral ischemia-reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ATAD3A knockdown/overexpression, TRIM25 manipulation, in vivo MCAO model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrating direct ubiquitination, functional in vivo model, single lab\",\n      \"pmids\": [\"39307194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ME2 (malic enzyme 2) competes with TRIM25 for binding to ATAD3A, disrupting TRIM25-ATAD3A interaction and thereby preventing ATAD3A ubiquitination and degradation. Loss of ME2 strengthens TRIM25-ATAD3A interaction, leading to ATAD3A ubiquitination, proteasomal degradation, PINK1 accumulation, and mitophagy activation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, ubiquitination assay, ME2 knockdown with PINK1/mitophagy readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competition assay, ubiquitination readout, functional mitophagy phenotype, single lab\",\n      \"pmids\": [\"41876455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXL6 E3 ubiquitin ligase directly targets ATAD3A and induces K63-linked polyubiquitination, which stabilizes ATAD3A (rather than degrading it) and activates aerobic glycolysis to promote TNBC malignancy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, ATAD3A knockdown, tumor growth assays in vitro and in vivo\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, functional tumor model, single lab\",\n      \"pmids\": [\"40975350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATAD3A directly interacts with complex I subunit NDUFS8 and is required for complex I assembly and activity. Knockdown of atad-3 reduces complex I activity and proton leakage, increases mitochondrial membrane potential, and thereby induces reverse electron transport (RET)-driven ROS production.\",\n      \"method\": \"Co-immunoprecipitation with NDUFS8, complex I activity assay, mitochondrial membrane potential measurement, ROS measurement in C. elegans and mammalian cells\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP with complex I subunit, enzymatic activity assay, functional RET-ROS measurement, single lab\",\n      \"pmids\": [\"40961994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATAD3A is an essential component of the mitochondrial permeability transition pore (mPTP). Genetic deletion of Atad3 in cardiomyocytes and hepatocytes abolishes Ca2+-induced mPTP-dependent swelling, and patch-clamp recordings of recombinant ATAD3A reconstituted in liposomes reveal intrinsic channel activity. Cardiac-specific Atad3 deletion markedly reduces infarct size following ischemia/reperfusion.\",\n      \"method\": \"Cardiomyocyte/hepatocyte-specific KO, Ca2+-induced mitochondrial swelling assay, patch-clamp of ATAD3A reconstituted in liposomes, I/R infarct size measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in liposomes with patch-clamp channel recording, genetic KO with mPTP functional assay, in vivo cardiac I/R model; novel finding not covered by peer-reviewed work\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.658955\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Thymoquinone (TQ) directly binds ATAD3A at its C-terminal L368 residue (validated by SPR and CETSA), stabilizes ATAD3A protein, and enhances ATAD3A-PERK interaction at MAMs. This preserves MAM integrity, attenuates PERK/eIF2α-mediated ER stress, and restores mitochondrial bioenergetics in myocardial ischemia-reperfusion models. ATAD3A-L368 mutant or PERK inhibition abolishes TQ's protective effects.\",\n      \"method\": \"Surface plasmon resonance (SPR), CETSA, co-immunoprecipitation-mass spectrometry, proximity ligation assay, MAM-SplitGFP system, ATAD3A-L368 mutant rescue experiment, in vivo MI/R mouse model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding validated by SPR and CETSA, interaction mapped by IP-MS, functional site confirmed by mutant rescue, in vivo model\",\n      \"pmids\": [\"40460607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATAD3A overexpression reduces mitochondria-lysosome contacts, limits mitochondrial Ca2+ influx, and suppresses the FDXR/FDX1/LIAS lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis in vascular smooth muscle cells, thereby protecting against aortic aneurysm and dissection. ATAD3A interacts with DLST as identified by co-immunoprecipitation.\",\n      \"method\": \"VSMC-specific knockdown and systemic overexpression knock-in mice, co-immunoprecipitation of ATAD3A-DLST, mitochondria-lysosome contact quantification, Ca2+ imaging, lipoylation assay, in vivo AAD models\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, genetic KO and OE in vivo models with defined pathway (lipoylation/cuproptosis), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"42237912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PARK7 directly interacts with mitochondrial ATAD3A and downregulates its lactylation level, thereby suppressing expression of mitochondrial-related genes and promoting CD8+ T-cell exhaustion. T-cell-specific PARK7 deficiency enhances mitochondrial function in CD8+ T cells and alleviates exhaustion.\",\n      \"method\": \"Co-immunoprecipitation, lactylation modification assay, T-cell specific PARK7 KO, mitochondrial function assays, tumor growth assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct interaction, post-translational modification (delactylation) with functional gene expression readout, genetic KO with defined phenotype, single lab\",\n      \"pmids\": [\"42162305\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both membranes (N-terminus facing cytoplasm/IMS, C-terminal ATPase domain in matrix), functions as an essential structural scaffold for inner membrane cristae organization, directly binds TFAM to drive nucleoid trafficking via ATP hydrolysis, interacts with Tom40/Tim23 to mediate PINK1 import and proteolytic processing (thereby suppressing PINK1-dependent mitophagy), forms complexes with PERK at mitochondria-ER contact sites to locally attenuate ER-stress-induced translational repression, interacts with Drp1 via oligomerization-dependent mechanisms to couple mitochondrial fission with mtDNA maintenance and bioenergetics, and constitutes an essential pore-forming component of the mitochondrial permeability transition pore; its activity and oligomeric state are regulated by post-translational modifications including deacetylation (SIRT3 at K134/K135), phosphorylation (TBK1 at S321), K63-linked ubiquitination (FBXL6), and proteasomal ubiquitination (TRIM25), collectively controlling mitophagy flux, cholesterol metabolism, cGAS-STING-mediated interferon signaling, and cell survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATAD3A is a mitochondrial AAA+ ATPase that spans both mitochondrial membranes—its N-terminus accessible from the cytoplasm/intermembrane space, a central transmembrane segment in the inner membrane, and the C-terminal ATPase domain in the matrix—where it serves as a structural scaffold coordinating membrane architecture, nucleoid organization, and mitochondria-ER crosstalk [#0, #1, #11]. Distributed regularly along the inner membrane, it associates with OXPHOS complex I (directly binding NDUFS8), Letm1, and prohibitin complexes and is required for cristae morphogenesis and complex I assembly, such that its loss perturbs respiratory function and drives reverse-electron-transport ROS [#11, #25]. Through its ATPase domain, ATAD3A directly binds TFAM and powers trafficking of mtDNA nucleoids via ATP hydrolysis, a function further requiring intermembrane-space coiled-coil-mediated oligomerization [#13]. A central regulatory theme is its control of PINK1-dependent mitophagy: ATAD3A bridges the Tom40/Tim23 import channels to facilitate PINK1 import and processing, thereby suppressing mitophagy, and it acts upstream of PINK1 in vivo, with PINK1 deletion rescuing ATAD3A-deficient hematopoietic defects [#6]. This mitophagy-suppressive activity is tuned by post-translational modifications and competing partners—TBK1 phosphorylation at Ser321 promotes PINK1 import [#21], AMBRA1, TRIM25-mediated proteasomal ubiquitination, and MUC1 destabilize ATAD3A to release PINK1 [#9, #22, #14]. The protein's oligomeric state is itself a master regulatory switch: deacetylation at K135/K134 by SIRT3 governs dimerization, and Drp1-driven oligomerization couples mitochondrial fission to impaired TFAM/mtDNA binding and bioenergetic deficits in Huntington's disease, while at mitochondria-ER contact sites oligomerization controls CYP46A1-dependent cholesterol turnover in Alzheimer's models and competition with eIF2α attenuates PERK-mediated translational repression [#8, #12, #19, #20]. ATAD3A also restrains mtDNA-driven cGAS-STING type I interferon signaling [#10] and functions as an essential pore-forming component of the mitochondrial permeability transition pore [#26]. Dominant-negative ATAD3A mutations affecting ATP binding (p.G355D, p.R528W) cause human mitochondrial disease characterized by aberrant mitochondrial dynamics and hyperactivated mitophagy [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing ATAD3A's dual-membrane topology answered where this AAA+ ATPase sits and how it could physically bridge the two mitochondrial membranes to sense and regulate membrane contacts.\",\n      \"evidence\": \"Topology/fractionation and back-titration ELISA/immunofluorescence on purified human mitochondria, plus dominant-negative mutants in Drosophila and steroidogenic cells\",\n      \"pmids\": [\"20154147\", \"20349121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how a single protein anchors both membranes not resolved\", \"Mechanism coupling topology to fission machinery sensing undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying S100B as a calcium-dependent ATAD3A chaperone addressed how ATAD3A achieves proper folding and mitochondrial targeting.\",\n      \"evidence\": \"NMR mapping of the S100B binding motif and rescue of an import-deficient ATAD3A mutant in oligodendrocyte progenitors\",\n      \"pmids\": [\"20351179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of S100B chaperoning beyond OPCs unclear\", \"Whether S100B affects endogenous ATAD3A import not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that the paralog ATAD3B antagonizes ATAD3A-nucleoid interactions introduced paralog-based regulation of ATAD3A function.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function in human ES and cancer cells with nucleoid and morphology readouts\",\n      \"pmids\": [\"22664726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of ATAD3A/ATAD3B complexes unknown\", \"Single lab; biochemical basis of dominant-negative effect not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing ATAD3A in a trimeric complex with WASF3 and GRP78 linked it to tumor cell stability of a metastasis driver and E-cadherin suppression.\",\n      \"evidence\": \"MS, Co-IP, mitochondrial proteolysis domain mapping, knockdown with invasion and tumor growth assays\",\n      \"pmids\": [\"25823022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATAD3A's ATPase activity is required for WASF3 stabilization not shown\", \"Mechanism connecting mitochondrial WASF3 to E-cadherin regulation incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dominant-negative ATAD3A disease variants established that perturbing ATAD3A triggers excess mitophagy and reduced mitochondrial content, defining a human disease mechanism.\",\n      \"evidence\": \"Whole-exome sequencing, Drosophila tissue-specific dominant-negative overexpression, patient fibroblast mitophagy assays\",\n      \"pmids\": [\"27640307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger linking small mitochondria to mitophagy not yet defined\", \"Tissue selectivity of phenotype unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies defined the upstream control of PINK1 by ATAD3A and demonstrated that ATP-binding-dead mutants are dominant-negative, mechanistically connecting ATPase activity to mitophagy suppression.\",\n      \"evidence\": \"Conditional KO mice with reciprocal Co-IP of Tom40/Tim23/PINK1 and PINK1 deletion epistasis rescue; in vitro ATPase assay of recombinant G355D mutant with patient fibroblast/iPSC-neuron phenotypes\",\n      \"pmids\": [\"29242539\", \"28158749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATAD3A physically presents PINK1 to the import channel not structurally resolved\", \"Link between ATPase activity and bridging function not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking deacetylation-driven dimerization and Drp1 interaction to fission established ATAD3A oligomeric state as a switch coupling fission, TFAM/mtDNA binding, and bioenergetics in disease.\",\n      \"evidence\": \"Proteomics, Co-IP, K135 acetylation-site mutagenesis, DA1 blocking peptide, in vivo rescue in HD transgenic mice\",\n      \"pmids\": [\"30914652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct deacetylase responsible not identified in this study\", \"Structural model of oligomer-TFAM competition lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies refined ATAD3A's mitophagy and immune roles—positioning it downstream of AMBRA1 in PINK1 stability and as a suppressor of mtDNA-driven cGAS-STING interferon signaling.\",\n      \"evidence\": \"Co-IP and epistasis rescue in AMBRA1-deficient cells; ATAD3A knockdown in THP-1 with mtDNA-depletion rescue and patient fibroblast validation\",\n      \"pmids\": [\"34798798\", \"34387651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATAD3A loss releases mtDNA to cGAS not mechanistically defined\", \"Interplay between AMBRA1/LONP1 and ATAD3A-PINK1 import unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating ATAD3A association with complex I, Letm1, and prohibitins plus its regular IMM distribution established it as a structural scaffold for cristae morphogenesis.\",\n      \"evidence\": \"Neuronal conditional KO mice, multi-omics, Co-IP with inner membrane components, STORM super-resolution imaging\",\n      \"pmids\": [\"34936866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural contribution to cristae versus indirect effects not separated\", \"Whether scaffolding requires ATPase activity untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A cluster of studies defined how ATAD3A oligomerization at MAMs and its ATPase-dependent TFAM binding govern nucleoid trafficking, cholesterol metabolism, and cancer mitophagy.\",\n      \"evidence\": \"In vitro ATPase-domain/TFAM binding and live nucleoid imaging; 5XFAD mice with CYP46A1/cholesterol readouts and DA1 peptide; MUC1/ATAD3A/PINK1 Co-IP and mitophagy flux\",\n      \"pmids\": [\"36383603\", \"35236834\", \"36289190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How oligomeric state at MAMs controls CYP46A1 transcription mechanistically unclear\", \"MUC1-ATAD3A axis validated in single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ATAD3A was shown to anchor RAS-independent mitochondrial ERK1/2 signaling, extending its scaffolding role to a growth-promoting kinase module.\",\n      \"evidence\": \"Co-IP with ERK1/2 and VDAC1, CRISPR KO, Walker A dead mutant (K358) dominant-negative, orthotopic HNSCC tumor model\",\n      \"pmids\": [\"35093151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ATAD3A activates mitochondrial ERK1/2 mechanistically unknown\", \"Single lab; generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Studies connected ATAD3A monomer/oligomer balance at MAMs to PD-L1 trafficking, σ1R-controlled fragmentation, and showed its oligomeric state is the regulatory node across contexts.\",\n      \"evidence\": \"Subcellular fractionation and mitophagy flux for PINK1/PD-L1; σ1R-deficient cells and SOD1-ALS mouse spinal cords with native PAGE oligomeric state\",\n      \"pmids\": [\"36627348\", \"36736924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"σ1R-ATAD3A regulation rests on single-lab Co-IP/native PAGE\", \"Direct structural determinant of monomer-to-dimer transition undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the ATAD3C paralog as a negative regulator that reduces complex size and shifts respiratory supercomplex assembly added a second paralog-based control of ATAD3A complexes.\",\n      \"evidence\": \"ATAD3C overexpression in fibroblasts, native PAGE complex analysis, OCR, ROS, and respiratory complex assays\",\n      \"pmids\": [\"38092275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous stoichiometry of ATAD3A/ATAD3C complexes unknown\", \"Single lab; physiological contexts of ATAD3C expression unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A set of studies established the post-translational and protein-protein code controlling ATAD3A's PERK competition, MAM calcium handling, mitophagy via phosphorylation, and proteasomal turnover.\",\n      \"evidence\": \"Live-cell translation imaging and Co-IP showing ATAD3A-eIF2α competition for PERK; SIRT3 deacetylation/K134 mutagenesis with IP3R1-GRP75-VDAC1 Co-IP; in vitro TBK1 kinase assay with S321A mutagenesis; TRIM25 ubiquitination assays\",\n      \"pmids\": [\"39116259\", \"38250153\", \"39520088\", \"39307194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct modifications are integrated on the same molecule unresolved\", \"Some axes (SIRT3, TRIM25) rest on single-lab Co-IP/ubiquitination assays\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies expanded the regulatory and functional network—competing E3/competitor inputs (FBXL6, ME2), direct complex I assembly via NDUFS8, and intrinsic mPTP channel activity.\",\n      \"evidence\": \"Linkage-specific K63 ubiquitination by FBXL6; ME2-TRIM25 competition assays; Co-IP with NDUFS8 and complex I activity/RET-ROS measurement; cardiomyocyte/hepatocyte KO with patch-clamp of liposome-reconstituted ATAD3A (preprint)\",\n      \"pmids\": [\"40975350\", \"41876455\", \"40961994\", \"bio_10.1101_2025.06.13.658955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing K63-stabilizing versus proteasomal ubiquitination integration unclear\", \"mPTP channel finding is a preprint awaiting peer review\", \"Direct pore architecture and gating mechanism undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of direct small-molecule binding at the C-terminal L368 residue showed ATAD3A is a druggable target whose stabilization enhances PERK interaction and protects against ischemia-reperfusion.\",\n      \"evidence\": \"SPR, CETSA, IP-MS, PLA, MAM-SplitGFP, L368 mutant rescue, in vivo MI/R model with thymoquinone\",\n      \"pmids\": [\"40460607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the ligand-binding pocket not solved\", \"Selectivity of thymoquinone for ATAD3A not fully characterized\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"New interactions placed ATAD3A within cuproptosis/lipoylation control via DLST and within CD8+ T-cell exhaustion via PARK7-regulated lactylation, broadening its roles into metabolic cell death and immune metabolism.\",\n      \"evidence\": \"VSMC-specific KD and overexpression knock-in mice with ATAD3A-DLST Co-IP and lipoylation assays; PARK7 Co-IP, lactylation assay, and T-cell-specific PARK7 KO\",\n      \"pmids\": [\"42237912\", \"42162305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ATAD3A interaction modulates DLST lipoylation mechanistically unclear\", \"PARK7-driven delactylation of ATAD3A rests on single-lab Co-IP/PTM assays\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, sometimes opposing, post-translational modifications and competing partners are integrated to set ATAD3A's oligomeric state and select among its many functions in a context-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the monomer-to-oligomer transition\", \"Hierarchy among acetylation, phosphorylation, and ubiquitination inputs unknown\", \"Whether a single ATAD3A pool serves all functions or distinct subpopulations exist is unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 7, 13]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11, 13]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12, 19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 9, 14, 21]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [11, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [26, 28]}\n    ],\n    \"complexes\": [\n      \"ATAD3A/ATAD3B/ATAD3C inner membrane complex\",\n      \"mitochondrial permeability transition pore\",\n      \"ATAD3A-WASF3-GRP78 complex\"\n    ],\n    \"partners\": [\n      \"TFAM\",\n      \"PINK1\",\n      \"Drp1\",\n      \"PERK\",\n      \"NDUFS8\",\n      \"TOMM40\",\n      \"TIMM23\",\n      \"TRIM25\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}