{"gene":"ATAD3A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2010,"finding":"ATAD3A spans both mitochondrial membranes: its N-terminal domain interacts with the outer membrane, a central transmembrane segment anchors it in the inner membrane, and the C-terminal AAA+ ATPase domain is positioned in the matrix. Using dominant-negative mutants (defective ATP-binding and truncated N-terminus), ATAD3A was shown to regulate dynamic interactions between the outer and inner mitochondrial membranes, and is required for normal cell growth and cholesterol channeling at contact sites.","method":"Dominant-negative mutagenesis, Drosophila invalidation, human steroidogenic cell knockdown, subcellular fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mutagenesis, genetic knockdown in two model systems, fractionation), replicated across organisms","pmids":["20154147"],"is_preprint":false},{"year":2010,"finding":"ATAD3A topology was directly determined: the N-terminal region (aa 40-53) is accessible from outside the inner membrane (cytoplasm or intermembrane space) and the C-terminal region (aa 572-586) is located within the matrix, confirmed by back-titration ELISA and immunofluorescence using domain-specific antibodies on purified human mitochondria.","method":"Anti-peptide antibody back-titration ELISA, immunofluorescence on purified human mitochondria","journal":"Journal of bioenergetics and biomembranes","confidence":"High","confidence_rationale":"Tier 1 — direct topology determination with two orthogonal immunological methods on purified organelles","pmids":["20349121"],"is_preprint":false},{"year":2010,"finding":"ATAD3A is a major, high-affinity, calcium-dependent binding target of S100B in oligodendrocyte progenitor cells. NMR spectroscopy defined a consensus calcium-dependent S100B binding motif on ATAD3A. S100B prevents cytoplasmic ATAD3A aggregation and restores its mitochondrial localization, suggesting S100B assists newly synthesized ATAD3A in proper folding and subcellular targeting.","method":"Co-immunoprecipitation, NMR spectroscopy, cellular truncation mutant studies, Far-Western assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structural mapping plus functional cellular validation with orthogonal binding assays","pmids":["20351179"],"is_preprint":false},{"year":2012,"finding":"ATAD3B, a paralog of ATAD3A, associates with ATAD3A and acts as a dominant negative regulator: it negatively regulates ATAD3A interaction with matrix nucleoid complexes and promotes mitochondrial fragmentation.","method":"Loss- and gain-of-function, co-immunoprecipitation, mitochondrial morphology analysis","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal functional interaction shown with both loss- and gain-of-function, single study","pmids":["22664726"],"is_preprint":false},{"year":2015,"finding":"ATAD3A interacts with the metastasis-promoting protein WASF3 at the mitochondrial membrane (N-terminal WASF3 interacts with N-terminal ATAD3A), and also forms a complex with GRP78. ATAD3A-mediated stabilization of WASF3 occurs through this interaction with GRP78, bridging ER and mitochondria. Knockdown of ATAD3A reduces WASF3 protein levels and suppresses invasion and metastasis.","method":"Mass spectrometry, co-immunoprecipitation, proteolysis of isolated mitochondria, siRNA knockdown, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction confirmed by Co-IP, domain mapping by proteolysis, functional validation in vitro and in vivo","pmids":["25823022"],"is_preprint":false},{"year":2016,"finding":"A recurrent de novo ATAD3A p.Arg528Trp variant acts through a dominant-negative mechanism, causing small mitochondria that trigger mitophagy and reduction in mitochondrial content. Tissue-specific overexpression of the homologous Drosophila mutation decreases mitochondrial content and causes aberrant morphology; patient fibroblasts show increased mitophagy.","method":"Drosophila tissue-specific overexpression, patient fibroblast mitophagy assay, whole-exome sequencing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — dominant-negative mechanism established across multiple patients and model organism, with orthogonal cellular assays","pmids":["27640307"],"is_preprint":false},{"year":2017,"finding":"ATAD3A interacts with mitochondrial channel components TOM40 and TIM23 and serves as a bridging factor to facilitate appropriate transport and processing of PINK1. Loss of ATAD3A causes PINK1 accumulation and hyperactivation of PINK1-dependent mitophagy, which can be rescued by deletion of Pink1.","method":"Co-immunoprecipitation, conditional knockout mouse, genetic epistasis (Atad3a/Pink1 double KO), flow cytometry, bone marrow analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of TOM40/TIM23, confirmed by genetic rescue with Pink1 deletion, clean KO with defined cellular phenotype","pmids":["29242539"],"is_preprint":false},{"year":2017,"finding":"A dominant-negative ATAD3A mutation (p.G355D) affecting the Walker A motif (responsible for ATP binding) causes markedly reduced ATPase activity in the recombinant mutant protein and fragments the mitochondrial network, induces lysosome mass, and upregulates basal autophagy through mTOR inactivation in patient fibroblasts and iPSC-derived neurons.","method":"In vitro ATPase activity assay on recombinant mutant protein, patient fibroblast and iPSC-derived neuron analysis, mitochondrial morphology imaging, mTOR pathway western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro ATPase assay demonstrating catalytic defect, with functional cellular validation in patient-derived cells","pmids":["28158749"],"is_preprint":false},{"year":2019,"finding":"In Huntington's disease, ATAD3A dimerization (driven by deacetylation at K135) is required for Drp1-mediated mitochondrial fragmentation. ATAD3A interacts with Drp1 in HD cells. ATAD3A oligomerization disrupts TFAM/mtDNA binding, impairing mtDNA maintenance. A blocking peptide (DA1) targeting the Drp1/ATAD3A interaction abolishes ATAD3A oligomerization, restores mtDNA maintenance, and reduces HD neurodegeneration in transgenic mice.","method":"Proteomic analysis, co-immunoprecipitation (Drp1/ATAD3A), mutagenesis (K135), TFAM/mtDNA ChIP, peptide inhibition (DA1), HD transgenic mouse behavioral/neuropathological analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods: Co-IP, site-specific mutagenesis, mtDNA assays, in vivo rescue with peptide inhibitor","pmids":["30914652"],"is_preprint":false},{"year":2021,"finding":"Knockdown of ATAD3A in THP-1 cells increases interferon signaling mediated by cGAS and STING. This enhanced interferon signaling is abrogated when cells are depleted of mitochondrial DNA, establishing that ATAD3A mutations lead to mtDNA-driven cGAS-STING activation and a type I interferonopathy.","method":"siRNA knockdown in THP-1 cells, mtDNA depletion, ISG expression measurement, interferon-alpha ELISA","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — epistasis via mtDNA depletion rescuing the phenotype, validated in patient fibroblasts and THP-1 cells","pmids":["34387651"],"is_preprint":false},{"year":2021,"finding":"AMBRA1, upon mitochondrial depolarization, is recruited to the outer mitochondrial membrane and interacts with both PINK1 and ATAD3A. AMBRA1 promotes PINK1 stability by preventing its enhanced degradation by the mitochondrial protease LONP1; ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells.","method":"Co-immunoprecipitation (AMBRA1/PINK1/ATAD3A), siRNA knockdown, LONP1 protease assay, ubiquitin phosphorylation assay, PARKIN recruitment assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of trimeric complex, genetic epistasis with ATAD3A silencing, protease identification, replicated in multiple cell types","pmids":["34798798"],"is_preprint":false},{"year":2021,"finding":"ATAD3A associates with different inner mitochondrial membrane components including OXPHOS complex I, Letm1, and prohibitin complexes. STORM microscopy shows ATAD3A is regularly distributed along the inner mitochondrial membrane. Neuronal conditional knockout mice develop severe encephalopathy with aberrant mitochondrial cristae morphogenesis, supporting a primary scaffolding role for ATAD3A in inner mitochondrial membrane organization.","method":"Multi-omics (proteomics), co-immunoprecipitation, STORM super-resolution microscopy, neuronal conditional knockout mouse","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, super-resolution microscopy, and conditional KO mouse with defined structural phenotype; multi-omics corroboration","pmids":["34936866"],"is_preprint":false},{"year":2022,"finding":"ATAD3A oligomerization in Alzheimer's disease models accumulates at mitochondria-associated ER membranes (MAMs) and inhibits gene expression of CYP46A1, an enzyme governing brain cholesterol clearance, leading to cholesterol accumulation. Suppression of ATAD3A oligomerization by heterozygous KO or DA1 peptide restores CYP46A1 levels, normalizes cholesterol turnover and MAM integrity, and reduces AD neuropathology.","method":"5XFAD mouse model, heterozygous ATAD3A KO, peptide inhibition (DA1), CYP46A1 gene expression analysis, cholesterol assay, MAM fractionation, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple models (transgenic AD mice, patient tissue, neuronal cultures), orthogonal genetic and pharmacological interventions","pmids":["35236834"],"is_preprint":false},{"year":2022,"finding":"ATAD3A's ATPase domain binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also requires ATAD3A oligomerization via coiled-coil domain interactions in the intermembrane space. In ATAD3A deficiency, nucleoid trafficking is impaired, leading to dispersed small nucleoids and enhanced respiratory complex formation.","method":"Live imaging of nucleoid dynamics, ATPase domain-TFAM direct binding assay, coiled-coil domain mutagenesis, ATAD3A-deficient cells, respiratory complex analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay between ATAD3A ATPase domain and TFAM, live imaging, and mutagenesis","pmids":["36383603"],"is_preprint":false},{"year":2022,"finding":"ATAD3A interacts with ERK1/2 in the mitochondria in the presence of VDAC1, and this interaction is essential for activation of mitochondrial ERK1/2 signaling in a RAS-independent manner. A Walker A dead mutant (K358) of ATAD3A acts as a dominant negative, demonstrating that ATPase activity is required for this signaling function.","method":"Co-immunoprecipitation (ATAD3A/ERK1/2/VDAC1), CRISPR/Cas9 knockout, dominant-negative mutagenesis, phospho-kinase profiling, orthotopic xenograft mouse","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying trimeric complex, mutagenesis confirming ATPase dependency, single lab study","pmids":["35093151"],"is_preprint":false},{"year":2022,"finding":"MUC1 translocates to mitochondria and interacts with ATAD3A, inducing its degradation. This relieves ATAD3A-mediated cleavage of PINK1, leading to PINK1 accumulation and increased mitophagy to promote cancer cell malignancy.","method":"Co-immunoprecipitation (MUC1/ATAD3A), western blot for PINK1 levels, mitophagy assay, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, functional rescue experiments, in vivo validation, single lab","pmids":["36289190"],"is_preprint":false},{"year":2023,"finding":"PINK1 is recruited to mitochondria for degradation via mitophagy upon ATAD3A-mediated regulation. The ATAD3A-PINK1 axis controls PD-L1 subcellular distribution: PINK1 recruits PD-L1 to mitochondria for degradation, while ATAD3A restrains this process. Paclitaxel increases ATAD3A expression to disrupt PD-L1 proteostasis by restraining PINK1-dependent mitophagy.","method":"Co-immunoprecipitation, subcellular fractionation, mitophagy assays, patient tumor sample analysis, preclinical mouse models","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic axis established with Co-IP and functional assays, corroborated in patient samples, single lab","pmids":["36627348"],"is_preprint":false},{"year":2023,"finding":"Sigma-1 receptor (σ1R) at the MAM interacts with ATAD3A and retains it as a monomer, thereby inhibiting ATAD3A dimerization and mitochondrial fragmentation. In σ1R-deficient or SOD1-ALS mouse spinal cords, ATAD3A dimerization and mitochondrial fragmentation are induced.","method":"Co-immunoprecipitation (σ1R/ATAD3A), σ1R-KO mouse, SOD1-ALS mouse, mitochondrial morphology analysis, Blue Native PAGE for ATAD3A oligomeric state","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, multiple genetic mouse models, oligomeric state analysis; single lab","pmids":["36736924"],"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 eIF2 for PERK binding, attenuating local PERK signaling and protecting active translation at mitochondria from global translational repression. ATAD3A binding to PERK thus mediates subcellular control of translational repression.","method":"Live-cell imaging of reporter mRNA translation, co-immunoprecipitation (PERK/ATAD3A/eIF2), proximity ligation assay for contact sites, ATAD3A knockdown","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — live-cell reporter imaging resolving subcellular translation rates, Co-IP, competitive binding assay with eIF2; published in Science with multiple orthogonal methods","pmids":["39116259"],"is_preprint":false},{"year":2024,"finding":"SIRT3 deacetylates ATAD3A; acetylation at K134 reduces ATAD3A self-oligomerization and promotes cardiac hypertrophy. Acetylated ATAD3A monomer interacts with the IP3R1-GRP75-VDAC1 complex at MAMs, leading to mitochondrial calcium overload. SIRT3 knockout mice show excessive MAM formation. ATAD3A oligomerization is thus regulated by SIRT3-dependent acetylation status.","method":"Co-immunoprecipitation, SIRT3 KO mouse, site-directed mutagenesis (K134), calcium imaging, MAM analysis, cardiac hypertrophy model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific mutagenesis, KO mouse, Co-IP, functional cardiac readout; single lab","pmids":["38250153"],"is_preprint":false},{"year":2024,"finding":"TBK1 is abnormally activated and localizes to mitochondria during senescence, where it directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A suppresses PINK1-mediated mitophagy by facilitating PINK1 mitochondrial import. A blocking peptide (TAT-PEP) abrogating this phosphorylation rescues cellular senescence and enhances tumor sensitivity to chemotherapy.","method":"In vitro kinase assay (TBK1 phosphorylating ATAD3A at S321), site-directed mutagenesis (S321A), blocking peptide, senescence assays, aging mouse models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphorylation assay identifying kinase-substrate relationship, mutagenesis confirmation, in vivo functional rescue","pmids":["39520088"],"is_preprint":false},{"year":2024,"finding":"TRIM25 E3 ubiquitin ligase interacts with and ubiquitinates ATAD3A via the proteasome pathway, reducing ATAD3A protein stability. Reduced ATAD3A allows PINK1 accumulation and activates PINK1/Parkin-dependent mitophagy. ME2 competes with TRIM25 for binding to ATAD3A, preventing ATAD3A ubiquitination and stabilizing it.","method":"Co-immunoprecipitation (TRIM25/ATAD3A), ubiquitination assay, proteasome inhibitor experiments, western blot, CI/RI rat model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay in cells, confirmed in vivo model; single lab","pmids":["39307194"],"is_preprint":false},{"year":2025,"finding":"FBXL6 E3 ubiquitin ligase directly targets ATAD3A and induces K63-linked polyubiquitination, stabilizing ATAD3A and activating aerobic glycolysis to promote tumor malignancy in TNBC.","method":"Co-immunoprecipitation, ubiquitination assay specifying K63-linkage, ATAD3A knockout/knockdown, in vivo xenograft","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — specific ubiquitin chain type identified, Co-IP, functional KO validation; single lab","pmids":["40975350"],"is_preprint":false},{"year":2025,"finding":"ATAD3A directly interacts with complex I subunit NDUFS8 and plays an integral role in complex I assembly and activity. Knockdown of ATAD3A reduces complex I activity and proton leakage, increases mitochondrial membrane potential, and induces reverse electron transport (RET) that increases mitochondrial ROS production.","method":"Co-immunoprecipitation (ATAD3A/NDUFS8), complex I activity assay, ROS measurement, mitochondrial membrane potential assay, C. elegans and mammalian cell knockdown","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding identified by Co-IP, functional complex I assays; single lab, two model systems","pmids":["40961994"],"is_preprint":false},{"year":2025,"finding":"ATAD3 is the first identified essential component of the mitochondrial permeability transition pore (mPTP). Cardiomyocyte- and hepatocyte-specific genetic deletion of Atad3 renders mitochondria incapable of Ca2+-induced mPTP-dependent swelling, yielding the highest Ca2+ retention capacity reported for any mPTP genetic perturbation. Recombinant ATAD3A reconstituted in liposomes displays intrinsic channel activity by patch-clamp. Cardiac Atad3 deletion markedly reduces infarct size following ischemia/reperfusion with no additive protection from cyclosporine A.","method":"Conditional cardiomyocyte/hepatocyte Atad3 KO, Ca2+-induced mitochondrial swelling assay, patch-clamp of ATAD3A in liposomes, I/R infarct size measurement","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of channel activity in liposomes with patch-clamp, plus tissue-specific KO with direct functional readout in two cell types","pmids":["bio_10.1101_2025.06.13.658955"],"is_preprint":true},{"year":2021,"finding":"ATAD3A stabilizes GRP78 to suppress ER stress-induced unfolded protein response, providing acquired chemoresistance. Knockdown of ATAD3A dysregulates protein processing, induces ER stress, reduces surface calreticulin exposure, and sensitizes colorectal cancer cells to chemotherapy-induced immunogenic cell death.","method":"Co-immunoprecipitation (ATAD3A/GRP78), RNA-seq, siRNA knockdown, calreticulin surface exposure assay, in vivo tumor model, T-cell infiltration analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, functional knockdown with ER stress readout, in vivo validation; single lab","pmids":["33580514"],"is_preprint":false}],"current_model":"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both membranes (N-terminus facing the cytoplasm/IMS, C-terminal ATPase domain in the matrix) and functions as a multifunctional scaffold: it regulates mitochondrial dynamics (fission/fusion) by controlling its own oligomerization state (modulated by acetylation at K134/K135 via SIRT3 and phosphorylation at S321 via TBK1, and by interaction with Drp1 and sigma-1 receptor), organizes mitochondrial nucleoids by directly binding TFAM to drive ATP-dependent nucleoid trafficking, suppresses PINK1-dependent mitophagy by facilitating PINK1 import and processing via its interaction with TOM40/TIM23 (itself regulated by TRIM25-mediated K48-ubiquitination and stabilized by FBXL6-mediated K63-ubiquitination), maintains mitochondria-ER contact sites (MAMs) where it interacts with PERK to protect localized translation and with the IP3R1-GRP75-VDAC1 complex to regulate calcium homeostasis, assembles with complex I subunit NDUFS8 to support respiratory chain function, and constitutes an essential, pore-forming component of the mitochondrial permeability transition pore (mPTP) as demonstrated by reconstituted channel activity in liposomes and genetic ablation abolishing Ca2+-induced mPTP opening."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing the dual-membrane topology and scaffolding function of ATAD3A resolved how a single AAA+ ATPase could coordinate outer and inner mitochondrial membrane dynamics and cholesterol channeling.","evidence":"Dominant-negative mutagenesis, Drosophila invalidation, subcellular fractionation, and back-titration ELISA/immunofluorescence on purified human mitochondria","pmids":["20154147","20349121"],"confidence":"High","gaps":["Mechanism by which ATAD3A mediates cholesterol transfer at contact sites is undefined","No structural model of the dual-membrane spanning architecture"]},{"year":2010,"claim":"Identification of S100B as a cytoplasmic chaperone for newly synthesized ATAD3A revealed a quality-control step that prevents ATAD3A aggregation prior to mitochondrial import.","evidence":"NMR mapping of S100B-binding motif on ATAD3A, Co-IP, and cellular localization assays in oligodendrocyte progenitors","pmids":["20351179"],"confidence":"High","gaps":["Whether S100B is the sole cytoplasmic chaperone for ATAD3A is untested","Relevance of this interaction outside oligodendrocyte lineage cells is unknown"]},{"year":2012,"claim":"Discovery that paralog ATAD3B hetero-oligomerizes with ATAD3A and acts as its dominant-negative regulator established that nucleoid interaction and mitochondrial morphology are tuned by the ATAD3A/ATAD3B ratio.","evidence":"Gain- and loss-of-function of ATAD3B, Co-IP with ATAD3A, morphology analysis","pmids":["22664726"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of ATAD3A–ATAD3B hetero-oligomers are undefined","Single-lab finding not independently replicated"]},{"year":2017,"claim":"Linking ATAD3A to the TOM40/TIM23 import machinery and showing that its loss triggers PINK1 accumulation and hyperactive mitophagy established ATAD3A as a gatekeeper of PINK1-dependent mitophagy.","evidence":"Co-IP of ATAD3A with TOM40/TIM23, conditional Atad3a KO mouse, genetic rescue by Pink1 deletion","pmids":["29242539"],"confidence":"High","gaps":["Whether ATAD3A directly chaperones PINK1 through the import channel or acts indirectly is unresolved","Relative contributions of ATAD3A versus other import factors to PINK1 processing are unclear"]},{"year":2017,"claim":"Demonstrating that a Walker A mutant (G355D) abolishes ATPase activity and fragments mitochondria provided the first direct evidence that catalytic cycling is required for ATAD3A's structural and signaling roles.","evidence":"In vitro ATPase assay on recombinant mutant, patient fibroblast and iPSC-neuron analysis","pmids":["28158749"],"confidence":"High","gaps":["No high-resolution structure of the ATPase domain to explain how the mutation disrupts cycling","Whether residual monomeric ATAD3A retains non-catalytic functions is untested"]},{"year":2019,"claim":"Revealing that ATAD3A dimerization is driven by deacetylation at K135, recruits Drp1, and disrupts TFAM/mtDNA binding unified the previously separate observations on mitochondrial dynamics and nucleoid maintenance under a single oligomerization-dependent mechanism.","evidence":"Co-IP of Drp1/ATAD3A, K135 mutagenesis, TFAM/mtDNA ChIP, DA1 peptide rescue in HD transgenic mice","pmids":["30914652"],"confidence":"High","gaps":["Structural basis for how oligomerization state switches TFAM binding versus Drp1 interaction is unknown","Whether DA1 peptide has off-target effects beyond blocking Drp1–ATAD3A interaction"]},{"year":2021,"claim":"Showing that ATAD3A deficiency triggers mtDNA-dependent cGAS-STING activation and type I interferon signaling established a direct link between ATAD3A's nucleoid-organizing role and innate immune surveillance.","evidence":"siRNA knockdown in THP-1, mtDNA depletion rescue, ISG expression and IFNα ELISA","pmids":["34387651"],"confidence":"High","gaps":["Route by which mtDNA escapes mitochondria upon ATAD3A loss (herniation vs. mPTP vs. BAX/BAK pores) is undefined","Whether interferon activation is direct or secondary to mitophagy defects is unresolved"]},{"year":2021,"claim":"Identification of ATAD3A as a scaffolding protein regularly distributed along the inner membrane and associated with complex I, Letm1, and prohibitin complexes—with neuronal KO causing cristae disorganization—established it as a general inner membrane organizer beyond its nucleoid and mitophagy roles.","evidence":"Proteomics, Co-IP, STORM super-resolution imaging, neuronal conditional KO mouse","pmids":["34936866"],"confidence":"High","gaps":["Whether ATAD3A directly shapes cristae or acts indirectly through MICOS/prohibitin interactions is unknown","Stoichiometry with inner membrane partners is not determined"]},{"year":2022,"claim":"Demonstrating that ATAD3A's ATPase domain directly binds TFAM and that oligomerization via the coiled-coil domain drives ATP-dependent nucleoid trafficking provided the first mechanistic model for active nucleoid movement along the inner membrane.","evidence":"Live imaging of nucleoid dynamics, direct binding assay ATAD3A-TFAM, coiled-coil mutagenesis","pmids":["36383603"],"confidence":"High","gaps":["Motor-like versus treadmilling mechanism for nucleoid movement is unresolved","Whether ATAD3A moves along a track or remodels the membrane to translocate nucleoids"]},{"year":2022,"claim":"Linking ATAD3A oligomerization at MAMs to suppression of CYP46A1 and cholesterol accumulation in Alzheimer's disease models extended the pathological consequences of aberrant oligomerization from mitochondrial dynamics to lipid metabolism and neurodegeneration.","evidence":"5XFAD AD mouse, heterozygous ATAD3A KO, DA1 peptide, CYP46A1 expression, cholesterol assays","pmids":["35236834"],"confidence":"High","gaps":["Mechanism by which ATAD3A oligomers at MAMs suppress CYP46A1 gene expression is unclear","Whether cholesterol accumulation is primary or secondary to mitochondrial/MAM disruption"]},{"year":2024,"claim":"Discovery that ATAD3A at MAMs competes with eIF2α for PERK binding to protect local mitochondrial translation from ER stress–induced repression revealed a subcellular compartmentalization of the integrated stress response mediated by ATAD3A.","evidence":"Live-cell translation reporter imaging, Co-IP of PERK/ATAD3A/eIF2, proximity ligation assay, ATAD3A knockdown","pmids":["39116259"],"confidence":"High","gaps":["Whether this mechanism extends to all MAM-localized mRNAs or a specific subset","Structural basis for the competitive PERK-binding mechanism"]},{"year":2024,"claim":"Identification of SIRT3-mediated deacetylation at K134 as a switch controlling ATAD3A oligomerization and its interaction with the IP3R1–GRP75–VDAC1 calcium-transfer complex at MAMs linked ATAD3A's oligomeric state to mitochondrial calcium homeostasis and cardiac hypertrophy.","evidence":"SIRT3 KO mouse, K134 site-directed mutagenesis, Co-IP, calcium imaging, MAM analysis, cardiac hypertrophy model","pmids":["38250153"],"confidence":"Medium","gaps":["Single-lab finding not independently confirmed","Whether K134 and K135 acetylation events are redundant or sequential is undetermined","Direct acetylation by a specific acetyltransferase is not identified"]},{"year":2024,"claim":"Demonstrating that TBK1 phosphorylates ATAD3A at S321 to enhance PINK1 import and suppress mitophagy during senescence identified the first kinase directly modifying ATAD3A and connected innate immune kinase signaling to mitophagy regulation.","evidence":"In vitro kinase assay, S321A mutagenesis, TAT-PEP blocking peptide, senescence assays, aging mouse models","pmids":["39520088"],"confidence":"High","gaps":["Whether phosphatases reverse S321 phosphorylation to re-enable mitophagy is unknown","Crosstalk between S321 phosphorylation and K134/K135 acetylation is unexplored"]},{"year":2024,"claim":"Defining opposing ubiquitination modes—TRIM25-mediated K48-linked degradation versus FBXL6-mediated K63-linked stabilization—established that ATAD3A protein levels are under bidirectional ubiquitin code control, with downstream effects on PINK1/Parkin mitophagy and metabolic reprogramming.","evidence":"Co-IP, ubiquitination assays with chain-type specificity, proteasome inhibitor experiments, in vivo tumor and ischemia models","pmids":["39307194","40975350"],"confidence":"Medium","gaps":["Each ubiquitin ligase studied by a different single lab; no integrated study of both pathways","Lysine residues on ATAD3A targeted by each E3 ligase are not mapped","Whether deubiquitinases regulate ATAD3A turnover is unknown"]},{"year":2025,"claim":"Demonstrating that ATAD3A interacts with complex I subunit NDUFS8 and is required for complex I assembly and activity resolved how ATAD3A contributes to respiratory chain function and linked its deficiency to reverse electron transport and mitochondrial ROS production.","evidence":"Co-IP of ATAD3A/NDUFS8, complex I activity assay, ROS and membrane potential measurements in C. elegans and mammalian cells","pmids":["40961994"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Whether ATAD3A is a bona fide assembly factor or stabilizes mature complex I is unresolved","No structural information on ATAD3A–NDUFS8 interface"]},{"year":null,"claim":"A high-resolution structural model of ATAD3A in its native dual-membrane context is lacking, and the precise mechanism by which its oligomerization state switches between scaffolding, nucleoid trafficking, mitophagy regulation, and pore formation remains to be dissected at the molecular level.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of full-length ATAD3A or its oligomeric assemblies","Hierarchy and crosstalk among post-translational modifications (acetylation, phosphorylation, ubiquitination) in regulating oligomeric state are uncharacterized","Whether ATAD3A constitutes the pore-forming subunit of the mPTP awaits peer-reviewed confirmation and independent replication"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,7,13,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,17]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,11,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12,18,19]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,10,15,16,20,21]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,8,11,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[18,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]}],"complexes":["TOM40/TIM23 import complex (bridging interaction)","IP3R1-GRP75-VDAC1 MAM calcium complex"],"partners":["PINK1","TFAM","DRP1","TOM40","TIM23","PERK","NDUFS8","VDAC1"],"other_free_text":[]},"mechanistic_narrative":"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both mitochondrial membranes—with its N-terminus facing the intermembrane space/cytoplasm and its C-terminal ATPase domain in the matrix—and functions as a central scaffold coupling mitochondrial membrane architecture, nucleoid dynamics, mitophagy regulation, and ER–mitochondria communication [PMID:20154147, PMID:20349121]. Its ATPase domain directly binds TFAM to drive ATP-dependent nucleoid trafficking along mitochondria, while its oligomerization state—modulated by SIRT3-dependent acetylation at K134, TBK1 phosphorylation at S321, and interaction with Drp1 and sigma-1 receptor—controls mitochondrial fission/fusion balance and mtDNA maintenance [PMID:36383603, PMID:30914652, PMID:38250153, PMID:39520088, PMID:36736924]. ATAD3A bridges the TOM40/TIM23 import machinery to facilitate PINK1 import and processing, thereby suppressing PINK1/Parkin-dependent mitophagy; its own stability is regulated by opposing ubiquitination by TRIM25 (K48-linked, destabilizing) and FBXL6 (K63-linked, stabilizing) [PMID:29242539, PMID:39307194, PMID:40975350]. At mitochondria-associated ER membranes, ATAD3A interacts with PERK to shield local translation from ER stress-induced repression, associates with the IP3R1–GRP75–VDAC1 complex to regulate calcium homeostasis, and interacts with NDUFS8 to support respiratory complex I assembly [PMID:39116259, PMID:38250153, PMID:40961994]."},"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 De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27640307","citation_count":144,"is_preprint":false},{"pmid":"20154147","id":"PMC_20154147","title":"The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20154147","citation_count":136,"is_preprint":false},{"pmid":"29242539","id":"PMC_29242539","title":"Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells.","date":"2017","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29242539","citation_count":115,"is_preprint":false},{"pmid":"36627348","id":"PMC_36627348","title":"Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36627348","citation_count":96,"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":82,"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":80,"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 : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33280610","citation_count":78,"is_preprint":false},{"pmid":"34387651","id":"PMC_34387651","title":"Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34387651","citation_count":77,"is_preprint":false},{"pmid":"34798798","id":"PMC_34798798","title":"AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34798798","citation_count":66,"is_preprint":false},{"pmid":"28158749","id":"PMC_28158749","title":"ATPase-deficient 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":"35236834","id":"PMC_35236834","title":"ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35236834","citation_count":63,"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":57,"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":51,"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":39,"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 physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33580514","citation_count":36,"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":33,"is_preprint":false},{"pmid":"33113782","id":"PMC_33113782","title":"Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33113782","citation_count":32,"is_preprint":false},{"pmid":"22664726","id":"PMC_22664726","title":"ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A.","date":"2012","source":"Mitochondrion","url":"https://pubmed.ncbi.nlm.nih.gov/22664726","citation_count":32,"is_preprint":false},{"pmid":"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":"36383603","id":"PMC_36383603","title":"Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36383603","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 metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32933822","citation_count":29,"is_preprint":false},{"pmid":"33845882","id":"PMC_33845882","title":"Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.","date":"2021","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33845882","citation_count":28,"is_preprint":false},{"pmid":"28393927","id":"PMC_28393927","title":"Baculovirus LEF-11 Hijack Host ATPase ATAD3A to Promote Virus Multiplication in Bombyx mori cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28393927","citation_count":28,"is_preprint":false},{"pmid":"31727539","id":"PMC_31727539","title":"Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities.","date":"2019","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31727539","citation_count":27,"is_preprint":false},{"pmid":"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":25,"is_preprint":false},{"pmid":"35513069","id":"PMC_35513069","title":"Loss of mitochondrial ATPase ATAD3A contributes to nonalcoholic fatty liver disease through accumulation of lipids and damaged mitochondria.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35513069","citation_count":23,"is_preprint":false},{"pmid":"30919342","id":"PMC_30919342","title":"ATAD3A on the Path to Cancer.","date":"2019","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/30919342","citation_count":20,"is_preprint":false},{"pmid":"37569886","id":"PMC_37569886","title":"ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37569886","citation_count":19,"is_preprint":false},{"pmid":"36736924","id":"PMC_36736924","title":"Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis.","date":"2023","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36736924","citation_count":14,"is_preprint":false},{"pmid":"29286187","id":"PMC_29286187","title":"Mitochondrial ATAD3A regulates milk biosynthesis and proliferation of mammary epithelial cells from dairy cow via the mTOR pathway.","date":"2018","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/29286187","citation_count":14,"is_preprint":false},{"pmid":"34413925","id":"PMC_34413925","title":"miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34413925","citation_count":12,"is_preprint":false},{"pmid":"39307194","id":"PMC_39307194","title":"Ubiquitination of ATAD3A by TRIM25 exacerbates cerebral ischemia-reperfusion injury via regulating PINK1/Parkin signaling pathway-mediated mitophagy.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39307194","citation_count":11,"is_preprint":false},{"pmid":"31239750","id":"PMC_31239750","title":"Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus.","date":"2019","source":"The application of clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31239750","citation_count":11,"is_preprint":false},{"pmid":"37095554","id":"PMC_37095554","title":"ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability.","date":"2023","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37095554","citation_count":9,"is_preprint":false},{"pmid":"36856321","id":"PMC_36856321","title":"Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum.","date":"2023","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36856321","citation_count":8,"is_preprint":false},{"pmid":"37031571","id":"PMC_37031571","title":"Ketogenic Diet Attenuates Refractory Epilepsy of Harel-Yoon Syndrome With ATAD3A Variants: A Case Report and Review of Literature.","date":"2023","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37031571","citation_count":7,"is_preprint":false},{"pmid":"36061954","id":"PMC_36061954","title":"Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion.","date":"2022","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/36061954","citation_count":6,"is_preprint":false},{"pmid":"39520088","id":"PMC_39520088","title":"Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39520088","citation_count":6,"is_preprint":false},{"pmid":"38018291","id":"PMC_38018291","title":"The value of ATAD3A as a potential biomarker for bladder cancer.","date":"2023","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38018291","citation_count":5,"is_preprint":false},{"pmid":"36000457","id":"PMC_36000457","title":"Deletion of ATAD3A inhibits osteogenesis by impairing mitochondria structure and function in pre-osteoblast.","date":"2022","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/36000457","citation_count":4,"is_preprint":false},{"pmid":"22542587","id":"PMC_22542587","title":"Yeast-based production and purification of HIS-tagged human ATAD3A, A specific target of S100B.","date":"2012","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/22542587","citation_count":4,"is_preprint":false},{"pmid":"38050826","id":"PMC_38050826","title":"Identification of ATAD3A as a key regulator in non-small cell lung cancer by promoting STAT3-induced cell proliferation and tumor angiogenesis.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38050826","citation_count":4,"is_preprint":false},{"pmid":"38092275","id":"PMC_38092275","title":"\"ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane\".","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38092275","citation_count":2,"is_preprint":false},{"pmid":"41163081","id":"PMC_41163081","title":"Empagliflozin-pretreated BMSC exosomes attenuate myocardial ischemia-reperfusion injury by enhancing atad3a/pink1-dependent mitophagy.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41163081","citation_count":2,"is_preprint":false},{"pmid":"40460607","id":"PMC_40460607","title":"Thymoquinone alleviates myocardial ischemia/reperfusion injury by stabilizing mitochondria-associated membrane homeostasis via targeting ATAD3A.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40460607","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":"38105692","id":"PMC_38105692","title":"ATAD3A gene variations in a family with Harel-Yoon syndrome.","date":"2023","source":"Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38105692","citation_count":2,"is_preprint":false},{"pmid":"41053045","id":"PMC_41053045","title":"P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41053045","citation_count":1,"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":"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":"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":"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":"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":0,"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":"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":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":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":31638,"output_tokens":6835,"usd":0.09872},"stage2":{"model":"claude-opus-4-6","input_tokens":10439,"output_tokens":4253,"usd":0.23778},"total_usd":0.3365,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","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, a central transmembrane segment anchors it in the inner membrane, and the C-terminal AAA+ ATPase domain is positioned in the matrix. Using dominant-negative mutants (defective ATP-binding and truncated N-terminus), ATAD3A was shown to regulate dynamic interactions between the outer and inner mitochondrial membranes, and is required for normal cell growth and cholesterol channeling at contact sites.\",\n      \"method\": \"Dominant-negative mutagenesis, Drosophila invalidation, human steroidogenic cell knockdown, subcellular fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mutagenesis, genetic knockdown in two model systems, fractionation), replicated across organisms\",\n      \"pmids\": [\"20154147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATAD3A topology was directly determined: the N-terminal region (aa 40-53) is accessible from outside the inner membrane (cytoplasm or intermembrane space) and the C-terminal region (aa 572-586) is located within the matrix, confirmed by back-titration ELISA and immunofluorescence using domain-specific antibodies on purified human mitochondria.\",\n      \"method\": \"Anti-peptide antibody back-titration ELISA, immunofluorescence on purified human mitochondria\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct topology determination with two orthogonal immunological methods on purified organelles\",\n      \"pmids\": [\"20349121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATAD3A is a major, high-affinity, calcium-dependent binding target of S100B in oligodendrocyte progenitor cells. NMR spectroscopy defined a consensus calcium-dependent S100B binding motif on ATAD3A. S100B prevents cytoplasmic ATAD3A aggregation and restores its mitochondrial localization, suggesting S100B assists newly synthesized ATAD3A in proper folding and subcellular targeting.\",\n      \"method\": \"Co-immunoprecipitation, NMR spectroscopy, cellular truncation mutant studies, Far-Western assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural mapping plus functional cellular validation with orthogonal binding assays\",\n      \"pmids\": [\"20351179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATAD3B, a paralog of ATAD3A, associates with ATAD3A and acts as a dominant negative regulator: it negatively regulates ATAD3A interaction with matrix nucleoid complexes and promotes mitochondrial fragmentation.\",\n      \"method\": \"Loss- and gain-of-function, co-immunoprecipitation, mitochondrial morphology analysis\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional interaction shown with both loss- and gain-of-function, single study\",\n      \"pmids\": [\"22664726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATAD3A interacts with the metastasis-promoting protein WASF3 at the mitochondrial membrane (N-terminal WASF3 interacts with N-terminal ATAD3A), and also forms a complex with GRP78. ATAD3A-mediated stabilization of WASF3 occurs through this interaction with GRP78, bridging ER and mitochondria. Knockdown of ATAD3A reduces WASF3 protein levels and suppresses invasion and metastasis.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, proteolysis of isolated mitochondria, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed by Co-IP, domain mapping by proteolysis, functional validation in vitro and in vivo\",\n      \"pmids\": [\"25823022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A recurrent de novo ATAD3A p.Arg528Trp variant acts through a dominant-negative mechanism, causing small mitochondria that trigger mitophagy and reduction in mitochondrial content. Tissue-specific overexpression of the homologous Drosophila mutation decreases mitochondrial content and causes aberrant morphology; patient fibroblasts show increased mitophagy.\",\n      \"method\": \"Drosophila tissue-specific overexpression, patient fibroblast mitophagy assay, whole-exome sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative mechanism established across multiple patients and model organism, with orthogonal cellular assays\",\n      \"pmids\": [\"27640307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATAD3A interacts with mitochondrial channel components TOM40 and TIM23 and serves as a bridging factor to facilitate appropriate transport and processing of PINK1. Loss of ATAD3A causes PINK1 accumulation and hyperactivation of PINK1-dependent mitophagy, which can be rescued by deletion of Pink1.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mouse, genetic epistasis (Atad3a/Pink1 double KO), flow cytometry, bone marrow analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of TOM40/TIM23, confirmed by genetic rescue with Pink1 deletion, clean KO with defined cellular phenotype\",\n      \"pmids\": [\"29242539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A dominant-negative ATAD3A mutation (p.G355D) affecting the Walker A motif (responsible for ATP binding) causes markedly reduced ATPase activity in the recombinant mutant protein and fragments the mitochondrial network, induces lysosome mass, and upregulates basal autophagy through mTOR inactivation in patient fibroblasts and iPSC-derived neurons.\",\n      \"method\": \"In vitro ATPase activity assay on recombinant mutant protein, patient fibroblast and iPSC-derived neuron analysis, mitochondrial morphology imaging, mTOR pathway western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ATPase assay demonstrating catalytic defect, with functional cellular validation in patient-derived cells\",\n      \"pmids\": [\"28158749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Huntington's disease, ATAD3A dimerization (driven by deacetylation at K135) is required for Drp1-mediated mitochondrial fragmentation. ATAD3A interacts with Drp1 in HD cells. ATAD3A oligomerization disrupts TFAM/mtDNA binding, impairing mtDNA maintenance. A blocking peptide (DA1) targeting the Drp1/ATAD3A interaction abolishes ATAD3A oligomerization, restores mtDNA maintenance, and reduces HD neurodegeneration in transgenic mice.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation (Drp1/ATAD3A), mutagenesis (K135), TFAM/mtDNA ChIP, peptide inhibition (DA1), HD transgenic mouse behavioral/neuropathological analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods: Co-IP, site-specific mutagenesis, mtDNA assays, in vivo rescue with peptide inhibitor\",\n      \"pmids\": [\"30914652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of ATAD3A in THP-1 cells increases interferon signaling mediated by cGAS and STING. This enhanced interferon signaling is abrogated when cells are depleted of mitochondrial DNA, establishing that ATAD3A mutations lead to mtDNA-driven cGAS-STING activation and a type I interferonopathy.\",\n      \"method\": \"siRNA knockdown in THP-1 cells, mtDNA depletion, ISG expression measurement, interferon-alpha ELISA\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via mtDNA depletion rescuing the phenotype, validated in patient fibroblasts and THP-1 cells\",\n      \"pmids\": [\"34387651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMBRA1, upon mitochondrial depolarization, is recruited to the outer mitochondrial membrane and interacts with both PINK1 and ATAD3A. AMBRA1 promotes PINK1 stability by preventing its enhanced degradation by the mitochondrial protease LONP1; ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells.\",\n      \"method\": \"Co-immunoprecipitation (AMBRA1/PINK1/ATAD3A), siRNA knockdown, LONP1 protease assay, ubiquitin phosphorylation assay, PARKIN recruitment assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of trimeric complex, genetic epistasis with ATAD3A silencing, protease identification, replicated in multiple cell types\",\n      \"pmids\": [\"34798798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATAD3A associates with different inner mitochondrial membrane components including OXPHOS complex I, Letm1, and prohibitin complexes. STORM microscopy shows ATAD3A is regularly distributed along the inner mitochondrial membrane. Neuronal conditional knockout mice develop severe encephalopathy with aberrant mitochondrial cristae morphogenesis, supporting a primary scaffolding role for ATAD3A in inner mitochondrial membrane organization.\",\n      \"method\": \"Multi-omics (proteomics), co-immunoprecipitation, STORM super-resolution microscopy, neuronal conditional knockout mouse\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, super-resolution microscopy, and conditional KO mouse with defined structural phenotype; multi-omics corroboration\",\n      \"pmids\": [\"34936866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A oligomerization in Alzheimer's disease models accumulates at mitochondria-associated ER membranes (MAMs) and inhibits gene expression of CYP46A1, an enzyme governing brain cholesterol clearance, leading to cholesterol accumulation. Suppression of ATAD3A oligomerization by heterozygous KO or DA1 peptide restores CYP46A1 levels, normalizes cholesterol turnover and MAM integrity, and reduces AD neuropathology.\",\n      \"method\": \"5XFAD mouse model, heterozygous ATAD3A KO, peptide inhibition (DA1), CYP46A1 gene expression analysis, cholesterol assay, MAM fractionation, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple models (transgenic AD mice, patient tissue, neuronal cultures), orthogonal genetic and pharmacological interventions\",\n      \"pmids\": [\"35236834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A's ATPase domain binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also requires ATAD3A oligomerization via coiled-coil domain interactions in the intermembrane space. In ATAD3A deficiency, nucleoid trafficking is impaired, leading to dispersed small nucleoids and enhanced respiratory complex formation.\",\n      \"method\": \"Live imaging of nucleoid dynamics, ATPase domain-TFAM direct binding assay, coiled-coil domain mutagenesis, ATAD3A-deficient cells, respiratory complex analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay between ATAD3A ATPase domain and TFAM, live imaging, and mutagenesis\",\n      \"pmids\": [\"36383603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATAD3A interacts with ERK1/2 in the mitochondria in the presence of VDAC1, and this interaction is essential for activation of mitochondrial ERK1/2 signaling in a RAS-independent manner. A Walker A dead mutant (K358) of ATAD3A acts as a dominant negative, demonstrating that ATPase activity is required for this signaling function.\",\n      \"method\": \"Co-immunoprecipitation (ATAD3A/ERK1/2/VDAC1), CRISPR/Cas9 knockout, dominant-negative mutagenesis, phospho-kinase profiling, orthotopic xenograft mouse\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying trimeric complex, mutagenesis confirming ATPase dependency, single lab study\",\n      \"pmids\": [\"35093151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MUC1 translocates to mitochondria and interacts with ATAD3A, inducing its degradation. This relieves ATAD3A-mediated cleavage of PINK1, leading to PINK1 accumulation and increased mitophagy to promote cancer cell malignancy.\",\n      \"method\": \"Co-immunoprecipitation (MUC1/ATAD3A), western blot for PINK1 levels, mitophagy assay, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, functional rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"36289190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PINK1 is recruited to mitochondria for degradation via mitophagy upon ATAD3A-mediated regulation. The ATAD3A-PINK1 axis controls PD-L1 subcellular distribution: PINK1 recruits PD-L1 to mitochondria for degradation, while ATAD3A restrains this process. Paclitaxel increases ATAD3A expression to disrupt PD-L1 proteostasis by restraining PINK1-dependent mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, mitophagy assays, patient tumor sample analysis, preclinical mouse models\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic axis established with Co-IP and functional assays, corroborated in patient samples, single lab\",\n      \"pmids\": [\"36627348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sigma-1 receptor (σ1R) at the MAM interacts with ATAD3A and retains it as a monomer, thereby inhibiting ATAD3A dimerization and mitochondrial fragmentation. In σ1R-deficient or SOD1-ALS mouse spinal cords, ATAD3A dimerization and mitochondrial fragmentation are induced.\",\n      \"method\": \"Co-immunoprecipitation (σ1R/ATAD3A), σ1R-KO mouse, SOD1-ALS mouse, mitochondrial morphology analysis, Blue Native PAGE for ATAD3A oligomeric state\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, multiple genetic mouse models, oligomeric state analysis; single lab\",\n      \"pmids\": [\"36736924\"],\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 eIF2 for PERK binding, attenuating local PERK signaling and protecting active translation at mitochondria from global translational repression. ATAD3A binding to PERK thus mediates subcellular control of translational repression.\",\n      \"method\": \"Live-cell imaging of reporter mRNA translation, co-immunoprecipitation (PERK/ATAD3A/eIF2), proximity ligation assay for contact sites, ATAD3A knockdown\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — live-cell reporter imaging resolving subcellular translation rates, Co-IP, competitive binding assay with eIF2; published in Science with multiple orthogonal methods\",\n      \"pmids\": [\"39116259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT3 deacetylates ATAD3A; acetylation at K134 reduces ATAD3A self-oligomerization and promotes cardiac hypertrophy. Acetylated ATAD3A monomer interacts with the IP3R1-GRP75-VDAC1 complex at MAMs, leading to mitochondrial calcium overload. SIRT3 knockout mice show excessive MAM formation. ATAD3A oligomerization is thus regulated by SIRT3-dependent acetylation status.\",\n      \"method\": \"Co-immunoprecipitation, SIRT3 KO mouse, site-directed mutagenesis (K134), calcium imaging, MAM analysis, cardiac hypertrophy model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutagenesis, KO mouse, Co-IP, functional cardiac readout; single lab\",\n      \"pmids\": [\"38250153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBK1 is abnormally activated and localizes to mitochondria during senescence, where it directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A suppresses PINK1-mediated mitophagy by facilitating PINK1 mitochondrial import. A blocking peptide (TAT-PEP) abrogating this phosphorylation rescues cellular senescence and enhances tumor sensitivity to chemotherapy.\",\n      \"method\": \"In vitro kinase assay (TBK1 phosphorylating ATAD3A at S321), site-directed mutagenesis (S321A), blocking peptide, senescence assays, aging mouse models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation assay identifying kinase-substrate relationship, mutagenesis confirmation, in vivo functional rescue\",\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, reducing ATAD3A protein stability. Reduced ATAD3A allows PINK1 accumulation and activates PINK1/Parkin-dependent mitophagy. ME2 competes with TRIM25 for binding to ATAD3A, preventing ATAD3A ubiquitination and stabilizing it.\",\n      \"method\": \"Co-immunoprecipitation (TRIM25/ATAD3A), ubiquitination assay, proteasome inhibitor experiments, western blot, CI/RI rat model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay in cells, confirmed in vivo model; single lab\",\n      \"pmids\": [\"39307194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXL6 E3 ubiquitin ligase directly targets ATAD3A and induces K63-linked polyubiquitination, stabilizing ATAD3A and activating aerobic glycolysis to promote tumor malignancy in TNBC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay specifying K63-linkage, ATAD3A knockout/knockdown, in vivo xenograft\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific ubiquitin chain type identified, Co-IP, functional KO validation; 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 plays an integral role in complex I assembly and activity. Knockdown of ATAD3A reduces complex I activity and proton leakage, increases mitochondrial membrane potential, and induces reverse electron transport (RET) that increases mitochondrial ROS production.\",\n      \"method\": \"Co-immunoprecipitation (ATAD3A/NDUFS8), complex I activity assay, ROS measurement, mitochondrial membrane potential assay, C. elegans and mammalian cell knockdown\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding identified by Co-IP, functional complex I assays; single lab, two model systems\",\n      \"pmids\": [\"40961994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATAD3 is the first identified essential component of the mitochondrial permeability transition pore (mPTP). Cardiomyocyte- and hepatocyte-specific genetic deletion of Atad3 renders mitochondria incapable of Ca2+-induced mPTP-dependent swelling, yielding the highest Ca2+ retention capacity reported for any mPTP genetic perturbation. Recombinant ATAD3A reconstituted in liposomes displays intrinsic channel activity by patch-clamp. Cardiac Atad3 deletion markedly reduces infarct size following ischemia/reperfusion with no additive protection from cyclosporine A.\",\n      \"method\": \"Conditional cardiomyocyte/hepatocyte Atad3 KO, Ca2+-induced mitochondrial swelling assay, patch-clamp of ATAD3A in liposomes, I/R infarct size measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of channel activity in liposomes with patch-clamp, plus tissue-specific KO with direct functional readout in two cell types\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.658955\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATAD3A stabilizes GRP78 to suppress ER stress-induced unfolded protein response, providing acquired chemoresistance. Knockdown of ATAD3A dysregulates protein processing, induces ER stress, reduces surface calreticulin exposure, and sensitizes colorectal cancer cells to chemotherapy-induced immunogenic cell death.\",\n      \"method\": \"Co-immunoprecipitation (ATAD3A/GRP78), RNA-seq, siRNA knockdown, calreticulin surface exposure assay, in vivo tumor model, T-cell infiltration analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, functional knockdown with ER stress readout, in vivo validation; single lab\",\n      \"pmids\": [\"33580514\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both membranes (N-terminus facing the cytoplasm/IMS, C-terminal ATPase domain in the matrix) and functions as a multifunctional scaffold: it regulates mitochondrial dynamics (fission/fusion) by controlling its own oligomerization state (modulated by acetylation at K134/K135 via SIRT3 and phosphorylation at S321 via TBK1, and by interaction with Drp1 and sigma-1 receptor), organizes mitochondrial nucleoids by directly binding TFAM to drive ATP-dependent nucleoid trafficking, suppresses PINK1-dependent mitophagy by facilitating PINK1 import and processing via its interaction with TOM40/TIM23 (itself regulated by TRIM25-mediated K48-ubiquitination and stabilized by FBXL6-mediated K63-ubiquitination), maintains mitochondria-ER contact sites (MAMs) where it interacts with PERK to protect localized translation and with the IP3R1-GRP75-VDAC1 complex to regulate calcium homeostasis, assembles with complex I subunit NDUFS8 to support respiratory chain function, and constitutes an essential, pore-forming component of the mitochondrial permeability transition pore (mPTP) as demonstrated by reconstituted channel activity in liposomes and genetic ablation abolishing Ca2+-induced mPTP opening.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATAD3A is a mitochondrial inner membrane AAA+ ATPase that spans both mitochondrial membranes—with its N-terminus facing the intermembrane space/cytoplasm and its C-terminal ATPase domain in the matrix—and functions as a central scaffold coupling mitochondrial membrane architecture, nucleoid dynamics, mitophagy regulation, and ER–mitochondria communication [PMID:20154147, PMID:20349121]. Its ATPase domain directly binds TFAM to drive ATP-dependent nucleoid trafficking along mitochondria, while its oligomerization state—modulated by SIRT3-dependent acetylation at K134, TBK1 phosphorylation at S321, and interaction with Drp1 and sigma-1 receptor—controls mitochondrial fission/fusion balance and mtDNA maintenance [PMID:36383603, PMID:30914652, PMID:38250153, PMID:39520088, PMID:36736924]. ATAD3A bridges the TOM40/TIM23 import machinery to facilitate PINK1 import and processing, thereby suppressing PINK1/Parkin-dependent mitophagy; its own stability is regulated by opposing ubiquitination by TRIM25 (K48-linked, destabilizing) and FBXL6 (K63-linked, stabilizing) [PMID:29242539, PMID:39307194, PMID:40975350]. At mitochondria-associated ER membranes, ATAD3A interacts with PERK to shield local translation from ER stress-induced repression, associates with the IP3R1–GRP75–VDAC1 complex to regulate calcium homeostasis, and interacts with NDUFS8 to support respiratory complex I assembly [PMID:39116259, PMID:38250153, PMID:40961994].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing the dual-membrane topology and scaffolding function of ATAD3A resolved how a single AAA+ ATPase could coordinate outer and inner mitochondrial membrane dynamics and cholesterol channeling.\",\n      \"evidence\": \"Dominant-negative mutagenesis, Drosophila invalidation, subcellular fractionation, and back-titration ELISA/immunofluorescence on purified human mitochondria\",\n      \"pmids\": [\"20154147\", \"20349121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which ATAD3A mediates cholesterol transfer at contact sites is undefined\",\n        \"No structural model of the dual-membrane spanning architecture\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of S100B as a cytoplasmic chaperone for newly synthesized ATAD3A revealed a quality-control step that prevents ATAD3A aggregation prior to mitochondrial import.\",\n      \"evidence\": \"NMR mapping of S100B-binding motif on ATAD3A, Co-IP, and cellular localization assays in oligodendrocyte progenitors\",\n      \"pmids\": [\"20351179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether S100B is the sole cytoplasmic chaperone for ATAD3A is untested\",\n        \"Relevance of this interaction outside oligodendrocyte lineage cells is unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that paralog ATAD3B hetero-oligomerizes with ATAD3A and acts as its dominant-negative regulator established that nucleoid interaction and mitochondrial morphology are tuned by the ATAD3A/ATAD3B ratio.\",\n      \"evidence\": \"Gain- and loss-of-function of ATAD3B, Co-IP with ATAD3A, morphology analysis\",\n      \"pmids\": [\"22664726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of ATAD3A–ATAD3B hetero-oligomers are undefined\",\n        \"Single-lab finding not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking ATAD3A to the TOM40/TIM23 import machinery and showing that its loss triggers PINK1 accumulation and hyperactive mitophagy established ATAD3A as a gatekeeper of PINK1-dependent mitophagy.\",\n      \"evidence\": \"Co-IP of ATAD3A with TOM40/TIM23, conditional Atad3a KO mouse, genetic rescue by Pink1 deletion\",\n      \"pmids\": [\"29242539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATAD3A directly chaperones PINK1 through the import channel or acts indirectly is unresolved\",\n        \"Relative contributions of ATAD3A versus other import factors to PINK1 processing are unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that a Walker A mutant (G355D) abolishes ATPase activity and fragments mitochondria provided the first direct evidence that catalytic cycling is required for ATAD3A's structural and signaling roles.\",\n      \"evidence\": \"In vitro ATPase assay on recombinant mutant, patient fibroblast and iPSC-neuron analysis\",\n      \"pmids\": [\"28158749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the ATPase domain to explain how the mutation disrupts cycling\",\n        \"Whether residual monomeric ATAD3A retains non-catalytic functions is untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing that ATAD3A dimerization is driven by deacetylation at K135, recruits Drp1, and disrupts TFAM/mtDNA binding unified the previously separate observations on mitochondrial dynamics and nucleoid maintenance under a single oligomerization-dependent mechanism.\",\n      \"evidence\": \"Co-IP of Drp1/ATAD3A, K135 mutagenesis, TFAM/mtDNA ChIP, DA1 peptide rescue in HD transgenic mice\",\n      \"pmids\": [\"30914652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how oligomerization state switches TFAM binding versus Drp1 interaction is unknown\",\n        \"Whether DA1 peptide has off-target effects beyond blocking Drp1–ATAD3A interaction\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that ATAD3A deficiency triggers mtDNA-dependent cGAS-STING activation and type I interferon signaling established a direct link between ATAD3A's nucleoid-organizing role and innate immune surveillance.\",\n      \"evidence\": \"siRNA knockdown in THP-1, mtDNA depletion rescue, ISG expression and IFNα ELISA\",\n      \"pmids\": [\"34387651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Route by which mtDNA escapes mitochondria upon ATAD3A loss (herniation vs. mPTP vs. BAX/BAK pores) is undefined\",\n        \"Whether interferon activation is direct or secondary to mitophagy defects is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of ATAD3A as a scaffolding protein regularly distributed along the inner membrane and associated with complex I, Letm1, and prohibitin complexes—with neuronal KO causing cristae disorganization—established it as a general inner membrane organizer beyond its nucleoid and mitophagy roles.\",\n      \"evidence\": \"Proteomics, Co-IP, STORM super-resolution imaging, neuronal conditional KO mouse\",\n      \"pmids\": [\"34936866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ATAD3A directly shapes cristae or acts indirectly through MICOS/prohibitin interactions is unknown\",\n        \"Stoichiometry with inner membrane partners is not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that ATAD3A's ATPase domain directly binds TFAM and that oligomerization via the coiled-coil domain drives ATP-dependent nucleoid trafficking provided the first mechanistic model for active nucleoid movement along the inner membrane.\",\n      \"evidence\": \"Live imaging of nucleoid dynamics, direct binding assay ATAD3A-TFAM, coiled-coil mutagenesis\",\n      \"pmids\": [\"36383603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Motor-like versus treadmilling mechanism for nucleoid movement is unresolved\",\n        \"Whether ATAD3A moves along a track or remodels the membrane to translocate nucleoids\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking ATAD3A oligomerization at MAMs to suppression of CYP46A1 and cholesterol accumulation in Alzheimer's disease models extended the pathological consequences of aberrant oligomerization from mitochondrial dynamics to lipid metabolism and neurodegeneration.\",\n      \"evidence\": \"5XFAD AD mouse, heterozygous ATAD3A KO, DA1 peptide, CYP46A1 expression, cholesterol assays\",\n      \"pmids\": [\"35236834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which ATAD3A oligomers at MAMs suppress CYP46A1 gene expression is unclear\",\n        \"Whether cholesterol accumulation is primary or secondary to mitochondrial/MAM disruption\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that ATAD3A at MAMs competes with eIF2α for PERK binding to protect local mitochondrial translation from ER stress–induced repression revealed a subcellular compartmentalization of the integrated stress response mediated by ATAD3A.\",\n      \"evidence\": \"Live-cell translation reporter imaging, Co-IP of PERK/ATAD3A/eIF2, proximity ligation assay, ATAD3A knockdown\",\n      \"pmids\": [\"39116259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this mechanism extends to all MAM-localized mRNAs or a specific subset\",\n        \"Structural basis for the competitive PERK-binding mechanism\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of SIRT3-mediated deacetylation at K134 as a switch controlling ATAD3A oligomerization and its interaction with the IP3R1–GRP75–VDAC1 calcium-transfer complex at MAMs linked ATAD3A's oligomeric state to mitochondrial calcium homeostasis and cardiac hypertrophy.\",\n      \"evidence\": \"SIRT3 KO mouse, K134 site-directed mutagenesis, Co-IP, calcium imaging, MAM analysis, cardiac hypertrophy model\",\n      \"pmids\": [\"38250153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding not independently confirmed\",\n        \"Whether K134 and K135 acetylation events are redundant or sequential is undetermined\",\n        \"Direct acetylation by a specific acetyltransferase is not identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that TBK1 phosphorylates ATAD3A at S321 to enhance PINK1 import and suppress mitophagy during senescence identified the first kinase directly modifying ATAD3A and connected innate immune kinase signaling to mitophagy regulation.\",\n      \"evidence\": \"In vitro kinase assay, S321A mutagenesis, TAT-PEP blocking peptide, senescence assays, aging mouse models\",\n      \"pmids\": [\"39520088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether phosphatases reverse S321 phosphorylation to re-enable mitophagy is unknown\",\n        \"Crosstalk between S321 phosphorylation and K134/K135 acetylation is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining opposing ubiquitination modes—TRIM25-mediated K48-linked degradation versus FBXL6-mediated K63-linked stabilization—established that ATAD3A protein levels are under bidirectional ubiquitin code control, with downstream effects on PINK1/Parkin mitophagy and metabolic reprogramming.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with chain-type specificity, proteasome inhibitor experiments, in vivo tumor and ischemia models\",\n      \"pmids\": [\"39307194\", \"40975350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Each ubiquitin ligase studied by a different single lab; no integrated study of both pathways\",\n        \"Lysine residues on ATAD3A targeted by each E3 ligase are not mapped\",\n        \"Whether deubiquitinases regulate ATAD3A turnover is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that ATAD3A interacts with complex I subunit NDUFS8 and is required for complex I assembly and activity resolved how ATAD3A contributes to respiratory chain function and linked its deficiency to reverse electron transport and mitochondrial ROS production.\",\n      \"evidence\": \"Co-IP of ATAD3A/NDUFS8, complex I activity assay, ROS and membrane potential measurements in C. elegans and mammalian cells\",\n      \"pmids\": [\"40961994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication needed\",\n        \"Whether ATAD3A is a bona fide assembly factor or stabilizes mature complex I is unresolved\",\n        \"No structural information on ATAD3A–NDUFS8 interface\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural model of ATAD3A in its native dual-membrane context is lacking, and the precise mechanism by which its oligomerization state switches between scaffolding, nucleoid trafficking, mitophagy regulation, and pore formation remains to be dissected at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of full-length ATAD3A or its oligomeric assemblies\",\n        \"Hierarchy and crosstalk among post-translational modifications (acetylation, phosphorylation, ubiquitination) in regulating oligomeric state are uncharacterized\",\n        \"Whether ATAD3A constitutes the pore-forming subunit of the mPTP awaits peer-reviewed confirmation and independent replication\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 7, 13, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 11, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12, 18, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 10, 15, 16, 20, 21]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 8, 11, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [18, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"TOM40/TIM23 import complex (bridging interaction)\",\n      \"IP3R1-GRP75-VDAC1 MAM calcium complex\"\n    ],\n    \"partners\": [\n      \"PINK1\",\n      \"TFAM\",\n      \"DRP1\",\n      \"TOM40\",\n      \"TIM23\",\n      \"PERK\",\n      \"NDUFS8\",\n      \"VDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}