Affinage

ATAD3A

ATPase family AAA domain-containing protein 3A · UniProt Q9NVI7

Length
586 aa
Mass
66.2 kDa
Annotated
2026-06-09
60 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATAD3A is a mitochondrial AAA+ ATPase that spans both mitochondrial membranes—its N-terminus accessible from the cytoplasm/intermembrane space, a central transmembrane segment in the inner membrane, and the C-terminal ATPase domain in the matrix—where it serves as a structural scaffold coordinating membrane architecture, nucleoid organization, and mitochondria-ER crosstalk (PMID:20154147, PMID:20349121, PMID:34936866). Distributed regularly along the inner membrane, it associates with OXPHOS complex I (directly binding NDUFS8), Letm1, and prohibitin complexes and is required for cristae morphogenesis and complex I assembly, such that its loss perturbs respiratory function and drives reverse-electron-transport ROS (PMID:34936866, PMID:40961994). Through its ATPase domain, ATAD3A directly binds TFAM and powers trafficking of mtDNA nucleoids via ATP hydrolysis, a function further requiring intermembrane-space coiled-coil-mediated oligomerization (PMID:36383603). A central regulatory theme is its control of PINK1-dependent mitophagy: ATAD3A bridges the Tom40/Tim23 import channels to facilitate PINK1 import and processing, thereby suppressing mitophagy, and it acts upstream of PINK1 in vivo, with PINK1 deletion rescuing ATAD3A-deficient hematopoietic defects (PMID:29242539). This mitophagy-suppressive activity is tuned by post-translational modifications and competing partners—TBK1 phosphorylation at Ser321 promotes PINK1 import (PMID:39520088), AMBRA1, TRIM25-mediated proteasomal ubiquitination, and MUC1 destabilize ATAD3A to release PINK1 (PMID:34798798, PMID:39307194, PMID:36289190). The protein's oligomeric state is itself a master regulatory switch: deacetylation at K135/K134 by SIRT3 governs dimerization, and Drp1-driven oligomerization couples mitochondrial fission to impaired TFAM/mtDNA binding and bioenergetic deficits in Huntington's disease, while at mitochondria-ER contact sites oligomerization controls CYP46A1-dependent cholesterol turnover in Alzheimer's models and competition with eIF2α attenuates PERK-mediated translational repression (PMID:30914652, PMID:35236834, PMID:39116259, PMID:38250153). ATAD3A also restrains mtDNA-driven cGAS-STING type I interferon signaling (PMID:34387651) and functions as an essential pore-forming component of the mitochondrial permeability transition pore [PMID:bio_10.1101_2025.06.13.658955]. Dominant-negative ATAD3A mutations affecting ATP binding (p.G355D, p.R528W) cause human mitochondrial disease characterized by aberrant mitochondrial dynamics and hyperactivated mitophagy (PMID:27640307, PMID:28158749).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2010 High

    Establishing ATAD3A's dual-membrane topology answered where this AAA+ ATPase sits and how it could physically bridge the two mitochondrial membranes to sense and regulate membrane contacts.

    Evidence Topology/fractionation and back-titration ELISA/immunofluorescence on purified human mitochondria, plus dominant-negative mutants in Drosophila and steroidogenic cells

    PMID:20154147 PMID:20349121

    Open questions at the time
    • Structural basis of how a single protein anchors both membranes not resolved
    • Mechanism coupling topology to fission machinery sensing undefined
  2. 2010 High

    Identifying S100B as a calcium-dependent ATAD3A chaperone addressed how ATAD3A achieves proper folding and mitochondrial targeting.

    Evidence NMR mapping of the S100B binding motif and rescue of an import-deficient ATAD3A mutant in oligodendrocyte progenitors

    PMID:20351179

    Open questions at the time
    • Physiological relevance of S100B chaperoning beyond OPCs unclear
    • Whether S100B affects endogenous ATAD3A import not tested
  3. 2012 Medium

    Discovery that the paralog ATAD3B antagonizes ATAD3A-nucleoid interactions introduced paralog-based regulation of ATAD3A function.

    Evidence Reciprocal gain/loss-of-function in human ES and cancer cells with nucleoid and morphology readouts

    PMID:22664726

    Open questions at the time
    • Stoichiometry of ATAD3A/ATAD3B complexes unknown
    • Single lab; biochemical basis of dominant-negative effect not defined
  4. 2015 High

    Placing ATAD3A in a trimeric complex with WASF3 and GRP78 linked it to tumor cell stability of a metastasis driver and E-cadherin suppression.

    Evidence MS, Co-IP, mitochondrial proteolysis domain mapping, knockdown with invasion and tumor growth assays

    PMID:25823022

    Open questions at the time
    • Whether ATAD3A's ATPase activity is required for WASF3 stabilization not shown
    • Mechanism connecting mitochondrial WASF3 to E-cadherin regulation incomplete
  5. 2016 High

    Dominant-negative ATAD3A disease variants established that perturbing ATAD3A triggers excess mitophagy and reduced mitochondrial content, defining a human disease mechanism.

    Evidence Whole-exome sequencing, Drosophila tissue-specific dominant-negative overexpression, patient fibroblast mitophagy assays

    PMID:27640307

    Open questions at the time
    • Molecular trigger linking small mitochondria to mitophagy not yet defined
    • Tissue selectivity of phenotype unexplained
  6. 2017 High

    Two studies defined the upstream control of PINK1 by ATAD3A and demonstrated that ATP-binding-dead mutants are dominant-negative, mechanistically connecting ATPase activity to mitophagy suppression.

    Evidence Conditional KO mice with reciprocal Co-IP of Tom40/Tim23/PINK1 and PINK1 deletion epistasis rescue; in vitro ATPase assay of recombinant G355D mutant with patient fibroblast/iPSC-neuron phenotypes

    PMID:28158749 PMID:29242539

    Open questions at the time
    • How ATAD3A physically presents PINK1 to the import channel not structurally resolved
    • Link between ATPase activity and bridging function not directly tested
  7. 2019 High

    Linking deacetylation-driven dimerization and Drp1 interaction to fission established ATAD3A oligomeric state as a switch coupling fission, TFAM/mtDNA binding, and bioenergetics in disease.

    Evidence Proteomics, Co-IP, K135 acetylation-site mutagenesis, DA1 blocking peptide, in vivo rescue in HD transgenic mice

    PMID:30914652

    Open questions at the time
    • Direct deacetylase responsible not identified in this study
    • Structural model of oligomer-TFAM competition lacking
  8. 2021 High

    Multiple studies refined ATAD3A's mitophagy and immune roles—positioning it downstream of AMBRA1 in PINK1 stability and as a suppressor of mtDNA-driven cGAS-STING interferon signaling.

    Evidence Co-IP and epistasis rescue in AMBRA1-deficient cells; ATAD3A knockdown in THP-1 with mtDNA-depletion rescue and patient fibroblast validation

    PMID:34387651 PMID:34798798

    Open questions at the time
    • How ATAD3A loss releases mtDNA to cGAS not mechanistically defined
    • Interplay between AMBRA1/LONP1 and ATAD3A-PINK1 import unresolved
  9. 2021 High

    Demonstrating ATAD3A association with complex I, Letm1, and prohibitins plus its regular IMM distribution established it as a structural scaffold for cristae morphogenesis.

    Evidence Neuronal conditional KO mice, multi-omics, Co-IP with inner membrane components, STORM super-resolution imaging

    PMID:34936866

    Open questions at the time
    • Direct structural contribution to cristae versus indirect effects not separated
    • Whether scaffolding requires ATPase activity untested
  10. 2022 High

    A cluster of studies defined how ATAD3A oligomerization at MAMs and its ATPase-dependent TFAM binding govern nucleoid trafficking, cholesterol metabolism, and cancer mitophagy.

    Evidence In vitro ATPase-domain/TFAM binding and live nucleoid imaging; 5XFAD mice with CYP46A1/cholesterol readouts and DA1 peptide; MUC1/ATAD3A/PINK1 Co-IP and mitophagy flux

    PMID:35236834 PMID:36289190 PMID:36383603

    Open questions at the time
    • How oligomeric state at MAMs controls CYP46A1 transcription mechanistically unclear
    • MUC1-ATAD3A axis validated in single lab
  11. 2022 Medium

    ATAD3A was shown to anchor RAS-independent mitochondrial ERK1/2 signaling, extending its scaffolding role to a growth-promoting kinase module.

    Evidence Co-IP with ERK1/2 and VDAC1, CRISPR KO, Walker A dead mutant (K358) dominant-negative, orthotopic HNSCC tumor model

    PMID:35093151

    Open questions at the time
    • How ATAD3A activates mitochondrial ERK1/2 mechanistically unknown
    • Single lab; generality across tumor types untested
  12. 2023 Medium

    Studies connected ATAD3A monomer/oligomer balance at MAMs to PD-L1 trafficking, σ1R-controlled fragmentation, and showed its oligomeric state is the regulatory node across contexts.

    Evidence Subcellular fractionation and mitophagy flux for PINK1/PD-L1; σ1R-deficient cells and SOD1-ALS mouse spinal cords with native PAGE oligomeric state

    PMID:36627348 PMID:36736924

    Open questions at the time
    • σ1R-ATAD3A regulation rests on single-lab Co-IP/native PAGE
    • Direct structural determinant of monomer-to-dimer transition undefined
  13. 2023 Medium

    Defining the ATAD3C paralog as a negative regulator that reduces complex size and shifts respiratory supercomplex assembly added a second paralog-based control of ATAD3A complexes.

    Evidence ATAD3C overexpression in fibroblasts, native PAGE complex analysis, OCR, ROS, and respiratory complex assays

    PMID:38092275

    Open questions at the time
    • Endogenous stoichiometry of ATAD3A/ATAD3C complexes unknown
    • Single lab; physiological contexts of ATAD3C expression unclear
  14. 2024 High

    A set of studies established the post-translational and protein-protein code controlling ATAD3A's PERK competition, MAM calcium handling, mitophagy via phosphorylation, and proteasomal turnover.

    Evidence Live-cell translation imaging and Co-IP showing ATAD3A-eIF2α competition for PERK; SIRT3 deacetylation/K134 mutagenesis with IP3R1-GRP75-VDAC1 Co-IP; in vitro TBK1 kinase assay with S321A mutagenesis; TRIM25 ubiquitination assays

    PMID:38250153 PMID:39116259 PMID:39307194 PMID:39520088

    Open questions at the time
    • How distinct modifications are integrated on the same molecule unresolved
    • Some axes (SIRT3, TRIM25) rest on single-lab Co-IP/ubiquitination assays
  15. 2025 Medium

    Multiple 2025 studies expanded the regulatory and functional network—competing E3/competitor inputs (FBXL6, ME2), direct complex I assembly via NDUFS8, and intrinsic mPTP channel activity.

    Evidence Linkage-specific K63 ubiquitination by FBXL6; ME2-TRIM25 competition assays; Co-IP with NDUFS8 and complex I activity/RET-ROS measurement; cardiomyocyte/hepatocyte KO with patch-clamp of liposome-reconstituted ATAD3A (preprint)

    PMID:40961994 PMID:40975350 PMID:41876455 PMID:bio_10.1101_2025.06.13.658955

    Open questions at the time
    • Opposing K63-stabilizing versus proteasomal ubiquitination integration unclear
    • mPTP channel finding is a preprint awaiting peer review
    • Direct pore architecture and gating mechanism undefined
  16. 2025 High

    Identification of direct small-molecule binding at the C-terminal L368 residue showed ATAD3A is a druggable target whose stabilization enhances PERK interaction and protects against ischemia-reperfusion.

    Evidence SPR, CETSA, IP-MS, PLA, MAM-SplitGFP, L368 mutant rescue, in vivo MI/R model with thymoquinone

    PMID:40460607

    Open questions at the time
    • Structure of the ligand-binding pocket not solved
    • Selectivity of thymoquinone for ATAD3A not fully characterized
  17. 2026 Medium

    New interactions placed ATAD3A within cuproptosis/lipoylation control via DLST and within CD8+ T-cell exhaustion via PARK7-regulated lactylation, broadening its roles into metabolic cell death and immune metabolism.

    Evidence VSMC-specific KD and overexpression knock-in mice with ATAD3A-DLST Co-IP and lipoylation assays; PARK7 Co-IP, lactylation assay, and T-cell-specific PARK7 KO

    PMID:42162305 PMID:42237912

    Open questions at the time
    • How ATAD3A interaction modulates DLST lipoylation mechanistically unclear
    • PARK7-driven delactylation of ATAD3A rests on single-lab Co-IP/PTM assays

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, sometimes opposing, post-translational modifications and competing partners are integrated to set ATAD3A's oligomeric state and select among its many functions in a context-specific manner remains unresolved.
  • No unified structural model of the monomer-to-oligomer transition
  • Hierarchy among acetylation, phosphorylation, and ubiquitination inputs unknown
  • Whether a single ATAD3A pool serves all functions or distinct subpopulations exist is unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 3 GO:0005198 structural molecule activity 2 GO:0005215 transporter activity 1
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
DRP1NDUFS8PERKPINK1TFAMTIMM23TOMM40TRIM25
Complex memberships
ATAD3A-WASF3-GRP78 complexATAD3A/ATAD3B/ATAD3C inner membrane complexmitochondrial permeability transition pore

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 ATAD3A spans both mitochondrial membranes: its N-terminal domain interacts with the outer membrane (OM), a central transmembrane segment anchors it in the inner membrane (IM), and the C-terminal AAA+ ATPase domain resides in the matrix. Using dominant-negative mutants (defective ATP-binding and truncated N-terminus), ATAD3A was shown to regulate dynamic OM-IM interactions sensed by the fission machinery and is required for normal cell growth and cholesterol channeling at contact sites. Dominant-negative mutant expression, invalidation studies in Drosophila and human steroidogenic cell line, topology/fractionation analysis Molecular and cellular biology High 20154147
2010 The N-terminal region of ATAD3A is accessible from outside the inner membrane (cytoplasm or intermembrane space) while the C-terminal region is located within the matrix, establishing the transmembrane topology of ATAD3A in purified human mitochondria. Back-titration ELISA and immunofluorescence on freshly purified human mitochondria using N-terminal and C-terminal specific anti-peptide antibodies Journal of bioenergetics and biomembranes High 20349121
2010 ATAD3A is a high-affinity, calcium-dependent target of S100B in oligodendrocyte progenitor cells (OPCs). NMR spectroscopy defined the S100B binding motif on ATAD3A. S100B prevents cytoplasmic aggregation of a mitochondrial-import-deficient ATAD3A mutant and restores its mitochondrial localization, suggesting S100B assists in proper ATAD3A folding and subcellular targeting. NMR spectroscopy, Far-Western assay, cellular studies with truncated ATAD3A mutant deficient for mitochondrial import Molecular and cellular biology High 20351179
2012 ATAD3B associates with ATAD3A, negatively regulates ATAD3A interaction with matrix nucleoid complexes, and contributes to mitochondrial fragmentation, functioning as a dominant-negative paralog of ATAD3A. Loss- and gain-of-function approaches in human embryonic stem cells and cancer cells Mitochondrion Medium 22664726
2015 ATAD3A interacts with the WASF3 metastasis-promoting protein and GRP78 in a trimeric complex at the mitochondrial membrane. The N-terminal domain of WASF3 interacts with the N-terminal domain of ATAD3A. Knockdown of ATAD3A leads to decreased WASF3 protein levels and loss of its stability at the mitochondrial membrane; suppression of GRP78 destabilizes WASF3 in an ATAD3A-dependent manner. ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability. Mass spectrometry, co-immunoprecipitation, proteolysis of isolated mitochondria, knockdown experiments with invasion and tumor growth assays Oncogene High 25823022
2016 The dominant-negative ATAD3A p.Arg528Trp variant causes small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. Tissue-specific overexpression of the homologous Drosophila borR534W mutation dramatically decreased mitochondrial content, caused aberrant mitochondrial morphology, and increased autophagy. Homozygous null larvae showed decreased mitochondria; wild-type overexpression produced larger, elongated mitochondria. Patient fibroblasts exhibited increased mitophagy. Drosophila tissue-specific overexpression of dominant-negative mutant, patient fibroblast mitophagy assay, whole-exome sequencing American journal of human genetics High 27640307
2017 ATAD3A interacts with the mitochondrial channel components Tom40 and Tim23 and serves as a bridging factor to facilitate appropriate transportation and processing of the PINK1 mitophagy kinase. Loss of Atad3a causes PINK1 accumulation and hyperactivated mitophagy. Genetic deletion of Pink1 in Atad3a-deficient mice rescued hematopoietic progenitor and HSC pool defects, establishing epistasis: ATAD3A acts upstream of PINK1 to suppress mitophagy. Conditional knockout mice, co-immunoprecipitation with Tom40/Tim23/PINK1, genetic epistasis (double knockout rescue), flow cytometry of hematopoietic compartments Nature immunology High 29242539
2017 A dominant-negative ATAD3A p.G355D mutation in the Walker A motif (responsible for ATP binding) markedly reduces ATPase activity of the recombinant protein. Overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass, and patient fibroblasts and iPSC-derived neurons show altered mitochondrial dynamics and increased lysosomes associated with upregulated autophagy via mTOR inactivation. In vitro ATPase activity assay of recombinant mutant protein, overexpression in cell lines, patient fibroblast and iPSC-neuron analysis Human molecular genetics High 28158749
2019 ATAD3A dimerization (driven by deacetylation at K135) is required for Drp1-mediated mitochondrial fragmentation in Huntington's disease. ATAD3A interacts with the mitochondrial fission GTPase Drp1. Drp1/ATAD3A interaction promotes ATAD3A oligomerization, which impairs TFAM/mtDNA binding and leads to bioenergetic deficits. A blocking peptide (DA1) abolishing Drp1/ATAD3A interaction suppresses oligomerization, reduces mtDNA lesion, and reduces HD neuropathology in transgenic mice. Proteomic analysis, co-immunoprecipitation, acetylation site mutagenesis (K135), peptide-blocking experiments in HD mouse and patient-derived cells, behavioral/neuropathological readouts in transgenic mice Nature communications High 30914652
2021 Upon mitochondrial depolarization, AMBRA1 is recruited to the outer mitochondrial membrane and interacts with both PINK1 and ATAD3A. AMBRA1 promotes PINK1 stability by counteracting ATAD3A-mediated PINK1 degradation by the mitochondrial protease LONP1. Silencing ATAD3A rescues defective PINK1 accumulation in AMBRA1-deficient cells, placing ATAD3A downstream of AMBRA1 in the PINK1-PARKIN mitophagy pathway. Co-immunoprecipitation, AMBRA1 knockdown, ATAD3A silencing rescue experiments, PINK1 ubiquitin phosphorylation assay, PRKN/PARKIN recruitment assay Autophagy High 34798798
2021 Knockdown of ATAD3A in THP-1 cells results in increased type I interferon signaling mediated by cGAS and STING. This enhanced interferon signaling is abrogated when cells are depleted of mitochondrial DNA, establishing that ATAD3A normally prevents mtDNA-driven cGAS-STING activation. ATAD3A knockdown in THP-1 cells, mtDNA depletion rescue, ISG expression measurement, patient fibroblast validation The Journal of experimental medicine High 34387651
2021 ATAD3A associates with multiple components of the inner mitochondrial membrane including OXPHOS complex I, Letm1, and prohibitin complexes. Neuronal-specific Atad3 knockout mice develop severe encephalopathy with aberrant mitochondrial cristae morphogenesis preceding symptoms. STORM microscopy shows ATAD3A is regularly distributed along the inner mitochondrial membrane, supporting a structural scaffolding role in inner membrane organization. Conditional neuronal KO mouse, multi-omics, co-immunoprecipitation with inner membrane components, STORM super-resolution microscopy Cell reports High 34936866
2022 ATAD3A oligomerization accumulates at mitochondria-associated ER membranes (MAMs) in Alzheimer's disease models and inhibits CYP46A1 gene expression, leading to cholesterol accumulation. Suppressing ATAD3A oligomerization (by heterozygous KO or peptide DA1) restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and reduces AD neuropathology and cognitive deficits in 5XFAD mice. 5XFAD mouse model, heterozygous ATAD3A KO, DA1 peptide treatment, CYP46A1 expression analysis, cholesterol turnover assay, APP processing assay, behavioral testing Nature communications High 35236834
2022 ATAD3A mediates nucleoid trafficking inside mitochondria: its ATPase domain directly binds TFAM and mediates nucleoid movement along mitochondria via ATP hydrolysis. ATAD3A oligomerization via coiled-coil domains in the intermembrane space is also required for nucleoid trafficking. ATAD3A deficiency leads to dispersed small nucleoids and enhanced respiratory complex formation. Live imaging of nucleoid dynamics, in vitro binding assay of ATPase domain with TFAM, ATAD3A knockout/mutant analysis, respiratory complex assay Proceedings of the National Academy of Sciences of the United States of America High 36383603
2022 MUC1 translocates to mitochondria and interacts with ATAD3A, inducing its degradation, which protects PINK1 from ATAD3A-mediated cleavage and thereby promotes PINK1-dependent mitophagy. This establishes a MUC1/ATAD3A/PINK1 axis in cancer cell mitophagy. Co-immunoprecipitation, knockdown/overexpression of MUC1 and ATAD3A, mitophagy flux assay, in vivo xenograft Cell death & disease Medium 36289190
2022 ATAD3A binds to ERK1/2 in mitochondria in the presence of VDAC1, and this interaction is essential for activation of mitochondrial ERK1/2 signaling in a RAS-independent manner. Walker A dead mutant (K358) of ATAD3A produces a dominant-negative effect on HNSCC growth. Co-immunoprecipitation, CRISPR/Cas9 knockout, Walker A mutant overexpression, phospho-kinase profiling, orthotopic tumor model Journal of experimental & clinical cancer research Medium 35093151
2023 PINK1 recruits PD-L1 to mitochondria for degradation via mitophagy. ATAD3A suppresses PINK1-dependent mitophagy, preventing mitochondrial redistribution of PD-L1 and thereby maintaining PD-L1 on the tumor cell membrane. Paclitaxel increases ATAD3A expression to restrain PINK1-dependent mitophagy and PD-L1 degradation. Subcellular fractionation, knockdown/overexpression of ATAD3A and PINK1, mitophagy flux assay, PD-L1 localization analysis, patient tumor sample correlation Cell research Medium 36627348
2023 Sigma-1 receptor (σ1R) retains ATAD3A as a monomer at the MAM, inhibiting mitochondrial fragmentation. Loss of σ1R or SOD1-linked ALS conditions cause ATAD3A dimerization and mitochondrial fragmentation. σ1R-mediated MAM formation depends on ATAD3A. σ1R-deficient cells and SOD1-ALS mouse spinal cords, co-immunoprecipitation, native PAGE for ATAD3A oligomeric state, mitochondrial morphology analysis Neurobiology of disease Medium 36736924
2023 ATAD3C incorporates into the ATAD3A complex in the mitochondrial inner membrane as a monomer, reducing complex size and negatively regulating ATAD3A function. ATAD3C overexpression decreases cell proliferation and oxygen consumption and increases ROS, and increases dimeric CIII at the expense of respiratory supercomplexes. ATAD3C overexpression in fibroblasts, native PAGE of ATAD3A complexes, oxygen consumption rate, ROS measurement, respiratory complex analysis Free radical biology & medicine Medium 38092275
2024 ATAD3A interacts with PERK at mitochondria-ER contact sites. During ER stress, PERK-ATAD3A interactions increase, and ATAD3A competes with eIF2α for PERK binding, attenuating local PERK signaling and protecting mitochondria-localized translation from ER stress-induced repression. This protects expression of some mitochondrial proteins. Live-cell imaging of reporter mRNA translation, co-immunoprecipitation, ATAD3A knockdown, proximity ligation assay for MAM contact sites Science High 39116259
2024 SIRT3 deacetylates ATAD3A; acetylation at K134 disrupts ATAD3A self-oligomerization. The ATAD3A monomer (de-oligomerized form) closely interacts with the IP3R1-GRP75-VDAC1 complex at MAMs, leading to mitochondrial calcium overload and dysfunction. SIRT3 knockout mice show excessive MAM formation. Co-immunoprecipitation with IP3R1-GRP75-VDAC1, acetylation site mutagenesis (K134), SIRT3 KO mouse model, mitochondrial calcium measurement, cardiac hypertrophy model International journal of biological sciences Medium 38250153
2024 TBK1 is activated and localizes to mitochondria during cellular senescence, where it directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A suppresses PINK1-mediated mitophagy by facilitating PINK1 mitochondrial import. Blocking ATAD3A phosphorylation at Ser321 (by TBK1 deficiency or S321A mutation) rescues cellular senescence. In vitro kinase assay (TBK1 phosphorylating ATAD3A), phospho-site mutagenesis (S321A), TBK1 KO, blocking peptide (TAT-PEP), PINK1 import assay, senescence markers Advanced science High 39520088
2024 TRIM25 E3 ubiquitin ligase interacts with and ubiquitinates ATAD3A via the proteasome pathway, destabilizing ATAD3A and promoting PINK1/Parkin-dependent mitophagy during cerebral ischemia-reperfusion injury. Co-immunoprecipitation, ubiquitination assay, ATAD3A knockdown/overexpression, TRIM25 manipulation, in vivo MCAO model Free radical biology & medicine Medium 39307194
2025 ME2 (malic enzyme 2) competes with TRIM25 for binding to ATAD3A, disrupting TRIM25-ATAD3A interaction and thereby preventing ATAD3A ubiquitination and degradation. Loss of ME2 strengthens TRIM25-ATAD3A interaction, leading to ATAD3A ubiquitination, proteasomal degradation, PINK1 accumulation, and mitophagy activation. Co-immunoprecipitation, competitive binding assay, ubiquitination assay, ME2 knockdown with PINK1/mitophagy readouts Cell death & disease Medium 41876455
2025 FBXL6 E3 ubiquitin ligase directly targets ATAD3A and induces K63-linked polyubiquitination, which stabilizes ATAD3A (rather than degrading it) and activates aerobic glycolysis to promote TNBC malignancy. Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, ATAD3A knockdown, tumor growth assays in vitro and in vivo International journal of biological macromolecules Medium 40975350
2025 ATAD3A directly interacts with complex I subunit NDUFS8 and is required for complex I assembly and activity. Knockdown of atad-3 reduces complex I activity and proton leakage, increases mitochondrial membrane potential, and thereby induces reverse electron transport (RET)-driven ROS production. Co-immunoprecipitation with NDUFS8, complex I activity assay, mitochondrial membrane potential measurement, ROS measurement in C. elegans and mammalian cells Free radical biology & medicine Medium 40961994
2025 ATAD3A is an essential component of the mitochondrial permeability transition pore (mPTP). Genetic deletion of Atad3 in cardiomyocytes and hepatocytes abolishes Ca2+-induced mPTP-dependent swelling, and patch-clamp recordings of recombinant ATAD3A reconstituted in liposomes reveal intrinsic channel activity. Cardiac-specific Atad3 deletion markedly reduces infarct size following ischemia/reperfusion. Cardiomyocyte/hepatocyte-specific KO, Ca2+-induced mitochondrial swelling assay, patch-clamp of ATAD3A reconstituted in liposomes, I/R infarct size measurement bioRxivpreprint High bio_10.1101_2025.06.13.658955
2025 Thymoquinone (TQ) directly binds ATAD3A at its C-terminal L368 residue (validated by SPR and CETSA), stabilizes ATAD3A protein, and enhances ATAD3A-PERK interaction at MAMs. This preserves MAM integrity, attenuates PERK/eIF2α-mediated ER stress, and restores mitochondrial bioenergetics in myocardial ischemia-reperfusion models. ATAD3A-L368 mutant or PERK inhibition abolishes TQ's protective effects. Surface plasmon resonance (SPR), CETSA, co-immunoprecipitation-mass spectrometry, proximity ligation assay, MAM-SplitGFP system, ATAD3A-L368 mutant rescue experiment, in vivo MI/R mouse model Phytomedicine High 40460607
2026 ATAD3A overexpression reduces mitochondria-lysosome contacts, limits mitochondrial Ca2+ influx, and suppresses the FDXR/FDX1/LIAS lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis in vascular smooth muscle cells, thereby protecting against aortic aneurysm and dissection. ATAD3A interacts with DLST as identified by co-immunoprecipitation. VSMC-specific knockdown and systemic overexpression knock-in mice, co-immunoprecipitation of ATAD3A-DLST, mitochondria-lysosome contact quantification, Ca2+ imaging, lipoylation assay, in vivo AAD models Circulation research Medium 42237912
2026 PARK7 directly interacts with mitochondrial ATAD3A and downregulates its lactylation level, thereby suppressing expression of mitochondrial-related genes and promoting CD8+ T-cell exhaustion. T-cell-specific PARK7 deficiency enhances mitochondrial function in CD8+ T cells and alleviates exhaustion. Co-immunoprecipitation, lactylation modification assay, T-cell specific PARK7 KO, mitochondrial function assays, tumor growth assays Cellular & molecular immunology Medium 42162305

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. American journal of human genetics 144 27640307
2010 The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes. Molecular and cellular biology 138 20154147
2017 Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. Nature immunology 118 29242539
2023 Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. Cell research 102 36627348
2015 Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein. Oncogene 85 25823022
2019 ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects. Nature communications 83 30914652
2020 Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis. Journal of experimental & clinical cancer research : CR 82 33280610
2021 Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A. The Journal of experimental medicine 77 34387651
2021 AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability. Autophagy 69 34798798
2022 ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models. Nature communications 66 35236834
2017 ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Human molecular genetics 66 28158749
2021 ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly. Cell reports 59 34936866
2022 The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization. Cell death & disease 55 36289190
2010 The calcium-dependent interaction between S100B and the mitochondrial AAA ATPase ATAD3A and the role of this complex in the cytoplasmic processing of ATAD3A. Molecular and cellular biology 41 20351179
2010 Topological analysis of ATAD3A insertion in purified human mitochondria. Journal of bioenergetics and biomembranes 40 20349121
2024 PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress. Science (New York, N.Y.) 38 39116259
2021 ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer. Journal of cellular physiology 36 33580514
2022 Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation. Proceedings of the National Academy of Sciences of the United States of America 33 36383603
2020 Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer. International journal of molecular sciences 33 33113782
2012 ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A. Mitochondrion 32 22664726
2024 The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy. International journal of biological sciences 30 38250153
2022 ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development. Journal of experimental & clinical cancer research : CR 30 35093151
2020 Mitochondrial dysfunction caused by novel ATAD3A mutations. Molecular genetics and metabolism 29 32933822
2017 Baculovirus LEF-11 Hijack Host ATPase ATAD3A to Promote Virus Multiplication in Bombyx mori cells. Scientific reports 29 28393927
2021 Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes. Genome medicine 28 33845882
2019 Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities. Molecular genetics and metabolism 27 31727539
2022 Loss of mitochondrial ATPase ATAD3A contributes to nonalcoholic fatty liver disease through accumulation of lipids and damaged mitochondria. The Journal of biological chemistry 23 35513069
2023 ATAD3A: A Key Regulator of Mitochondria-Associated Diseases. International journal of molecular sciences 22 37569886
2019 ATAD3A on the Path to Cancer. Advances in experimental medicine and biology 20 30919342
2023 Sigma-1 receptor maintains ATAD3A as a monomer to inhibit mitochondrial fragmentation at the mitochondria-associated membrane in amyotrophic lateral sclerosis. Neurobiology of disease 15 36736924
2018 Mitochondrial ATAD3A regulates milk biosynthesis and proliferation of mammary epithelial cells from dairy cow via the mTOR pathway. Cell biology international 14 29286187
2024 Ubiquitination of ATAD3A by TRIM25 exacerbates cerebral ischemia-reperfusion injury via regulating PINK1/Parkin signaling pathway-mediated mitophagy. Free radical biology & medicine 12 39307194
2021 miRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a. Oxidative medicine and cellular longevity 12 34413925
2019 Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus. The application of clinical genetics 11 31239750
2023 ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability. Orphanet journal of rare diseases 9 37095554
2023 Harel Yoon syndrome: a novel mutation in ATAD3A gene and expansion of the clinical spectrum. Ophthalmic genetics 8 36856321
2023 Ketogenic Diet Attenuates Refractory Epilepsy of Harel-Yoon Syndrome With ATAD3A Variants: A Case Report and Review of Literature. Pediatric neurology 7 37031571
2024 Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 39520088
2022 Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion. Molecular genetics and metabolism reports 6 36061954
2023 The value of ATAD3A as a potential biomarker for bladder cancer. Cancer medicine 5 38018291
2025 Thymoquinone alleviates myocardial ischemia/reperfusion injury by stabilizing mitochondria-associated membrane homeostasis via targeting ATAD3A. Phytomedicine : international journal of phytotherapy and phytopharmacology 4 40460607
2025 Empagliflozin-pretreated BMSC exosomes attenuate myocardial ischemia-reperfusion injury by enhancing atad3a/pink1-dependent mitophagy. Stem cell research & therapy 4 41163081
2023 Identification of ATAD3A as a key regulator in non-small cell lung cancer by promoting STAT3-induced cell proliferation and tumor angiogenesis. Molecular carcinogenesis 4 38050826
2022 Deletion of ATAD3A inhibits osteogenesis by impairing mitochondria structure and function in pre-osteoblast. Developmental dynamics : an official publication of the American Association of Anatomists 4 36000457
2012 Yeast-based production and purification of HIS-tagged human ATAD3A, A specific target of S100B. Protein expression and purification 4 22542587
2025 P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma. Cell death & disease 2 41053045
2023 "ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane". Free radical biology & medicine 2 38092275
2023 ATAD3A gene variations in a family with Harel-Yoon syndrome. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 2 38105692
2023 Harel-Yoon syndrome caused by a novel variant in ATAD3A: A case report. Heliyon 2 38173481
2026 Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25. Cell death & disease 1 41876455
2025 ATAD3A deficiency induces oxidative eustress via the complex I reverse electron transport. Free radical biology & medicine 1 40961994
2025 Elevated FBXL6 activates ATAD3A through K63-linked polyubiquitination and promotes the malignant progression of TNBC via metabolic reprogramming. International journal of biological macromolecules 1 40975350
2020 Using Genome-Editing Tools to Develop a Novel In Situ Coincidence Reporter Assay for Screening ATAD3A Transcriptional Inhibitors. Methods in molecular biology (Clifton, N.J.) 1 32219745
2026 Single-cell transcriptomic analysis and machine learning identify ATAD3A as a key gene that stabilizes mitochondrial-endoplasmic reticulum membranes, promoting bladder cancer progression. Journal of translational medicine 0 41715136
2026 ATAD3A promotes bladder cancer progression by regulating glycolysis through MYC stabilization. Journal of translational medicine 0 42001122
2026 PARK7-induced delactylation of ATAD3A impairs mitochondrial fitness to promote exhaustion of tumor-infiltrating CD8+ T cells. Cellular & molecular immunology 0 42162305
2026 ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation. Circulation research 0 42237912
2025 Clinical characteristics and induced pluripotent stem cells (iPSCs) disease model of Harel-Yoon syndrome caused by compound heterozygous ATAD3A variants. Human cell 0 40246775
2025 Allele-specific correction of ATAD3A pathogenic variants via template-free CRISPR-Cas9 editing and gene conversion. bioRxiv : the preprint server for biology 0 41280066
2025 [A case of Harel-Yoon syndrome with seizures caused by an ATAD3A variant]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 0 41401963

Missed literature

Know a paper Affinage missed for ATAD3A? Flag it for the maintainers and the community.

No submissions yet.