Affinage

ATAD3B

ATPase family AAA domain-containing protein 3B · UniProt Q5T9A4

Length
648 aa
Mass
72.6 kDa
Annotated
2026-06-09
28 papers in source corpus 4 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATAD3B is a mitochondrial membrane protein that acts as a stress-responsive mitophagy receptor for selective clearance of damaged mitochondrial DNA (PMID:33665835). Under basal conditions it hetero-oligomerizes with ATAD3A, which targets the ATAD3B C-terminus to the intermembrane space and negatively regulates ATAD3A's interaction with matrix nucleoid complexes, positioning ATAD3B as a dominant-negative modulator of ATAD3A whose loss perturbs mitochondrial morphology (PMID:33665835, PMID:22664726). Oxidative stress-induced mtDNA damage or depletion disrupts the ATAD3B-ATAD3A hetero-oligomer, exposing the ATAD3B C-terminus at the outer mitochondrial membrane where its LIR motif directly binds LC3 to initiate mitophagy independently of PINK1 (PMID:33665835). This pathway is functionally consequential: ATAD3B re-expression promotes clearance of pathogenic m.3243A>G mutant mtDNA (PMID:33665835). ATAD3B is encoded as two mitochondrially localized isoforms that are early transcriptional targets of c-Myc and are required for normal cell division, with knockdown producing polynuclear cells, reduced proliferation, and apoptosis (PMID:16909202). At mitochondria-associated membranes, the ER protein SEC62 directly binds ATAD3B and suppresses its expression, dampening mitophagy and amplifying mitochondrial ROS and inflammation (PMID:42001994).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2006 Medium

    Establishing that the ATAD3B locus produces mitochondrial protein isoforms under c-Myc control and is needed for faithful cell division placed the gene within mitochondrial biology and growth regulation rather than leaving it uncharacterized.

    Evidence RT-PCR, Western blot, siRNA knockdown, flow cytometry and c-Myc target validation in cultured cells

    PMID:16909202

    Open questions at the time
    • Molecular basis of the cell-division requirement not defined
    • No mechanistic link drawn yet to mitophagy or ATAD3A
    • Functional difference between the two isoforms unresolved
  2. 2012 Medium

    Identifying ATAD3B as a hetero-oligomerization partner that antagonizes ATAD3A nucleoid interactions reframed it from a standalone protein to a dominant-negative regulator of ATAD3A and mitochondrial morphology.

    Evidence Co-immunoprecipitation and mitochondrial morphology assays in hESCs and cancer cells

    PMID:22664726

    Open questions at the time
    • Stoichiometry and structural basis of hetero-oligomerization unknown
    • Single-lab Co-IP with two methods
    • Physiological trigger that modulates the ATAD3A-ATAD3B balance not identified
  3. 2021 High

    Discovery of a functional LIR motif that binds LC3 and drives PINK1-independent mitophagy defined the core molecular activity of ATAD3B as a mitophagy receptor, and coupling this to stress-induced loss of ATAD3A oligomerization explained how the receptor is conditionally activated; rescue of mutant mtDNA clearance established physiological relevance.

    Evidence LIR identification, LC3 binding assay, PINK1-independence, reciprocal Co-IP, subcellular fractionation, and mtDNA clearance in m.3243A>G/MELAS cells

    PMID:33665835

    Open questions at the time
    • Structural detail of LIR-LC3 engagement not resolved
    • How mtDNA damage is sensed upstream of oligomer disruption unknown
    • Selectivity for damaged versus healthy nucleoids not mechanistically defined
  4. 2026 Medium

    Identifying SEC62 as a direct MAM-resident binder that suppresses ATAD3B added a regulatory input controlling ATAD3B-dependent mitophagy and linked the pathway to ROS and inflammatory disease (MASH).

    Evidence Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, mitophagy and ROS assays

    PMID:42001994

    Open questions at the time
    • Single-lab, single-study Co-IP without reciprocal/structural validation
    • Mechanism by which SEC62 suppresses ATAD3B expression unclear
    • Whether SEC62 acts on the oligomerization or LIR steps not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream mtDNA damage is sensed and transduced into ATAD3B-ATAD3A hetero-oligomer disruption, and the structural basis of the receptor's stress-dependent reorientation, remain open.
  • No structural model of the ATAD3A-ATAD3B complex or its disassembly
  • Damage-sensing trigger upstream of oligomer disruption unidentified
  • Relationship between cell-division role and mitophagy role unintegrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-9612973 Autophagy 1
Partners
ATAD3AMAP1LC3BSEC62

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 ATAD3B contains a LIR (LC3-interacting region) motif that directly binds LC3 and functions as a mitophagy receptor, promoting oxidative stress-induced mitophagy in a PINK1-independent manner to clear damaged mtDNA. Loss- and gain-of-function experiments, LIR motif identification, LC3 binding assay, mitophagy assay in cells The EMBO journal High 33665835
2021 Under normal conditions, ATAD3B hetero-oligomerizes with ATAD3A, which promotes targeting of the ATAD3B C-terminal region to the mitochondrial intermembrane space. Oxidative stress-induced mtDNA damage or depletion reduces this ATAD3B-ATAD3A hetero-oligomerization, leading to exposure of the ATAD3B C-terminus at the mitochondrial outer membrane and subsequent LC3 recruitment for mitophagy initiation. Co-immunoprecipitation, subcellular fractionation, oxidative stress treatment, mtDNA depletion, fluorescence microscopy The EMBO journal High 33665835
2012 ATAD3B associates with ATAD3A (hetero-oligomerization), negatively regulates the interaction of ATAD3A with matrix nucleoid complexes, and contributes to a mitochondrial fragmentation phenotype. ATAD3B thus functions as a dominant negative regulator of ATAD3A. Loss- and gain-of-function approaches, Co-immunoprecipitation, mitochondrial morphology assays in hESCs and cancer cells Mitochondrion Medium 22664726
2006 The ATAD3B gene encodes two distinct protein isoforms (AAA-TOB3s and AAA-TOB3l) generated from distinct transcription initiation sites, both localized to mitochondria. Both isoforms are early transcriptional targets of c-Myc. Knockdown of both isoforms results in polynuclear cells, decreased proliferation, dysfunctional cell division, and increased apoptosis, indicating a required role in cell division. RT-PCR, Western blot, siRNA knockdown, flow cytometry, immunofluorescence microscopy, c-Myc target validation Cellular and molecular life sciences : CMLS Medium 16909202
2026 SEC62, an ER transmembrane protein at mitochondria-associated membranes (MAMs), directly interacts with ATAD3B and suppresses ATAD3B expression, leading to defective mitophagy, increased mitochondrial ROS, and amplified inflammatory responses in MASH. Co-immunoprecipitation, hepatocyte-specific overexpression and knockout, Western blot, mitophagy assay, ROS measurement Metabolism: clinical and experimental Medium 42001994
2021 ATAD3B re-expression in cells with m.3243A>G mutated mtDNA promotes clearance of the mutant mtDNA, demonstrating a functional role of ATAD3B-mediated mitophagy in eliminating pathogenic mtDNA variants. ATAD3B overexpression in MELAS patient fibroblasts and m.3243A>G mutated cells, mtDNA quantification The EMBO journal Medium 33665835

Source papers

Stage 0 corpus · 28 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
2021 ATAD3B is a mitophagy receptor mediating clearance of oxidative stress-induced damaged mitochondrial DNA. The EMBO journal 112 33665835
2017 ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain : a journal of neurology 109 28549128
2010 ATPase family AAA domain-containing 3A is a novel anti-apoptotic factor in lung adenocarcinoma cells. Journal of cell science 80 20332122
2017 ATAD3 proteins: brokers of a mitochondria-endoplasmic reticulum connection in mammalian cells. Biological reviews of the Cambridge Philosophical Society 76 28941010
2004 Profile identification of disease-associated humoral antigens using AMIDA, a novel proteomics-based technology. Cellular and molecular life sciences : CMLS 57 15141305
2017 Three TOB1-related YABBY genes are required to maintain proper function of the spikelet and branch meristems in rice. The New phytologist 51 28556940
2012 ATAD3, a vital membrane bound mitochondrial ATPase involved in tumor progression. Journal of bioenergetics and biomembranes 48 22318359
2017 Machine Learning-Assisted Network Inference Approach to Identify a New Class of Genes that Coordinate the Functionality of Cancer Networks. Scientific reports 45 28765560
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
2019 Novel ATAD3A recessive mutation associated to fatal cerebellar hypoplasia with multiorgan involvement and mitochondrial structural abnormalities. Molecular genetics and metabolism 27 31727539
2020 NEK10 interactome and depletion reveal new roles in mitochondria. Proteome science 26 32368190
2006 Molecular characterization of the tumor-associated antigen AAA-TOB3. Cellular and molecular life sciences : CMLS 26 16909202
2013 Expression analysis of ATAD3 isoforms in rodent and human cell lines and tissues. Gene 23 24239551
2022 ATAD3B and SKIL polymorphisms associated with antipsychotic-induced QTc interval change in patients with schizophrenia: a genome-wide association study. Translational psychiatry 18 35136033
2022 Epigenome-wide DNA methylation study of whole blood in patients with sporadic amyotrophic lateral sclerosis. Chinese medical journal 18 35853630
2019 Differentially Expressed Mitochondrial Proteins in Human MCF7 Breast Cancer Cells Resistant to Paclitaxel. International journal of molecular sciences 13 31248089
2023 Circ_ATAD3B inhibits cell proliferation of breast cancer via mediating the miR-570-3p/MX2 axis. Preventive medicine 6 37286092
2022 Severe spinal cord hypoplasia due to a novel ATAD3A compound heterozygous deletion. Molecular genetics and metabolism reports 6 36061954
2022 CRISPR/Cas9-induced gene conversion between ATAD3 paralogs. HGG advances 3 35199044
2022 Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products. BMC cancer 3 35525914
2023 "ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane". Free radical biology & medicine 2 38092275
2017 Increased AAA-TOB3 correlates with lymph node metastasis and advanced stage of lung adenocarcinoma. The International journal of biological markers 2 28623644
2011 [ATAD3, a vital membrane-bound mitochondrial ATPase involved in tumor progression]. Medecine sciences : M/S 2 22192748
2025 Exploring potential therapeutic targets for colorectal tumors based on whole genome sequencing of colorectal tumors and paracancerous tissues. Frontiers in molecular biosciences 1 40688112
2026 SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control. Metabolism: clinical and experimental 0 42001994
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 Multiomics analyses of human colorectal cancer reveal changes in mitochondrial metabolism associated with chemotherapy resistance. Frontiers in oncology 0 41293266

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