id: Q9NVI7 gene_symbol: ATAD3A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATAD3A encodes a mitochondrial AAA+ ATPase that is anchored in the mitochondrial inner membrane, enriched at inner/outer membrane and mitochondria-ER contact regions, and associated with mitochondrial nucleoids. It supports mitochondrial network organization, mtDNA/nucleoid organization, and mitochondrial protein synthesis, and it can participate in stress-response signaling from mitochondria, including PERK modulation at mitochondria-ER contact sites and HRI-mediated integrated stress response signaling after mitochondrial DNA breaks. alternative_products: - name: '2' id: Q9NVI7-2 - name: '1' id: Q9NVI7-1 sequence_note: VSP_062536 - name: '3' id: Q9NVI7-3 sequence_note: VSP_062535 existing_annotations: - term: id: GO:0005739 label: mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- Phylogenetic inference to mitochondrion is consistent with experimental localization of ATAD3A to mitochondria and the mitochondrial inner membrane/nucleoid region. action: ACCEPT reason: >- ATAD3A is a mitochondrial AAA+ protein with multiple independent experimental localization studies. This cellular component captures a core location. supported_by: - reference_id: PMID:20154147 supporting_text: The N-terminal domain interacts with the OM - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - term: id: GO:0007005 label: mitochondrion organization evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- ATAD3A is required for normal mitochondrial network organization and dynamic inner/outer membrane interactions. action: ACCEPT reason: >- Mitochondrion organization is a core process for ATAD3A, supported by dominant-negative and depletion phenotypes affecting mitochondrial morphology and membrane interactions. supported_by: - reference_id: PMID:20154147 supporting_text: ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- ATP binding is consistent with the conserved AAA+ ATPase domain and mutational evidence from ATAD3A functional studies. action: ACCEPT reason: >- ATP binding is an intrinsic molecular feature of the ATAD3A AAA+ ATPase domain and supports the core ATP hydrolysis activity. supported_by: - reference_id: PMID:20154147 supporting_text: positions the C-terminal AAA(+) ATPase domain in the matrix - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- UniProt subcellular-location mapping to mitochondrial inner membrane is supported by experimental topology and membrane-association studies. action: ACCEPT reason: >- The inner-membrane assignment is well supported and is a core location for ATAD3A function. supported_by: - reference_id: PMID:20154147 supporting_text: central transmembrane segment (TMS) anchors the protein in the IM - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- ATP hydrolysis activity is consistent with ATAD3A being a functional AAA+ ATPase. action: ACCEPT reason: >- The catalytic ATPase activity is a core molecular function of ATAD3A. supported_by: - reference_id: PMID:17210950 supporting_text: The ATPase of ATAD3 is functional - reference_id: PMID:20154147 supporting_text: positions the C-terminal AAA(+) ATPase domain in the matrix - term: id: GO:0042645 label: mitochondrial nucleoid evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- Mitochondrial nucleoid localization is supported by ATAD3A colocalization with mtDNA/nucleoids and effects on nucleoid organization. action: ACCEPT reason: >- ATAD3A is not necessarily a core mtDNA-packaging protein in all nucleoids, but its nucleoid association and nucleoid-organizing role are well supported. supported_by: - reference_id: PMID:17210950 supporting_text: human ATAD3 is a component of many, but not all, mitochondrial nucleoids - reference_id: PMID:18063578 supporting_text: Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22664726 qualifier: enables review: summary: >- ATAD3A interacts with ATAD3B and HSPD1 in the cited study, but GO:0005515 protein binding is too generic to capture the functional implication. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction is real, but protein binding alone is uninformative and should not be treated as a molecular-function annotation for ATAD3A. The biologically meaningful context is mitochondrial homeostasis/nucleoid regulation. supported_by: - reference_id: PMID:22664726 supporting_text: ATAD3B associates with the ubiquitous ATAD3A species - reference_id: PMID:22664726 supporting_text: negatively regulates the interaction of ATAD3A with matrix nucleoid complexes - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30914652 qualifier: enables review: summary: >- ATAD3A interacts with Drp1/DNM1L in neurodegeneration models, but the generic protein binding term is not an informative GO molecular function. action: MARK_AS_OVER_ANNOTATED reason: >- The direct evidence supports a Drp1-ATAD3A mitochondrial-fragmentation mechanism, not a broad protein-binding function term. supported_by: - reference_id: PMID:30914652 supporting_text: ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. - reference_id: PMID:30914652 supporting_text: ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- Orthology-based mitochondrion localization is consistent with experimental human ATAD3A localization. action: ACCEPT reason: >- ATAD3A is robustly mitochondrial; this is a correct cellular-component annotation. supported_by: - reference_id: PMID:20332122 supporting_text: Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA immunofluorescence mitochondrion localization agrees with the curated mitochondrial literature. action: ACCEPT reason: >- The mitochondrion location is correct and supported by independent experimental studies. supported_by: - reference_id: PMID:20332122 supporting_text: Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. - reference_id: PMID:20154147 supporting_text: The N-terminal domain interacts with the OM - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: EXP original_reference_id: PMID:18063578 qualifier: located_in review: summary: >- Mitochondrial inner membrane localization is supported, with PMID:18063578 refining ATAD3A as peripheral to nucleoids rather than a core mtDNA-crosslinked protein. action: ACCEPT reason: >- The cellular-component term is correct. The evidence should be interpreted as inner-membrane/nucleoid-associated localization, not necessarily direct mtDNA core binding. supported_by: - reference_id: PMID:18063578 supporting_text: Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA - reference_id: PMID:18063578 supporting_text: translation and complex assembly may occur in the peripheral region - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: EXP original_reference_id: PMID:20332122 qualifier: located_in review: summary: >- The lung adenocarcinoma study confirms experimental ATAD3A detection; mitochondrial inner-membrane localization is supported by the broader ATAD3A topology literature. action: ACCEPT reason: >- The term captures a well-supported core cellular location, even though the cited paper focuses on cancer phenotypes. supported_by: - reference_id: PMID:20332122 supporting_text: Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. - reference_id: PMID:20332122 supporting_text: Our results show that ATAD3A is the major form expressed in LADC. - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IMP original_reference_id: PMID:39116259 qualifier: enables review: summary: >- ATAD3A is a AAA+ ATPase. The cited PERK paper uses ATPase mutants to separate PERK inhibition from ATPase activity, while other ATAD3A studies support ATPase activity as core. action: ACCEPT reason: >- ATP hydrolysis is an intrinsic ATAD3A molecular function. The specific PERK-inhibition mechanism appears ATPase-independent, but that does not invalidate ATAD3A ATPase activity. supported_by: - reference_id: PMID:17210950 supporting_text: The ATPase of ATAD3 is functional - reference_id: PMID:20154147 supporting_text: positions the C-terminal AAA(+) ATPase domain in the matrix - term: id: GO:0030291 label: protein serine/threonine kinase inhibitor activity evidence_type: IDA original_reference_id: PMID:39116259 qualifier: enables review: summary: >- ATAD3A inhibits PERK kinase signaling at mitochondria-ER contacts during ER stress. action: KEEP_AS_NON_CORE reason: >- The PERK inhibitor activity is experimentally supported and biologically meaningful, but it is a context-specific stress-response function rather than the core AAA ATPase/nucleoid/mitochondrial-organization role. supported_by: - reference_id: PMID:39116259 supporting_text: ATAD3A interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) - reference_id: PMID:39116259 supporting_text: ATAD3A binding attenuated local PERK signaling - term: id: GO:0044233 label: mitochondria-associated endoplasmic reticulum membrane contact site evidence_type: IDA original_reference_id: PMID:39116259 qualifier: is_active_in review: summary: >- ATAD3A is active at mitochondria-associated ER membrane contact sites during ER stress through its PERK interaction. action: KEEP_AS_NON_CORE reason: >- This contact-site localization is supported, but it describes a stress-regulated sublocation rather than the primary mitochondrial inner-membrane/nucleoid location. supported_by: - reference_id: PMID:39116259 supporting_text: PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. - term: id: GO:1903898 label: negative regulation of PERK-mediated unfolded protein response evidence_type: IDA original_reference_id: PMID:39116259 qualifier: involved_in review: summary: >- ATAD3A negatively regulates local PERK-mediated unfolded-protein-response signaling to preserve mitochondrial protein synthesis during ER stress. action: KEEP_AS_NON_CORE reason: >- This is a real, experimentally supported stress-context function, but it is secondary to the core mitochondrial AAA ATPase/nucleoid/organization functions. supported_by: - reference_id: PMID:39116259 supporting_text: ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. - reference_id: PMID:39116259 supporting_text: active translation at mitochondria was significantly protected - term: id: GO:0005524 label: ATP binding evidence_type: IMP original_reference_id: PMID:20154147 qualifier: enables review: summary: >- ATP binding is supported by ATAD3A AAA+ domain function and ATP-sensitive oligomer/membrane interaction phenotypes. action: ACCEPT reason: >- This is a core molecular feature of the ATAD3A AAA+ ATPase. supported_by: - reference_id: PMID:20154147 supporting_text: positions the C-terminal AAA(+) ATPase domain in the matrix - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: IDA original_reference_id: PMID:20154147 qualifier: is_active_in review: summary: >- ATAD3A acts at mitochondrial inner/outer membrane contact regions, anchored in the mitochondrial inner membrane. action: ACCEPT reason: >- The mitochondrial inner membrane is a core location for ATAD3A and is directly supported by topology experiments. supported_by: - reference_id: PMID:20154147 supporting_text: central transmembrane segment (TMS) anchors the protein in the IM - reference_id: PMID:20154147 supporting_text: ATAD3A is required for normal cell growth and cholesterol channeling at contact sites. - term: id: GO:0007005 label: mitochondrion organization evidence_type: IMP original_reference_id: PMID:20154147 qualifier: involved_in review: summary: >- ATAD3A controls mitochondrial dynamics and organization at inner/outer membrane interfaces. action: ACCEPT reason: >- Mitochondrion organization is one of the best-supported ATAD3A biological-process terms. supported_by: - reference_id: PMID:20154147 supporting_text: ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IMP original_reference_id: PMID:20154147 qualifier: enables review: summary: >- ATAD3A ATPase activity is supported by its AAA+ domain and functional studies. action: ACCEPT reason: >- ATP hydrolysis activity is a core molecular function of ATAD3A. supported_by: - reference_id: PMID:17210950 supporting_text: The ATPase of ATAD3 is functional - reference_id: PMID:20154147 supporting_text: positions the C-terminal AAA(+) ATPase domain in the matrix - term: id: GO:0005739 label: mitochondrion evidence_type: HTP original_reference_id: PMID:34800366 qualifier: located_in review: summary: >- High-throughput mitochondrial proteome evidence is consistent with ATAD3A being a mitochondrial protein. action: ACCEPT reason: >- Although high-throughput, this annotation agrees with strong targeted evidence for mitochondrial localization. supported_by: - reference_id: PMID:34800366 supporting_text: A systematic analysis of mitochondrial protein dynamics is essential toward an understanding of mitochondrial proteostasis and its regulation under physiological and pathophysiological conditions. - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - term: id: GO:0006974 label: DNA damage response evidence_type: IDA original_reference_id: PMID:37832546 qualifier: involved_in review: summary: >- PMID:37832546 supports ATAD3A participation in mtDNA-break-triggered integrated stress response signaling, not a broad DNA damage response or DNA repair role. action: MODIFY reason: >- The cited evidence places ATAD3A between damaged mitochondrial genomes and the inner membrane to promote DELE1-HRI/eIF2alpha integrated stress response signaling. A generic DNA damage response annotation is too broad. proposed_replacement_terms: - id: GO:0140468 label: HRI-mediated signaling - id: GO:0140467 label: integrated stress response signaling supported_by: - reference_id: PMID:37832546 supporting_text: mtDSBs triggered the integrated stress response (ISR) - reference_id: PMID:37832546 supporting_text: we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. - term: id: GO:0140468 label: HRI-mediated signaling evidence_type: IDA original_reference_id: PMID:37832546 qualifier: acts_upstream_of review: summary: >- ATAD3A acts upstream of HRI-mediated signaling after mitochondrial DNA breaks. action: KEEP_AS_NON_CORE reason: >- This signaling role is supported, but it is a stress-response context rather than the primary housekeeping role in mitochondrial organization/nucleoids/translation. supported_by: - reference_id: PMID:37832546 supporting_text: cells with mtDNA breaks activate the ISR in a DELE1-HRI-dependent manner - reference_id: PMID:37832546 supporting_text: ATAD3A, an AAA+ ATPase located at the inner mitochondrial membrane (IMM), as a factor that potentially signals from defective genomes to mitochondrial membranes. - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: IDA original_reference_id: PMID:20349121 qualifier: located_in review: summary: >- Topological analysis supports ATAD3A as a mitochondrial inner membrane-associated protein with the C-terminal region facing the matrix. action: ACCEPT reason: >- This is a well-supported core location. supported_by: - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - reference_id: PMID:20349121 supporting_text: the N-terminal part of ATAD3A is outside the inner membrane and that the C-terminal part is inside the matrix - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31522117 qualifier: enables review: summary: >- ATAD3A participates in a mitochondrial scaffold/interactome with CLPB and MAVS-related antiviral signaling components, but GO:0005515 protein binding is too generic. action: MARK_AS_OVER_ANNOTATED reason: >- The interaction evidence is better captured by the antiviral innate immune response context. Generic protein binding should not be retained as an informative ATAD3A molecular-function annotation. supported_by: - reference_id: PMID:31522117 supporting_text: AKAP1 and ATAD3A both co-immunoprecipitated with endogenous MAVS - reference_id: PMID:31522117 supporting_text: CLPB bridges PHB complexes (IMM) and MAVS (OMM) with the assistance of AKAP1 and ATAD3A at the IMS and invokes an immune response from the mitochondrial signalosome - term: id: GO:0140374 label: antiviral innate immune response evidence_type: IMP original_reference_id: PMID:31522117 qualifier: involved_in review: summary: >- ATAD3A contributes to mitochondrial antiviral innate immune signaling in a CLPB/PHB/MAVS scaffold context. action: KEEP_AS_NON_CORE reason: >- The antiviral phenotype is supported, but it is a specialized signaling context rather than the central ATAD3A mitochondrial organization/nucleoid/translation function. supported_by: - reference_id: PMID:31522117 supporting_text: depletion of these molecules in the cells exhibited strikingly defective antiviral innate immune responses against SeV infection - reference_id: PMID:31522117 supporting_text: CLPB bridges PHB complexes (IMM) and MAVS (OMM) with the assistance of AKAP1 and ATAD3A at the IMS and invokes an immune response from the mitochondrial signalosome - term: id: GO:0001558 label: regulation of cell growth evidence_type: IMP original_reference_id: PMID:20332122 qualifier: involved_in review: summary: >- ATAD3A depletion and expression changes affect lung adenocarcinoma survival and drug-response phenotypes. action: KEEP_AS_NON_CORE reason: >- Cell-growth regulation is a real phenotype in the cited cancer context, but it is downstream of the mitochondrial role rather than a core ATAD3A process term. supported_by: - reference_id: PMID:20332122 supporting_text: Serum deprivation increased ATAD3A expression and drug resistance. - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: PMID:20332122 qualifier: located_in review: summary: >- The cited lung adenocarcinoma study confirms ATAD3A detection, while independent topology evidence supports mitochondrial localization. action: ACCEPT reason: >- The mitochondrion location is correct and consistent with many independent ATAD3A studies. supported_by: - reference_id: PMID:20332122 supporting_text: Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. - reference_id: PMID:20349121 supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - term: id: GO:0043066 label: negative regulation of apoptotic process evidence_type: IMP original_reference_id: PMID:20332122 qualifier: involved_in review: summary: >- ATAD3A depletion sensitizes lung adenocarcinoma cells to cisplatin and is interpreted as anti-apoptotic in that cancer setting. action: KEEP_AS_NON_CORE reason: >- The apoptotic phenotype is supported but cancer-contextual and downstream of mitochondrial homeostasis, not a core molecular function of ATAD3A. supported_by: - reference_id: PMID:20332122 supporting_text: Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity. - reference_id: PMID:20332122 supporting_text: These results suggest that ATAD3A could be an anti-apoptotic marker in LADC. - term: id: GO:0032042 label: mitochondrial DNA metabolic process evidence_type: IMP original_reference_id: PMID:22453275 qualifier: involved_in review: summary: >- NEW annotation. ATAD3A supports mitochondrial DNA/nucleoid maintenance and replication-associated organization at the inner membrane. action: NEW reason: >- ATAD3A is repeatedly linked to mitochondrial nucleoid organization and mtDNA maintenance/replication. The current GOA captures mitochondrial nucleoid location but not the related mitochondrial DNA process. GO:0032042 is preferable to obsolete GO:0000002. supported_by: - reference_id: PMID:22453275 supporting_text: Altered ATAD3 expression also perturbs mtDNA maintenance and replication. - reference_id: PMID:17210950 supporting_text: altered the structure of mitochondrial nucleoids and led to the dissociation of mitochondrial DNA fragments held together by protein, specifically, ones containing the D-loop region - reference_id: file:human/ATAD3A/ATAD3A-deep-research-manual.md supporting_text: The core evidence supports mitochondrial organization, ATP hydrolysis, mitochondrial nucleoid organization, mtDNA maintenance, and support of mitochondrial protein synthesis. - term: id: GO:0032543 label: mitochondrial translation evidence_type: IMP original_reference_id: PMID:22453275 qualifier: involved_in review: summary: >- NEW annotation. ATAD3A is required for mitochondrial protein synthesis and binds the mitochondrial ribosome. action: NEW reason: >- PMID:22453275 directly supports a role for ATAD3A in mitochondrial protein synthesis. This is part of the synthesized core ATAD3A function and is not currently represented in GOA. supported_by: - reference_id: PMID:22453275 supporting_text: Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. - reference_id: file:human/ATAD3A/ATAD3A-deep-research-manual.md supporting_text: ATAD3A encodes a mitochondrial AAA+ ATPase located mainly at the mitochondrial inner membrane, enriched near inner/outer membrane contact sites and associated with mitochondrial nucleoids. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:18063578 title: The layered structure of human mitochondrial DNA nucleoids. findings: - statement: ATAD3 is associated with native nucleoids but does not cross-link to mtDNA, supporting a peripheral/layered nucleoid interpretation. supporting_text: Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA - id: PMID:20154147 title: The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes. findings: - statement: ATAD3A spans mitochondrial membrane interfaces with an N-terminal outer-membrane-facing region, inner-membrane anchoring segment, and matrix-facing AAA+ ATPase domain. supporting_text: The N-terminal domain interacts with the OM - statement: ATAD3A regulates mitochondrial inner/outer membrane interactions and mitochondrial dynamics. supporting_text: ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. - id: PMID:20332122 title: ATPase family AAA domain-containing 3A is a novel anti-apoptotic factor in lung adenocarcinoma cells. findings: - statement: ATAD3A is experimentally detected in lung adenocarcinoma and supports survival/drug-response phenotypes. supporting_text: Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. - statement: ATAD3A silencing increases mitochondrial fragmentation and cisplatin sensitivity in lung adenocarcinoma cells. supporting_text: Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity. - id: PMID:20349121 title: Topological analysis of ATAD3A insertion in purified human mitochondria. findings: - statement: ATAD3A is a mitochondrial inner membrane-associated protein with N- and C-terminal topology across the inner membrane. supporting_text: ATAD3 is a mitochondrial inner membrane-associated protein - id: PMID: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. findings: - statement: ATAD3B associates with ATAD3A and negatively regulates ATAD3A interaction with matrix nucleoid complexes. supporting_text: ATAD3B associates with the ubiquitous ATAD3A species - id: PMID:30914652 title: ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects. findings: - statement: ATAD3A interacts with Drp1 and links mitochondrial fragmentation to mtDNA damage and bioenergetic defects in neurodegeneration models. supporting_text: ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance - id: PMID:31522117 title: 'Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region.' findings: - statement: ATAD3A participates in a mitochondrial CLPB/PHB/MAVS scaffold required for antiviral innate immune signaling. supporting_text: CLPB bridges PHB complexes (IMM) and MAVS (OMM) with the assistance of AKAP1 and ATAD3A at the IMS and invokes an immune response from the mitochondrial signalosome - id: PMID:34800366 title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. findings: [] - id: PMID:37832546 title: Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis. findings: - statement: ATAD3A participates in mitochondrial DNA break-triggered ISR signaling from damaged genomes to the inner membrane. supporting_text: we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. - statement: Mitochondrial DNA breaks activate integrated stress response signaling. supporting_text: mtDSBs triggered the integrated stress response (ISR) - id: PMID:39116259 title: PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress. findings: - statement: ATAD3A binds PERK during ER stress and forms mitochondria-ER contact sites. supporting_text: PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. - statement: ATAD3A attenuates local PERK signaling and helps preserve mitochondrial protein synthesis during ER stress. supporting_text: ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. - id: PMID:17210950 title: The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. findings: - statement: ATAD3 is a mitochondrial nucleoid-associated AAA+ protein with D-loop binding properties. supporting_text: human ATAD3 is a component of many, but not all, mitochondrial nucleoids - statement: ATAD3 depletion alters mitochondrial nucleoid structure and affects protein-bound D-loop-containing mtDNA fragments. supporting_text: altered the structure of mitochondrial nucleoids and led to the dissociation of mitochondrial DNA fragments held together by protein, specifically, ones containing the D-loop region - statement: ATAD3 has functional ATPase activity. supporting_text: The ATPase of ATAD3 is functional - id: PMID:22453275 title: Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis. findings: - statement: ATAD3 supports mitochondrial protein synthesis and binds mitochondrial ribosomes. supporting_text: Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. - statement: Altered ATAD3 expression perturbs mtDNA maintenance and replication. supporting_text: Altered ATAD3 expression also perturbs mtDNA maintenance and replication. - id: file:human/ATAD3A/ATAD3A-deep-research-manual.md title: Manual deep research synthesis for ATAD3A findings: - statement: Provider-backed deep research was unavailable, so this review used a manual synthesis. supporting_text: Falcon deep research was requested but timed out after 600 seconds, and the configured Perplexity fallback failed with an insufficient-quota 401 error. - statement: The PN mitophagy projection was not propagated for ATAD3A. supporting_text: 'Manual synthesis decision: ATAD3A is not currently supported as a direct mitophagy cargo-marking or PINK/PRKN pathway factor.' - id: file:human/ATAD3A/ATAD3A-notes.md title: Curator notes for ATAD3A PN review findings: - statement: The Proteostasis PN mitophagy projection was evaluated conservatively and not added. supporting_text: I did not add GO:0000423 mitophagy. - statement: Generic protein binding annotations were marked as over-annotations. supporting_text: Marked generic protein binding annotations as over-annotated. core_functions: - description: >- ATAD3A functions as a mitochondrial inner-membrane AAA+ ATPase/scaffold at contact-site and nucleoid-adjacent regions, supporting mitochondrial network organization, mtDNA/nucleoid organization, and mitochondrial protein synthesis. molecular_function: id: GO:0016887 label: ATP hydrolysis activity directly_involved_in: - id: GO:0007005 label: mitochondrion organization - id: GO:0032042 label: mitochondrial DNA metabolic process - id: GO:0032543 label: mitochondrial translation locations: - id: GO:0005743 label: mitochondrial inner membrane - id: GO:0042645 label: mitochondrial nucleoid supported_by: - reference_id: PMID:20154147 supporting_text: ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery. - reference_id: PMID:17210950 supporting_text: human ATAD3 is a component of many, but not all, mitochondrial nucleoids - reference_id: PMID:22453275 supporting_text: Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. proposed_new_terms: [] suggested_questions: - question: >- Does endogenous ATAD3A have a direct PINK1/PRKN-dependent cargo-marking, receptor-regulatory, or mitophagic-flux role that is separable from secondary consequences of mitochondrial fragmentation and mtDNA damage? - question: >- Should ATAD3A receive an explicit mitochondrial translation or mitochondrial genome maintenance annotation based on PMID:22453275 and PMID:17210950, and if so what evidence code and term granularity best reflect a scaffold/support role? suggested_experiments: - description: >- Test ATAD3A loss, rescue, ATPase mutants, and oligomerization/contact-site mutants in PINK1 stabilization, PRKN recruitment, mitochondrial ubiquitination, LC3 recruitment, and mitophagic flux assays after mitochondrial depolarization or damage. - description: >- Separate ATAD3A PERK-binding and ATPase/nucleoid functions using domain mutants, measuring mitochondrial-localized translation during ER stress alongside mitochondrial morphology and mtDNA/nucleoid organization.