Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference to mitochondrion is consistent with experimental localization of ATAD3A to mitochondria and the mitochondrial inner membrane/nucleoid region. Reason: ATAD3A is a mitochondrial AAA+ protein with multiple independent experimental localization studies. This cellular component captures a core location. Supporting Evidence: PMID:20154147 The N-terminal domain interacts with the OM PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein
GO:0007005 mitochondrion organization	IBA GO_REF:0000033	ACCEPT	Summary: ATAD3A is required for normal mitochondrial network organization and dynamic inner/outer membrane interactions. Reason: Mitochondrion organization is a core process for ATAD3A, supported by dominant-negative and depletion phenotypes affecting mitochondrial morphology and membrane interactions. Supporting Evidence: PMID:20154147 ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP binding is consistent with the conserved AAA+ ATPase domain and mutational evidence from ATAD3A functional studies. Reason: ATP binding is an intrinsic molecular feature of the ATAD3A AAA+ ATPase domain and supports the core ATP hydrolysis activity. Supporting Evidence: PMID:20154147 positions the C-terminal AAA(+) ATPase domain in the matrix
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location mapping to mitochondrial inner membrane is supported by experimental topology and membrane-association studies. Reason: The inner-membrane assignment is well supported and is a core location for ATAD3A function. Supporting Evidence: PMID:20154147 central transmembrane segment (TMS) anchors the protein in the IM PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: ATP hydrolysis activity is consistent with ATAD3A being a functional AAA+ ATPase. Reason: The catalytic ATPase activity is a core molecular function of ATAD3A. Supporting Evidence: PMID:17210950 The ATPase of ATAD3 is functional PMID:20154147 positions the C-terminal AAA(+) ATPase domain in the matrix
GO:0042645 mitochondrial nucleoid	IEA GO_REF:0000044	ACCEPT	Summary: Mitochondrial nucleoid localization is supported by ATAD3A colocalization with mtDNA/nucleoids and effects on nucleoid organization. Reason: ATAD3A is not necessarily a core mtDNA-packaging protein in all nucleoids, but its nucleoid association and nucleoid-organizing role are well supported. Supporting Evidence: PMID:17210950 human ATAD3 is a component of many, but not all, mitochondrial nucleoids PMID:18063578 Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA
GO:0005515 protein binding	IPI PMID:22664726 ATAD3B is a human embryonic stem cell specific mitochondrial...	MARK AS OVER ANNOTATED	Summary: ATAD3A interacts with ATAD3B and HSPD1 in the cited study, but GO:0005515 protein binding is too generic to capture the functional implication. 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. Supporting Evidence: PMID:22664726 ATAD3B associates with the ubiquitous ATAD3A species PMID:22664726 negatively regulates the interaction of ATAD3A with matrix nucleoid complexes
GO:0005515 protein binding	IPI PMID:30914652 ATAD3A oligomerization causes neurodegeneration by coupling ...	MARK AS OVER ANNOTATED	Summary: ATAD3A interacts with Drp1/DNM1L in neurodegeneration models, but the generic protein binding term is not an informative GO molecular function. Reason: The direct evidence supports a Drp1-ATAD3A mitochondrial-fragmentation mechanism, not a broad protein-binding function term. Supporting Evidence: PMID:30914652 ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. PMID:30914652 ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-based mitochondrion localization is consistent with experimental human ATAD3A localization. Reason: ATAD3A is robustly mitochondrial; this is a correct cellular-component annotation. Supporting Evidence: PMID:20332122 Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence mitochondrion localization agrees with the curated mitochondrial literature. Reason: The mitochondrion location is correct and supported by independent experimental studies. Supporting Evidence: PMID:20332122 Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. PMID:20154147 The N-terminal domain interacts with the OM
GO:0005743 mitochondrial inner membrane	EXP PMID:18063578 The layered structure of human mitochondrial DNA nucleoids.	ACCEPT	Summary: Mitochondrial inner membrane localization is supported, with PMID:18063578 refining ATAD3A as peripheral to nucleoids rather than a core mtDNA-crosslinked protein. Reason: The cellular-component term is correct. The evidence should be interpreted as inner-membrane/nucleoid-associated localization, not necessarily direct mtDNA core binding. Supporting Evidence: PMID:18063578 Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA PMID:18063578 translation and complex assembly may occur in the peripheral region
GO:0005743 mitochondrial inner membrane	EXP PMID:20332122 ATPase family AAA domain-containing 3A is a novel anti-apopt...	ACCEPT	Summary: The lung adenocarcinoma study confirms experimental ATAD3A detection; mitochondrial inner-membrane localization is supported by the broader ATAD3A topology literature. Reason: The term captures a well-supported core cellular location, even though the cited paper focuses on cancer phenotypes. Supporting Evidence: PMID:20332122 Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. PMID:20332122 Our results show that ATAD3A is the major form expressed in LADC.
GO:0016887 ATP hydrolysis activity	IMP PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo...	ACCEPT	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. 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. Supporting Evidence: PMID:17210950 The ATPase of ATAD3 is functional PMID:20154147 positions the C-terminal AAA(+) ATPase domain in the matrix
GO:0030291 protein serine/threonine kinase inhibitor activity	IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo...	KEEP AS NON CORE	Summary: ATAD3A inhibits PERK kinase signaling at mitochondria-ER contacts during ER stress. 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. Supporting Evidence: PMID:39116259 ATAD3A interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) PMID:39116259 ATAD3A binding attenuated local PERK signaling
GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site	IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo...	KEEP AS NON CORE	Summary: ATAD3A is active at mitochondria-associated ER membrane contact sites during ER stress through its PERK interaction. Reason: This contact-site localization is supported, but it describes a stress-regulated sublocation rather than the primary mitochondrial inner-membrane/nucleoid location. Supporting Evidence: PMID:39116259 PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites.
GO:1903898 negative regulation of PERK-mediated unfolded protein response	IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo...	KEEP AS NON CORE	Summary: ATAD3A negatively regulates local PERK-mediated unfolded-protein-response signaling to preserve mitochondrial protein synthesis during ER stress. Reason: This is a real, experimentally supported stress-context function, but it is secondary to the core mitochondrial AAA ATPase/nucleoid/organization functions. Supporting Evidence: PMID:39116259 ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. PMID:39116259 active translation at mitochondria was significantly protected
GO:0005524 ATP binding	IMP PMID:20154147 The AAA+ ATPase ATAD3A controls mitochondrial dynamics at th...	ACCEPT	Summary: ATP binding is supported by ATAD3A AAA+ domain function and ATP-sensitive oligomer/membrane interaction phenotypes. Reason: This is a core molecular feature of the ATAD3A AAA+ ATPase. Supporting Evidence: PMID:20154147 positions the C-terminal AAA(+) ATPase domain in the matrix
GO:0005743 mitochondrial inner membrane	IDA PMID:20154147 The AAA+ ATPase ATAD3A controls mitochondrial dynamics at th...	ACCEPT	Summary: ATAD3A acts at mitochondrial inner/outer membrane contact regions, anchored in the mitochondrial inner membrane. Reason: The mitochondrial inner membrane is a core location for ATAD3A and is directly supported by topology experiments. Supporting Evidence: PMID:20154147 central transmembrane segment (TMS) anchors the protein in the IM PMID:20154147 ATAD3A is required for normal cell growth and cholesterol channeling at contact sites.
GO:0007005 mitochondrion organization	IMP PMID:20154147 The AAA+ ATPase ATAD3A controls mitochondrial dynamics at th...	ACCEPT	Summary: ATAD3A controls mitochondrial dynamics and organization at inner/outer membrane interfaces. Reason: Mitochondrion organization is one of the best-supported ATAD3A biological-process terms. Supporting Evidence: PMID:20154147 ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery.
GO:0016887 ATP hydrolysis activity	IMP PMID:20154147 The AAA+ ATPase ATAD3A controls mitochondrial dynamics at th...	ACCEPT	Summary: ATAD3A ATPase activity is supported by its AAA+ domain and functional studies. Reason: ATP hydrolysis activity is a core molecular function of ATAD3A. Supporting Evidence: PMID:17210950 The ATPase of ATAD3 is functional PMID:20154147 positions the C-terminal AAA(+) ATPase domain in the matrix
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteome evidence is consistent with ATAD3A being a mitochondrial protein. Reason: Although high-throughput, this annotation agrees with strong targeted evidence for mitochondrial localization. Supporting Evidence: PMID:34800366 A systematic analysis of mitochondrial protein dynamics is essential toward an understanding of mitochondrial proteostasis and its regulation under physiological and pathophysiological conditions. PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein
GO:0006974 DNA damage response	IDA PMID:37832546 Mitochondrial DNA breaks activate an integrated stress respo...	MODIFY	Summary: PMID:37832546 supports ATAD3A participation in mtDNA-break-triggered integrated stress response signaling, not a broad DNA damage response or DNA repair role. 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 replacements: HRI-mediated signaling integrated stress response signaling Supporting Evidence: PMID:37832546 mtDSBs triggered the integrated stress response (ISR) PMID:37832546 we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane.
GO:0140468 HRI-mediated signaling	IDA PMID:37832546 Mitochondrial DNA breaks activate an integrated stress respo...	KEEP AS NON CORE	Summary: ATAD3A acts upstream of HRI-mediated signaling after mitochondrial DNA breaks. Reason: This signaling role is supported, but it is a stress-response context rather than the primary housekeeping role in mitochondrial organization/nucleoids/translation. Supporting Evidence: PMID:37832546 cells with mtDNA breaks activate the ISR in a DELE1-HRI-dependent manner PMID:37832546 ATAD3A, an AAA+ ATPase located at the inner mitochondrial membrane (IMM), as a factor that potentially signals from defective genomes to mitochondrial membranes.
GO:0005743 mitochondrial inner membrane	IDA PMID:20349121 Topological analysis of ATAD3A insertion in purified human m...	ACCEPT	Summary: Topological analysis supports ATAD3A as a mitochondrial inner membrane-associated protein with the C-terminal region facing the matrix. Reason: This is a well-supported core location. Supporting Evidence: PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein PMID:20349121 the N-terminal part of ATAD3A is outside the inner membrane and that the C-terminal part is inside the matrix
GO:0005515 protein binding	IPI PMID:31522117 Structural Basis of Mitochondrial Scaffolds by Prohibitin Co...	MARK AS OVER ANNOTATED	Summary: ATAD3A participates in a mitochondrial scaffold/interactome with CLPB and MAVS-related antiviral signaling components, but GO:0005515 protein binding is too generic. 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. Supporting Evidence: PMID:31522117 AKAP1 and ATAD3A both co-immunoprecipitated with endogenous MAVS PMID:31522117 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
GO:0140374 antiviral innate immune response	IMP PMID:31522117 Structural Basis of Mitochondrial Scaffolds by Prohibitin Co...	KEEP AS NON CORE	Summary: ATAD3A contributes to mitochondrial antiviral innate immune signaling in a CLPB/PHB/MAVS scaffold context. Reason: The antiviral phenotype is supported, but it is a specialized signaling context rather than the central ATAD3A mitochondrial organization/nucleoid/translation function. Supporting Evidence: PMID:31522117 depletion of these molecules in the cells exhibited strikingly defective antiviral innate immune responses against SeV infection PMID:31522117 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
GO:0001558 regulation of cell growth	IMP PMID:20332122 ATPase family AAA domain-containing 3A is a novel anti-apopt...	KEEP AS NON CORE	Summary: ATAD3A depletion and expression changes affect lung adenocarcinoma survival and drug-response phenotypes. 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. Supporting Evidence: PMID:20332122 Serum deprivation increased ATAD3A expression and drug resistance.
GO:0005739 mitochondrion	IDA PMID:20332122 ATPase family AAA domain-containing 3A is a novel anti-apopt...	ACCEPT	Summary: The cited lung adenocarcinoma study confirms ATAD3A detection, while independent topology evidence supports mitochondrial localization. Reason: The mitochondrion location is correct and consistent with many independent ATAD3A studies. Supporting Evidence: PMID:20332122 Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. PMID:20349121 ATAD3 is a mitochondrial inner membrane-associated protein
GO:0043066 negative regulation of apoptotic process	IMP PMID:20332122 ATPase family AAA domain-containing 3A is a novel anti-apopt...	KEEP AS NON CORE	Summary: ATAD3A depletion sensitizes lung adenocarcinoma cells to cisplatin and is interpreted as anti-apoptotic in that cancer setting. Reason: The apoptotic phenotype is supported but cancer-contextual and downstream of mitochondrial homeostasis, not a core molecular function of ATAD3A. Supporting Evidence: PMID:20332122 Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity. PMID:20332122 These results suggest that ATAD3A could be an anti-apoptotic marker in LADC.
GO:0032042 mitochondrial DNA metabolic process	IMP PMID:22453275 Mitochondrial nucleoid interacting proteins support mitochon...	NEW	Summary: NEW annotation. ATAD3A supports mitochondrial DNA/nucleoid maintenance and replication-associated organization at the inner membrane. 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. Supporting Evidence: PMID:22453275 Altered ATAD3 expression also perturbs mtDNA maintenance and replication. PMID:17210950 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 file:human/ATAD3A/ATAD3A-deep-research-manual.md The core evidence supports mitochondrial organization, ATP hydrolysis, mitochondrial nucleoid organization, mtDNA maintenance, and support of mitochondrial protein synthesis.
GO:0032543 mitochondrial translation	IMP PMID:22453275 Mitochondrial nucleoid interacting proteins support mitochon...	NEW	Summary: NEW annotation. ATAD3A is required for mitochondrial protein synthesis and binds the mitochondrial ribosome. 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. Supporting Evidence: PMID:22453275 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. file:human/ATAD3A/ATAD3A-deep-research-manual.md 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.

Core Functions

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:

ATP hydrolysis activity

Directly Involved In:

mitochondrion organization mitochondrial DNA metabolic process mitochondrial translation

Cellular Locations:

mitochondrial inner membrane mitochondrial nucleoid

Supporting Evidence:

PMID:20154147
ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery.
PMID:17210950
human ATAD3 is a component of many, but not all, mitochondrial nucleoids
PMID:22453275
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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:18063578

The layered structure of human mitochondrial DNA nucleoids.

ATAD3 is associated with native nucleoids but does not cross-link to mtDNA, supporting a peripheral/layered nucleoid interpretation.

"Several other metabolic proteins and chaperones identified in native nucleoids, including ATAD3, were not observed to cross-link to mtDNA"

PMID:20154147

The AAA+ ATPase ATAD3A controls mitochondrial dynamics at the interface of the inner and outer membranes.

ATAD3A spans mitochondrial membrane interfaces with an N-terminal outer-membrane-facing region, inner-membrane anchoring segment, and matrix-facing AAA+ ATPase domain.

"The N-terminal domain interacts with the OM"
ATAD3A regulates mitochondrial inner/outer membrane interactions and mitochondrial dynamics.

"ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery."

PMID:20332122

ATPase family AAA domain-containing 3A is a novel anti-apoptotic factor in lung adenocarcinoma cells.

ATAD3A is experimentally detected in lung adenocarcinoma and supports survival/drug-response phenotypes.

"Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy."
ATAD3A silencing increases mitochondrial fragmentation and cisplatin sensitivity in lung adenocarcinoma cells.

"Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity."

PMID:20349121

Topological analysis of ATAD3A insertion in purified human mitochondria.

ATAD3A is a mitochondrial inner membrane-associated protein with N- and C-terminal topology across the inner membrane.

"ATAD3 is a mitochondrial inner membrane-associated protein"

PMID:22664726

ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A.

ATAD3B associates with ATAD3A and negatively regulates ATAD3A interaction with matrix nucleoid complexes.

"ATAD3B associates with the ubiquitous ATAD3A species"

PMID:30914652

ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.

ATAD3A interacts with Drp1 and links mitochondrial fragmentation to mtDNA damage and bioenergetic defects in neurodegeneration models.

"ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance"

PMID:31522117

Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region.

ATAD3A participates in a mitochondrial CLPB/PHB/MAVS scaffold required for antiviral innate immune signaling.

"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"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:37832546

Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.

ATAD3A participates in mitochondrial DNA break-triggered ISR signaling from damaged genomes to the inner membrane.

"we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane."
Mitochondrial DNA breaks activate integrated stress response signaling.

"mtDSBs triggered the integrated stress response (ISR)"

PMID:39116259

PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress.

ATAD3A binds PERK during ER stress and forms mitochondria-ER contact sites.

"PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites."
ATAD3A attenuates local PERK signaling and helps preserve mitochondrial protein synthesis during ER stress.

"ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins."

PMID:17210950

The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization.

ATAD3 is a mitochondrial nucleoid-associated AAA+ protein with D-loop binding properties.

"human ATAD3 is a component of many, but not all, mitochondrial nucleoids"
ATAD3 depletion alters mitochondrial nucleoid structure and affects protein-bound D-loop-containing mtDNA fragments.

"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"
ATAD3 has functional ATPase activity.

"The ATPase of ATAD3 is functional"

PMID:22453275

Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis.

ATAD3 supports mitochondrial protein synthesis and binds mitochondrial ribosomes.

"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."
Altered ATAD3 expression perturbs mtDNA maintenance and replication.

"Altered ATAD3 expression also perturbs mtDNA maintenance and replication."

file:human/ATAD3A/ATAD3A-deep-research-manual.md

Manual deep research synthesis for ATAD3A

Provider-backed deep research was unavailable, so this review used a manual synthesis.

"Falcon deep research was requested but timed out after 600 seconds, and the configured Perplexity fallback failed with an insufficient-quota 401 error."
The PN mitophagy projection was not propagated for ATAD3A.

"Manual synthesis decision: ATAD3A is not currently supported as a direct mitophagy cargo-marking or PINK/PRKN pathway factor."

file:human/ATAD3A/ATAD3A-notes.md

Curator notes for ATAD3A PN review

The Proteostasis PN mitophagy projection was evaluated conservatively and not added.

"I did not add GO:0000423 mitophagy."
Generic protein binding annotations were marked as over-annotations.

"Marked generic protein binding annotations as over-annotated."

Suggested Experiments

Experiment: 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.

Experiment: 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.

Deep Research

Manual

(ATAD3A-deep-research-manual.md)

ATAD3A manual deep research synthesis Manual

ATAD3A manual deep research synthesis

Falcon deep research was requested but timed out after 600 seconds, and the configured Perplexity fallback failed with an insufficient-quota 401 error. This manual synthesis is therefore based on the cached UniProt record, GOA, local publication cache, and the Proteostasis PN projection report.

Manual synthesis decision: ATAD3A is not currently supported as a direct mitophagy cargo-marking or PINK/PRKN pathway factor.

Core function

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. The core evidence supports mitochondrial organization, ATP hydrolysis, mitochondrial nucleoid organization, mtDNA maintenance, and support of mitochondrial protein synthesis.

Key support:

PMID:20154147 shows membrane topology and mitochondrial organization functions. The abstract states that "The N-terminal domain interacts with the OM" and that a "central transmembrane segment (TMS) anchors the protein in the IM and positions the C-terminal AAA(+) ATPase domain in the matrix." It also states that "ATAD3A regulates dynamic interactions between the mitochondrial OM and IM sensed by the cell fission machinery."
PMID:17210950 identifies ATAD3 as a nucleoid-associated AAA+ protein. The abstract reports that "human ATAD3 is a component of many, but not all, mitochondrial nucleoids" and that ATAD3 RNAi "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."
PMID:22453275 links ATAD3 to mitochondrial protein synthesis. The abstract reports that "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." It further states that altered ATAD3 expression perturbs mtDNA maintenance and replication.

Context-specific functions

ATAD3A also participates in several context-specific mitochondrial signaling settings. PMID:39116259 reports that ATAD3A interacts with PERK during ER stress, forms mitochondria-ER contact sites, and attenuates local PERK signaling to preserve mitochondrial protein synthesis. These observations support the existing PERK inhibitor and mitochondria-associated ER membrane contact-site annotations, but they are not the central evolved function of ATAD3A.

PMID:37832546 places ATAD3A in the response to mitochondrial DNA breaks. The paper reports that mtDSBs trigger an integrated stress response via DELE1 and HRI and identifies ATAD3A as potentially relaying signals from impaired mitochondrial genomes to the inner membrane. This supports HRI-mediated/integrated stress response signaling more directly than a generic DNA damage response term.

PMID:31522117 supports a role in mitochondrial antiviral innate immune signaling through a prohibitin/CLPB/MAVS/AKAP1/ATAD3A scaffold. This is plausible and experimentally supported, but it is context-specific relative to the core mitochondrial organization/nucleoid/translation role.

PMID:20332122 supports mitochondrial localization, cell growth, and anti-apoptotic phenotypes in lung adenocarcinoma cells. These are retained as non-core phenotypic or disease-context annotations.

Proteostasis PN projection

The Proteostasis PN projection file maps ATAD3A to GO:0000423 mitophagy from a PINK/PRKN mitophagy cargo-marking category. I reviewed this conservatively and did not add mitophagy as a proposed new term. The strongest ATAD3A literature does not show ATAD3A acting as a mitophagy receptor, PINK1/PRKN cargo-marking factor, mitochondrial ubiquitination factor, LC3 recruitment factor, or direct executor of mitochondrial autophagic clearance.

PMID:30914652 provides important mitochondrial dynamics evidence and mentions disease-associated mitochondrial damage/mitophagy context, but the direct ATAD3A findings are Drp1 interaction, ATAD3A oligomerization, mitochondrial fragmentation, mtDNA lesion, bioenergetic defects, and cell death. That evidence is insufficient for a direct mitophagy annotation.

Recommended expert question: Does endogenous ATAD3A have any direct PINK1/PRKN-dependent cargo-marking, receptor-regulatory, or mitophagic-flux role that is separable from secondary consequences of mitochondrial fragmentation and mtDNA damage?

📚 Additional Documentation

Notes

(ATAD3A-notes.md)

ATAD3A notes

2026-06-03: Initialized ATAD3A for the Proteostasis PN batch with just fetch-gene human ATAD3A.
2026-06-03: Falcon deep research was requested using just deep-research-falcon human ATAD3A --fallback perplexity-lite. Falcon timed out after 600 seconds and the configured Perplexity fallback failed with an insufficient-quota 401 error, so I completed a manual synthesis in ATAD3A-deep-research-manual.md.

Functional synthesis

ATAD3A is best reviewed as a mitochondrial inner-membrane AAA+ ATPase/scaffold that acts at inner/outer membrane contact and nucleoid-adjacent regions. UniProt summarizes it as "Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level" and places it in the mitochondrial inner membrane and mitochondrial nucleoid region.
The strongest core evidence is mitochondrial organization, membrane/contact-site positioning, and ATPase activity: the ATAD3A domain study reports that "The N-terminal domain interacts with the OM" and that a "central transmembrane segment (TMS) anchors the protein in the IM" PMID:20154147.
Nucleoid involvement is supported by D-loop/nucleoid evidence: "human ATAD3 is a component of many, but not all, mitochondrial nucleoids" and ATAD3 RNAi "altered the structure of mitochondrial nucleoids" PMID:17210950.
Mitochondrial translation support is well supported but not currently a GOA annotation for ATAD3A: "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" PMID:22453275.
The PERK interaction is real but context-specific. During ER stress, "ATAD3A interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK)" and "PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites" PMID:39116259. I therefore kept the PERK inhibitor/contact-site/UPR annotations as non-core rather than core.
The mtDNA-break paper supports stress signaling from damaged mitochondrial genomes, not a broad DNA repair role. It reports that mtDSBs triggered ISR signaling through DELE1-HRI and identified ATAD3A as "potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane" PMID:37832546.

PN projection review

The Proteostasis PN projection proposes ATAD3A -> GO:0000423 mitophagy from the "Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway" category in projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv.
I did not add GO:0000423 mitophagy. The available ATAD3A literature supports mitochondrial morphology, mtDNA/nucleoid organization, mitochondrial protein synthesis, mitochondrial contact-site signaling, and secondary stress responses. I did not find direct evidence that endogenous ATAD3A marks mitochondrial cargo, recruits PINK1/PRKN machinery, functions as a mitophagy receptor, or otherwise executes mitophagy.
The neurodegeneration paper mentions mutant/pathology-linked mitochondrial fragmentation and mitophagy context, but its direct ATAD3A evidence is Drp1 interaction, ATAD3A oligomerization, fragmentation, mtDNA lesion, and bioenergetic defects PMID:30914652. This is insufficient for a direct mitophagy process annotation.

Annotation review notes

Accepted core terms: ATP binding, ATP hydrolysis activity, mitochondrial inner membrane, mitochondrion, mitochondrial nucleoid, and mitochondrion organization.
Marked generic protein binding annotations as over-annotated. ATAD3A interactions with ATAD3B/HSPD1, DNM1L/Drp1, and CLPB/MAVS-related complexes are biologically informative in context, but GO:0005515 protein binding alone does not capture ATAD3A function.
Kept as non-core: PERK inhibition/mitochondria-ER contact site/negative regulation of PERK-mediated UPR, antiviral innate immune response, cell growth regulation, and anti-apoptotic process in lung adenocarcinoma.
Modified the broad DNA damage response annotation from PMID:37832546 toward the more specific integrated stress response and HRI-mediated signaling terms because the paper supports mtDNA-break-triggered signaling rather than DNA repair.

Pn Notes

(ATAD3A-pn-notes.md)

ATAD3A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9NVI7
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1379)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATAD3A/ATAD3A-ai-review.yaml
AIGR review HTML: present - genes/human/ATAD3A/ATAD3A-ai-review.html
Gene notes: present - genes/human/ATAD3A/ATAD3A-notes.md
GOA TSV: present - genes/human/ATAD3A/ATAD3A-goa.tsv
UniProt record: present - genes/human/ATAD3A/ATAD3A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATAD3A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATAD3A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATAD3A/ATAD3A-deep-research-manual.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 3; MODIFY: 1; NEW: 2

PN Consistency Summary

Consistency: Consistent, with a deliberate, well-documented divergence from the projection. Deep research (manual synthesis), review YAML, and notes all describe ATAD3A as a mitochondrial inner-membrane AAA+ ATPase for network/nucleoid/mtDNA organization and mitochondrial translation, with secondary stress signaling (PERK, HRI/ISR). The PN mitophagy projection is explicitly evaluated and rejected in notes ("I did not add GO:0000423 mitophagy"). No internal contradiction.
PN story / NEW pressure: PN asserts ATAD3A in mitophagy (GO:0000423, real term). PN Notes base this on a mouse Atad3a/Pink1 study (Nat Immunology) where Atad3a suppresses mitophagy. The review correctly declined to ADD mitophagy: human evidence shows ATAD3A normally restrains PINK1 accumulation, so a positive "involved_in mitophagy" annotation would mis-state directionality, and no direct cargo-marking/receptor role is shown. Verdict: PN story over-reaches; appropriately NOT added. Review instead ADDED GO:0032042 (mtDNA metabolic process) and GO:0032543 (mitochondrial translation) as NEW — both better-supported core functions.
Evidence alignment: No overlap. PN cites one mouse mitophagy paper (Atad3a/Pink1, Nat Immunology); review is built on mitochondrial topology/nucleoid/translation papers (PMID:20154147, 17210950, 22453275, 18063578) plus stress-signaling papers (PMID:37832546, 39116259) — none shared with the PN row. The projection rests on evidence the review judged insufficient for a human mitophagy assertion.
Verdict: Consistent; PN mitophagy projection correctly NOT added (over-reaches; directionally suppressive in source). No edits required.

Full Consistency Review

UniProt: Q9NVI7 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: ALP|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway ; PN-node mapping: PINK/PRKN subtype no_mapping; Mitophagy type mapped, ok_for_propagation_to_go → GO:0000423 mitophagy (new_to_goa).
Consistency: Consistent, with a deliberate, well-documented divergence from the projection. Deep research (manual synthesis), review YAML, and notes all describe ATAD3A as a mitochondrial inner-membrane AAA+ ATPase for network/nucleoid/mtDNA organization and mitochondrial translation, with secondary stress signaling (PERK, HRI/ISR). The PN mitophagy projection is explicitly evaluated and rejected in notes ("I did not add GO:0000423 mitophagy"). No internal contradiction.
PN story / NEW pressure: PN asserts ATAD3A in mitophagy (GO:0000423, real term). PN Notes base this on a mouse Atad3a/Pink1 study (Nat Immunology) where Atad3a suppresses mitophagy. The review correctly declined to ADD mitophagy: human evidence shows ATAD3A normally restrains PINK1 accumulation, so a positive "involved_in mitophagy" annotation would mis-state directionality, and no direct cargo-marking/receptor role is shown. Verdict: PN story over-reaches; appropriately NOT added. Review instead ADDED GO:0032042 (mtDNA metabolic process) and GO:0032543 (mitochondrial translation) as NEW — both better-supported core functions.
Mapping strategy: Gene is a defensible decline at this node (parallel to RAB7A/HSPA8 broader-rejection precedent): the Mitophagy type-leaf mapping is a class-level statement, but this gene's role is suppressive/indirect, so the projected term (GO:0000423) is broader/wrong-signed relative to the review's evidence.
Evidence alignment: No overlap. PN cites one mouse mitophagy paper (Atad3a/Pink1, Nat Immunology); review is built on mitochondrial topology/nucleoid/translation papers (PMID:20154147, 17210950, 22453275, 18063578) plus stress-signaling papers (PMID:37832546, 39116259) — none shared with the PN row. The projection rests on evidence the review judged insufficient for a human mitophagy assertion.
Verdict: Consistent; PN mitophagy projection correctly NOT added (over-reaches; directionally suppressive in source). No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATAD3A/ATAD3A-ai-review.yaml
PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | Mitophagy | PINK/PRKN pathway

UniProt: Q9NVI7
In branches: ALP
Notes: AAA+ ATPase involved in mitochondrial dynamics. By homology with mouse: deletion of Atad3a hyperactivates mitophagy. Atad3a normally facilitates import and processing of Pink1, absence causes accumulation and activates mitophagy.
PN references (titles):
- Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells | Nature Immunology
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy|PINK/PRKN pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
  rationale: The PN marking category for mitophagy captures upstream cargo-marking steps that commit mitochondrial substrates to the mitophagy pathway. That supports propagation to mitophagy.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|Mitophagy

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

ATAD3A

Gene Description