Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003924 GTPase activity	IBA GO_REF:0000033	ACCEPT	Summary: EAT-3 is a dynamin-like GTPase with a conserved GTPase domain containing G1-G4 motifs. The primary eat-3(ad426) mutation affects a residue near the G2 motif, and intragenic suppressors cluster around GTPase domain residues (PMID:18454199). Reason: GTPase activity is the core enzymatic function of EAT-3. The protein contains canonical dynamin GTPase, middle, and GED domains. Mutations in the GTPase domain cause loss of function, and second-site suppressors restore GTPase function (PMID:18454199). Supporting Evidence: PMID:18454199 Similar to yeast Mgm1 and mammalian Opa1, this C. elegans protein has a putative mitochondrial targeting sequence followed by domains that are typical of dynamin family members: a conserved GTPase domain, a middle domain and a GED or assembly domain PMID:18454199 The affected residue is just downstream of the G2 threonine in the effector binding loop of the dynamin-like GTPase, where it may disrupt the GTPase cycle. file:worm/eat-3/eat-3-deep-research-falcon.md model: Edison Scientific Literature
GO:0005737 cytoplasm	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: This annotation is overly broad. EAT-3 localizes specifically to mitochondria, not the general cytoplasm. While technically mitochondria are within the cytoplasm, more specific localization terms are available. Reason: EAT-3 has a mitochondrial targeting sequence and localizes to mitochondria. More specific compartment annotations (mitochondrial inner membrane, intermembrane space) are more informative. This IBA annotation likely derives from broader dynamin family members that have cytoplasmic localization. Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0008053 mitochondrial fusion	IBA GO_REF:0000033	ACCEPT	Summary: EAT-3 is required for mitochondrial fusion, specifically the inner membrane fusion step. This is the core biological process function of the protein (PMID:18454199). Reason: Mitochondrial fusion is the primary biological process function of EAT-3. Loss of eat-3 causes mitochondrial fragmentation that can be suppressed by loss of the fission protein DRP-1, confirming a role in fusion. The IBA annotation is well-supported by phylogenetic inference from mammalian OPA1 and yeast Mgm1. Supporting Evidence: PMID:18454199 Evidence for the role of Opa1 in fusion between mitochondrial inner membranes initially came from studies of the yeast homologue of Opa1, which is called Mgm1. PMID:18454199 Similar mitochondrial fragmentation is observed in muscle cells of fzo-1(tm1133) mutants... The mitochondria of eat-3 and fzo-1 mutants are similarly fragmented consistent with their roles in mitochondrial fusion.
GO:0031966 mitochondrial membrane	IBA GO_REF:0000033	ACCEPT	Summary: EAT-3 is localized to mitochondrial membranes, specifically the inner membrane. This annotation is acceptable but could be more specific. Reason: The annotation is correct - EAT-3 is a mitochondrial membrane protein. More specific annotations to inner membrane and intermembrane space are also present, making this a reasonable general annotation. Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0016559 peroxisome fission	IBA GO_REF:0000033	REMOVE	Summary: This annotation is questionable for EAT-3. While some dynamin family members are involved in peroxisome fission, there is no direct evidence for EAT-3 function in peroxisomes. EAT-3/OPA1 is specifically a mitochondrial protein. Reason: EAT-3 is specifically localized to mitochondria via its mitochondrial targeting sequence and functions in mitochondrial inner membrane fusion. There is no published evidence for peroxisomal localization or function of EAT-3 in C. elegans. This IBA annotation appears to be an over-extension from other dynamin family members (like DRP1/DNM1) that do participate in peroxisome fission, but OPA1/Mgm1/EAT-3 orthologs are mitochondria-specific. Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0005758 mitochondrial intermembrane space	IBA GO_REF:0000033	ACCEPT	Summary: EAT-3 localizes to the mitochondrial intermembrane space, consistent with its ortholog OPA1/Mgm1 (PMID:18454199). Reason: The protein contains a mitochondrial leader sequence that targets it to the intermembrane space, and it functions at the inner membrane, consistent with IMS localization. This is well-supported by studies of the mammalian and yeast orthologs. Supporting Evidence: PMID:18454199 Biochemical analysis shows that yeast Mgm1 and mammalian Opa1 are localized to the mitochondrial intermembrane space PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0005874 microtubule	IBA GO_REF:0000033	REMOVE	Summary: This annotation appears to be an over-extension from other dynamin family members. EAT-3 is a mitochondrial protein with no evidence for microtubule localization. Reason: EAT-3/OPA1/Mgm1 are mitochondrial inner membrane/intermembrane space proteins. There is no published evidence for EAT-3 localization to microtubules in C. elegans. This IBA annotation likely derives from classical dynamins (like DYN-1) or DRP-1 which can associate with microtubules, but this does not apply to the OPA1 subfamily. Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0008017 microtubule binding	IBA GO_REF:0000033	REMOVE	Summary: This annotation is inappropriate for EAT-3. The protein is localized to mitochondria and has no documented microtubule binding activity. Reason: EAT-3 is a mitochondrial inner membrane/IMS protein with a mitochondrial targeting sequence. There is no evidence that EAT-3 binds microtubules. This IBA annotation appears to be an inappropriate transfer from other dynamin family members (classical dynamins, not the OPA1/Mgm1 subfamily). Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: EAT-3 is a GTPase that binds GTP/GDP. This annotation is correct but very general; GTP binding is the more specific and informative annotation. Reason: As a GTPase, EAT-3 binds nucleotides (GTP and GDP). This is a correct but general annotation derived from UniProt keyword mapping. The more specific GTP binding annotation is also present. Supporting Evidence: PMID:18454199 Similar to yeast Mgm1 and mammalian Opa1, this C. elegans protein has a putative mitochondrial targeting sequence followed by domains that are typical of dynamin family members: a conserved GTPase domain
GO:0003924 GTPase activity	IEA GO_REF:0000002	ACCEPT	Summary: GTPase activity is the core enzymatic function of EAT-3, derived from InterPro domain annotation. This duplicates the IBA annotation above. Reason: The InterPro-based annotation correctly identifies GTPase activity based on the dynamin GTPase domain. This is a core function well-supported by the protein structure and mutant analysis. Supporting Evidence: PMID:18454199 Similar to yeast Mgm1 and mammalian Opa1, this C. elegans protein has a putative mitochondrial targeting sequence followed by domains that are typical of dynamin family members: a conserved GTPase domain
GO:0005525 GTP binding	IEA GO_REF:0000120	ACCEPT	Summary: EAT-3 is a GTPase that binds GTP. This is a core molecular function annotation derived from domain analysis. Reason: GTP binding is required for GTPase activity. The dynamin GTPase domain contains conserved GTP binding motifs (G1-G4). The eat-3(ad426) mutation near the G2 motif disrupts function, confirming the importance of GTP binding. Supporting Evidence: PMID:18454199 The affected residue is just downstream of the G2 threonine in the effector binding loop of the dynamin-like GTPase, where it may disrupt the GTPase cycle.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000044	ACCEPT	Summary: EAT-3 is localized to the mitochondrial inner membrane, consistent with its function in inner membrane fusion. Reason: EAT-3 functions at the mitochondrial inner membrane where it mediates inner membrane fusion. The UniProt subcellular location annotation is well-supported by the biological function and ortholog studies. Supporting Evidence: PMID:18454199 Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane.
GO:0005758 mitochondrial intermembrane space	IEA GO_REF:0000044	ACCEPT	Summary: EAT-3 is targeted to the mitochondrial intermembrane space. This duplicates the IBA annotation but is derived from UniProt subcellular location mapping. Reason: The protein has a mitochondrial leader sequence that targets it to the intermembrane space, consistent with the localization of OPA1 and Mgm1 orthologs. Supporting Evidence: PMID:18454199 EAT-3 has a mitochondrial leader sequence (mls) that targets the protein to the mitochondrial intermembrane space.
GO:0006915 apoptotic process	IEA GO_REF:0000043	REMOVE	Summary: Mammalian OPA1 has an established anti-apoptotic function. However, in C. elegans, eat-3 does not appear to function in canonical apoptosis (PMID:18454199, PMID:18722182). Reason: While mammalian OPA1 has anti-apoptotic functions, the C. elegans eat-3 mutant phenotypes are not suppressed by ced-3 or ced-4 mutations, indicating that caspase-dependent cell death does not contribute to eat-3 phenotypes. The annotation is derived from UniProt keyword mapping but is not supported by experimental evidence in C. elegans. Supporting Evidence: PMID:18454199 Although mammalian Opa1 is antiapoptotic, mutations in the canonical C. elegans cell death genes ced-3 and ced-4 do not suppress the slow growth and small broodsize phenotypes of eat-3 mutants. PMID:18722182 Here we report that profusion genes fzo-1 and eat-3 or the profission gene drp-1 are not required for apoptosis activation in C. elegans.
GO:0008289 lipid binding	IEA GO_REF:0000043	ACCEPT	Summary: OPA1 family proteins interact with cardiolipin in the inner membrane. This annotation from UniProt keyword mapping has some basis in the function. Reason: OPA1/Mgm1 proteins are known to interact with cardiolipin, a lipid enriched in the mitochondrial inner membrane, which is important for their membrane fusion function. While not directly demonstrated for C. elegans EAT-3, this is a conserved feature of the protein family. Supporting Evidence: PMID:18454199 EAT-3 is required for fusion of mitochondrial inner membranes [implying membrane interaction]
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: GTPase activity is a form of hydrolase activity (hydrolyzes GTP to GDP + Pi). This is a correct but very general annotation. Reason: GTPases catalyze hydrolysis of GTP, making them hydrolases. This annotation is correct but very general; the more specific GTPase activity annotation is more informative. Supporting Evidence: PMID:18454199 Similar to yeast Mgm1 and mammalian Opa1, this C. elegans protein has a putative mitochondrial targeting sequence followed by domains that are typical of dynamin family members: a conserved GTPase domain
GO:0005739 mitochondrion	IDA PMID:21248201 A novel mitochondrial outer membrane protein, MOMA-1, that a...	ACCEPT	Summary: EAT-3 localizes to mitochondria as demonstrated by co-fractionation and protease protection experiments in PMID:21248201. Reason: This IDA annotation is supported by experimental data showing EAT-3 co-fractionates with mitochondria and is protected from protease digestion in intact mitochondria, confirming mitochondrial localization. Supporting Evidence: PMID:21248201 Subcellular distribution of MOMA-1 determined by differential centrifugation... The distributions were quantified with densitometry of P2 and S2 fractions: 88% of EAT-3, 12% of tubulin, and 98% of MOMA-1 is in the mitochondrial pellet. PMID:21248201 Protease protection experiment to determine the submitochondrial localization... MOMA-1 is digested when no detergent is added, like MFF-1, while EAT-3 and F1beta are protease protected.
GO:0002119 nematode larval development	IGI PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	KEEP AS NON CORE	Summary: eat-3 mutants have slow development and growth defects. This is a phenotypic consequence of mitochondrial dysfunction rather than a core function. Reason: While eat-3 mutants do have developmental defects (slow growth, delayed development), these are secondary consequences of impaired mitochondrial function rather than a direct role in development. The core function is mitochondrial inner membrane fusion. Supporting Evidence: PMID:18454199 Worms injected with eat-3 dsRNA give viable progeny but their brood size is reduced... The F1 worms remain small, are sluggish and develop slowly.
GO:0040014 regulation of multicellular organism growth	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	KEEP AS NON CORE	Summary: eat-3 mutants show growth defects, but this is a pleiotropic consequence of mitochondrial dysfunction rather than a direct regulatory role in growth. Reason: eat-3 loss of function causes slow growth and small body size, but this is due to impaired mitochondrial function (oxidative phosphorylation defects) rather than a direct role in regulating organismal growth. The growth defects are consistent with metabolic insufficiency. Supporting Evidence: PMID:18454199 eat-3 RNAi worms rarely reach 0.5 mm, consistent with a previous study showing that the eat-3(ad426) mutant also remains small... developmental decisions are normal, but the rate of development is greatly reduced as one might expect from a general decrease in metabolic activity.
GO:0040014 regulation of multicellular organism growth	IGI PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	KEEP AS NON CORE	Summary: This is a duplicate annotation with IGI evidence, showing genetic interactions affecting growth. Same reasoning as above - secondary phenotype. Reason: Growth phenotype is a secondary consequence of mitochondrial dysfunction, not a core regulatory function. Supporting Evidence: PMID:18454199 the phenotypes of eat-3 mutants are consistent with defects in oxidative phosphorylation.
GO:0008053 mitochondrial fusion	IMP PMID:18722182 Caenorhabditis elegans drp-1 and fis-2 regulate distinct cel...	ACCEPT	Summary: Experimental evidence from PMID:18722182 supporting mitochondrial fusion role. Reason: This is direct experimental evidence from C. elegans showing eat-3 is required for mitochondrial fusion. This is the core biological process function. Supporting Evidence: PMID:18722182 profusion genes fzo-1 and eat-3 or the profission gene drp-1 are not required for apoptosis activation in C. elegans [but are required for fusion/fission respectively]
GO:0000303 response to superoxide	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	KEEP AS NON CORE	Summary: eat-3 mutants are hypersensitive to paraquat and show induction of SOD-2. This is a stress response consequence of mitochondrial dysfunction. Reason: eat-3 mutants show hypersensitivity to paraquat (superoxide) and compensatory induction of SOD-2, but this is a consequence of mitochondrial dysfunction leading to increased ROS production, not a primary function in oxidative stress response. Supporting Evidence: PMID:18454199 eat-3 mutants are hypersensitive to paraquat, which promotes damage by free radicals, and they are sensitive to loss of the mitochondrial superoxide dismutase sod-2. We conclude that free radicals contribute to the pathology of C. elegans eat-3 mutants. PMID:18454199 Fe/Mn-SOD expression is induced more than two-fold in eat-3(ad426) animals... This induction is almost entirely attributable to SOD-2
GO:0007005 mitochondrion organization	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	ACCEPT	Summary: EAT-3 is essential for proper mitochondrial organization, particularly inner membrane and cristae organization. Reason: EAT-3 is required for proper mitochondrial morphology and organization. Loss of EAT-3 leads to fragmented mitochondria with disorganized inner membranes and reduced cristae. This is a direct function of the protein. Supporting Evidence: PMID:18454199 The eat-3 mitochondria had on average 1.21 µm total cristae length (n = 20, SD = 0.78), compared with 7.34 µm in wildtype mitochondria (n = 16, SD = 3.80)
GO:0008053 mitochondrial fusion	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	ACCEPT	Summary: Primary experimental evidence for mitochondrial fusion function from the foundational eat-3 study. Reason: This is the core biological process function of EAT-3, demonstrated by mitochondrial fragmentation in mutants and suppression by drp-1 loss of function. Supporting Evidence: PMID:18454199 We find that mutations in the C. elegans eat-3 locus cause mitochondria to fragment in agreement with the mutant phenotypes observed in yeast and mammalian cells. Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane. PMID:18454199 DRP-1(K40A) gives rise to interconnected mitochondria, regardless of whether it is expressed in a wildtype background, with antisense eat-3, or in an eat-3 mutant... We conclude that a functioning mitochondrial division apparatus is required for the mitochondrial fragmentation induced by mutant eat-3.
GO:0035264 multicellular organism growth	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	KEEP AS NON CORE	Summary: eat-3 mutants show reduced body size and growth, a consequence of mitochondrial dysfunction. Reason: Growth defects are a secondary phenotype of mitochondrial dysfunction, not a core function of EAT-3. Supporting Evidence: PMID:18454199 The F1 worms remain small, are sluggish and develop slowly... eat-3 RNAi worms rarely reach 0.5 mm
GO:1990627 mitochondrial inner membrane fusion	IMP PMID:18454199 The C. elegans Opa1 homologue EAT-3 is essential for resista...	NEW	Summary: EAT-3 specifically mediates mitochondrial inner membrane fusion, as demonstrated by the characteristic inner membrane septae phenotype in eat-3 mutants. Reason: The existing GO:0008053 (mitochondrial fusion) annotation is correct but GO:1990627 (mitochondrial inner membrane fusion) is more specific and accurately describes the precise function of EAT-3. The inner membrane septae phenotype is diagnostic for inner membrane fusion defects. Proposed replacements: mitochondrial inner membrane fusion Supporting Evidence: PMID:18454199 Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane. PMID:18454199 EAT-3 is required for fusion of mitochondrial inner membranes.

Core Functions

EAT-3 contains a conserved dynamin-type GTPase domain. Mutations near the G2 motif disrupt function, and intragenic suppressors restore GTPase activity (PMID:18454199).

Molecular Function:

GTPase activity

Directly Involved In:

mitochondrial inner membrane fusion

Cellular Locations:

mitochondrial inner membrane mitochondrial intermembrane space

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:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:18454199

The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals.

EAT-3 is the C. elegans ortholog of OPA1/Mgm1, with conserved dynamin domains

"Similar to yeast Mgm1 and mammalian Opa1, this C. elegans protein has a putative mitochondrial targeting sequence followed by domains that are typical of dynamin family members: a conserved GTPase domain, a middle domain and a GED or assembly domain"
eat-3 mutations cause mitochondrial fragmentation with inner membrane septae

"We find that mutations in the C. elegans eat-3 locus cause mitochondria to fragment in agreement with the mutant phenotypes observed in yeast and mammalian cells. Electron microscopy shows that the matrices of fragmented mitochondria in eat-3 mutants are divided by inner membrane septae, suggestive of a specific defect in fusion of the mitochondrial inner membrane."
eat-3 mutants have reduced cristae content (66% reduction)

"The eat-3 mitochondria had on average 1.21 µm total cristae length (n = 20, SD = 0.78), compared with 7.34 µm in wildtype mitochondria (n = 16, SD = 3.80)"
eat-3 mutants are hypersensitive to paraquat and induce SOD-2

"eat-3 mutants are hypersensitive to paraquat, which promotes damage by free radicals, and they are sensitive to loss of the mitochondrial superoxide dismutase sod-2. We conclude that free radicals contribute to the pathology of C. elegans eat-3 mutants."
drp-1 mutations suppress eat-3 phenotypes

"DRP-1(K40A) gives rise to interconnected mitochondria, regardless of whether it is expressed in a wildtype background, with antisense eat-3, or in an eat-3 mutant... We conclude that a functioning mitochondrial division apparatus is required for the mitochondrial fragmentation induced by mutant eat-3."
ced-3/ced-4 mutations do not suppress eat-3 phenotypes

"Although mammalian Opa1 is antiapoptotic, mutations in the canonical C. elegans cell death genes ced-3 and ced-4 do not suppress the slow growth and small broodsize phenotypes of eat-3 mutants."

PMID:18722182

Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death execution pathways downstream of ced-3 and independent of ced-9.

eat-3 and fzo-1 are not required for apoptosis activation in C. elegans

"Here we report that profusion genes fzo-1 and eat-3 or the profission gene drp-1 are not required for apoptosis activation in C. elegans."

PMID:21248201

A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans.

EAT-3 co-fractionates with mitochondria (88% in mitochondrial pellet)

"Subcellular distribution of MOMA-1 determined by differential centrifugation... The distributions were quantified with densitometry of P2 and S2 fractions: 88% of EAT-3, 12% of tubulin, and 98% of MOMA-1 is in the mitochondrial pellet."
EAT-3 is protease-protected in intact mitochondria

"Protease protection experiment to determine the submitochondrial localization... MOMA-1 is digested when no detergent is added, like MFF-1, while EAT-3 and F1beta are protease protected."
EAT-3 used as IMS marker in protease protection experiments

"MOMA-1 is digested when no detergent is added, like MFF-1, while EAT-3 and F1beta are protease protected."

file:worm/eat-3/eat-3-deep-research-falcon.md

Deep research review of eat-3 gene function

Suggested Experiments

Experiment: Determine if EAT-3 exists in long and short forms like mammalian OPA1

Experiment: Test for physical interaction between EAT-3 and IMMT-1 (mitofilin)

Experiment: Measure in vitro GTPase activity of purified EAT-3

📚 Additional Documentation

Deep Research Falcon

(eat-3-deep-research-falcon.md)

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gene_id: eat-3
gene_symbol: eat-3
uniprot_accession: Q18965
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EC=3.6.5.5 {ECO:0000256|ARBA:ARBA00011980};'
gene_info: Name=eat-3 {ECO:0000313|EMBL:CAA87771.3, ECO:0000313|WormBase:D2013.5};
ORFNames=CELE_D2013.5 {ECO:0000313|EMBL:CAA87771.3}, D2013.5 {ECO:0000313|WormBase:D2013.5};
organism_full: Caenorhabditis elegans.
protein_family: Not specified in UniProt
protein_domains: Dynamin. (IPR022812); Dynamin_GTPase. (IPR001401); Dynamin_N. (IPR045063);
G_DYNAMIN_dom. (IPR030381); OPA1_C. (IPR045817)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q18965
Protein Description: RecName: Full=Dynamin-like GTPase OPA1, mitochondrial {ECO:0000256|ARBA:ARBA00044791}; EC=3.6.5.5 {ECO:0000256|ARBA:ARBA00011980};
Gene Information: Name=eat-3 {ECO:0000313|EMBL:CAA87771.3, ECO:0000313|WormBase:D2013.5}; ORFNames=CELE_D2013.5 {ECO:0000313|EMBL:CAA87771.3}, D2013.5 {ECO:0000313|WormBase:D2013.5};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: Dynamin. (IPR022812); Dynamin_GTPase. (IPR001401); Dynamin_N. (IPR045063); G_DYNAMIN_dom. (IPR030381); OPA1_C. (IPR045817)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "eat-3" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'eat-3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene eat-3 (gene ID: eat-3, UniProt: Q18965) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q18965
Protein Description: RecName: Full=Dynamin-like GTPase OPA1, mitochondrial {ECO:0000256|ARBA:ARBA00044791}; EC=3.6.5.5 {ECO:0000256|ARBA:ARBA00011980};
Gene Information: Name=eat-3 {ECO:0000313|EMBL:CAA87771.3, ECO:0000313|WormBase:D2013.5}; ORFNames=CELE_D2013.5 {ECO:0000313|EMBL:CAA87771.3}, D2013.5 {ECO:0000313|WormBase:D2013.5};
Organism (full): Caenorhabditis elegans.
Protein Family: Not specified in UniProt
Key Domains: Dynamin. (IPR022812); Dynamin_GTPase. (IPR001401); Dynamin_N. (IPR045063); G_DYNAMIN_dom. (IPR030381); OPA1_C. (IPR045817)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "eat-3" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene eat-3 (gene ID: eat-3, UniProt: Q18965) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Functional annotation of C. elegans eat-3 (UniProt Q18965)

Identity verification and gene/protein definition
- Gene/protein identity: eat-3 (WormBase locus D2013.5) in Caenorhabditis elegans encodes the ortholog of mammalian OPA1 and yeast Mgm1, a dynamin-family large GTPase required for mitochondrial inner membrane (IMM) fusion and cristae organization. The EAT-3 protein contains a mitochondrial targeting sequence and the canonical dynamin GTPase, middle, and GED/assembly domains, consistent with a membrane-remodeling GTPase mechanism (UniProt Q18965 context supported by Kanazawa et al., 2008). Domain location and orthology match the UniProt note on Dynamin_GTPase and OPA1_C domains (IPR001401; IPR045817) (kanazawa2008thec.elegans pages 2-3, kanazawa2008thec.elegans pages 3-4, kanazawa2008thec.elegans pages 1-2).
- Organism: Caenorhabditis elegans (confirmed in PLoS Genetics foundational study) (kanazawa2008thec.elegans pages 1-2).

Key concepts and current understanding
- Molecular function: EAT-3/OPA1 is a dynamin-like GTPase that catalyzes IMM fusion and remodels cristae. In C. elegans, eat-3 loss causes mitochondrial fragmentation with inner membrane septation, indicating a specific defect in IMM fusion. Mechanistically, conserved GTP-binding motifs in EAT-3 underpin GTPase-driven membrane remodeling; intragenic suppressors cluster near the GTPase G2 loop, supporting functional importance of nucleotide-coupled conformational changes (Kanazawa et al., 2008). Recent human OPA1 structural work elucidates how OPA1 assemblies remodel membranes, reinforcing the conserved mechanistic paradigm relevant to EAT-3 (von der Malsburg et al., 2023 Nature) (kanazawa2008thec.elegans pages 1-2, kanazawa2008thec.elegans pages 3-4, malsburg2023structuralmechanismof pages 1-4).
- Subcellular localization: EAT-3 is a mitochondrial protein with an N-terminal leader that targets to the intermembrane space/IMM, consistent with its role in IMM fusion/cristae organization (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 1-2).
- Biological processes and pathways: EAT-3 functions in mitochondrial dynamics—coordinated with FZO-1/mitofusin (outer membrane fusion) and DRP-1 (fission)—to maintain tubular networks and cristae architecture that support oxidative phosphorylation and mtDNA maintenance. Disruption of eat-3 impacts organismal physiology (growth, brood size, stress resistance) and oxidative metabolism (Kanazawa et al., 2008; Byrne et al., 2019). Reviews emphasize OPA1’s pleiotropic roles in cristae shaping, bioenergetics, and stress signaling (Caron & Bertolin, 2024 J Cell Sci; Wai, 2024 Trends Endocrinol Metab) (kanazawa2008thec.elegans pages 9-10, byrne2019disruptionofmitochondrial pages 1-2, caron2024cristaeshapingand pages 1-4, wai2024ismitochondrialmorphology pages 1-4).

Recent developments and latest research (2023–2024 priority)
- Structural mechanism and in situ architecture: High-resolution structural and in situ cell studies reveal how the balance of OPA1 forms controls cristae architecture. Cryo-ET in mammalian cells shows increased long-form OPA1 (l-OPA1) promotes crista stacking and elongated mitochondria, whereas elevated short-form OPA1 (s-OPA1) correlates with irregular crista packing and round mitochondria; l/s imbalance compromises respiration, linking OPA1 state to function (Fry et al., 2024 EMBO J; published online Jan 15, 2024; DOI: 10.1038/s44318-024-00027-2) (fry2024insituarchitecture pages 1-2). Complementary structural work delineates human OPA1 membrane-remodeling assemblies (von der Malsburg et al., 2023 Nature; Aug 2023; DOI: 10.1038/s41586-023-06441-6) (malsburg2023structuralmechanismof pages 1-4).
- Proteolytic regulation and stress signaling: Reviews synthesize evidence that OMA1/YME1L/Parl-mediated processing of OPA1 regulates fusion competence. Acute loss of mitochondrial membrane potential activates OMA1, cleaving fusion-active l-OPA1 to s-OPA1, reducing fusion and favoring DRP1-mediated fragmentation; this positions OMA1 upstream of apoptosis, autophagy, and integrated stress response cascades (Gilkerson et al., 2024 Int J Mol Sci; Apr 22, 2024; DOI: 10.3390/ijms25084566). These regulatory insights generalize to OPA1 orthologs, informing interpretation of EAT-3 function under stress (gilkerson2024oma1mediatedmitochondrialdynamics pages 1-2).
- Nucleoid distribution and mtDNA: OPA1 loss decreases mtDNA and nucleoid abundance, and both OPA1 loss and disease-causing mutants perturb nucleoid distribution relative to cristae; OPA1 isoform-specific rescue partially restores defects (Macuada et al., 2024 Cell Death & Disease; Nov 2024; DOI: 10.1038/s41419-024-07165-9). These findings mechanistically connect cristae remodeling by OPA1-family GTPases to genome organization, supporting observations that eat-3 affects oxidative capacity and mitochondrial integrity (macuada2024opa1anddiseasecausing pages 1-2).
- Worm implementations for resilience and aging: In C. elegans, ubiquitous overexpression of eat-3 (and of fzo-1/drp-1) unexpectedly increases mitochondrial fragmentation yet extends lifespan and enhances stress resistance, indicating that boosting dynamics machinery can induce pro-resilience programs independent of maintaining youthful morphology (Traa et al., 2024 Aging Cell; Jul 2024; DOI: 10.1111/acel.14262) (traa2024overexpressionofmitochondrial pages 1-2).

Primary function, substrates, and specificity
- Enzymatic activity: EAT-3 is a large dynamin-like GTPase (EC 3.6.5.5) that hydrolyzes GTP to drive IMM fusion and cristae membrane remodeling. Substrate: GTP; functional substrate context: juxtaposed inner mitochondrial membranes enriched in cardiolipin (inferred from OPA1 literature) and crista junction regions; specificity derives from IMM localization and proteolytic state (l- vs s-EAT-3/OPA1) (Kanazawa et al., 2008; von der Malsburg et al., 2023; Fry et al., 2024) (kanazawa2008thec.elegans pages 3-4, malsburg2023structuralmechanismof pages 1-4, fry2024insituarchitecture pages 1-2).

Cellular localization and site of action
- EAT-3 localizes to the IMM/IMS and acts at inner boundary membranes and crista junctions to mediate IMM fusion and maintain cristae ultrastructure, consistent with the observed inner-septation phenotype upon loss (Kanazawa et al., 2008; Fry et al., 2024) (kanazawa2008thec.elegans pages 1-2, fry2024insituarchitecture pages 1-2).

Pathways and mechanistic integration
- Mitochondrial dynamics: EAT-3 acts in concert with FZO-1 (outer membrane fusion) and is balanced against DRP-1-driven fission. Genetic interactions in worms show that reducing fission (drp-1 loss) can suppress some eat-3 oxidative-stress phenotypes, illustrating network-level compensation (Kanazawa et al., 2008; Byrne et al., 2019) (kanazawa2008thec.elegans pages 8-9, byrne2019disruptionofmitochondrial pages 1-2).
- Stress signaling and proteolysis: OMA1 activation under Δψm loss cleaves l-OPA1 to s-OPA1, limiting IMM fusion and promoting fragmentation, coupling EAT-3/OPA1 to apoptosis/autophagy/ISR readiness. This regulation explains stress-dependent morphology transitions seen across models (Gilkerson et al., 2024) (gilkerson2024oma1mediatedmitochondrialdynamics pages 1-2).
- Genome maintenance: OPA1-family function maintains cristae organization that positions nucleoids; loss or mutant OPA1 disrupts nucleoid arrays and reduces mtDNA, linking membrane remodeling to genetic stability. This underpins observations that eat-3 mutants have respiration-linked defects (Macuada et al., 2024) (macuada2024opa1anddiseasecausing pages 1-2).

Organismal phenotypes and quantitative data in C. elegans
- Mitochondrial ultrastructure: In eat-3 mutants, internal IMM septa are frequent (~63% of mitochondria) versus ~0.5% in wild type. Total cristae length per mitochondrion is reduced to 1.21 mm (n=20, SD=0.78) from 7.34 mm in WT (n=16, SD=3.80); inner boundary membrane length is reduced to 2.62 mm (n=20, SD=0.91) from 5.38 mm in WT (n=16, SD=2.64), indicating ~66–70% loss of cristae content (Kanazawa et al., 2008; PLoS Genet; Feb 2008; DOI: 10.1371/journal.pgen.1000022) (kanazawa2008thec.elegans pages 4-5).
- Oxidative stress and compensation: eat-3(ad426) animals are hypersensitive to paraquat; Fe/Mn-SOD is induced >2-fold, largely via mitochondrial SOD-2. sod-2 RNAi or sod-2(gk257) exacerbates eat-3 phenotypes, while reducing fission (drp-1 RNAi or nonsense alleles) suppresses SOD induction and paraquat sensitivity (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 8-9, kanazawa2008thec.elegans pages 9-10).
- Growth, fertility, and rescue: eat-3 mutants are small, slow-growing, and have reduced brood size. Transgenic rescue increases progeny reaching L4 from mean 10 (SD=8, n=28) to 30 (SD=22, n=26), confirming causality (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 3-4).
- Behavior and lifespan context: Disruption of fusion (EAT-3/FZO-1) versus fission (DRP-1) produces distinct, progressive deficits in locomotion and tissue function; fusion disruption tends to be more severe. Median lifespan is reduced, while maximum lifespan remains unchanged in dynamics mutants, implicating mitochondrial dynamics in lifespan variance (Byrne et al., 2019; CMLS; Mar 2019; DOI: 10.1007/s00018-019-03024-5) (byrne2019disruptionofmitochondrial pages 1-2).

Current applications and real-world implementations in C. elegans research
- Genetic models: eat-3 null/strong loss-of-function (tm1107, ad426) and transgenic rescue lines are standard tools to dissect IMM fusion, cristae formation, and oxidative stress responses in vivo. Quantitative EM, paraquat survival, SOD induction, and brood/fitness assays are routinely used readouts (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 4-5, kanazawa2008thec.elegans pages 8-9, kanazawa2008thec.elegans pages 3-4).
- Aging and resilience: Overexpression of eat-3 and fzo-1 or drp-1 is used to probe how augmenting dynamics machinery modulates stress resistance and lifespan; despite increased fragmentation, both fission and fusion gene overexpression extend lifespan and increase stress resistance, indicating a mitohormetic mechanism and network-level remodeling of stress pathways (Traa et al., 2024) (traa2024overexpressionofmitochondrial pages 1-2).

Expert opinions and authoritative analyses
- Reviews synthesize that OPA1’s role in crista maintenance is mechanistically distinct from IMM fusion per se, with proteolytic regulation by OMA1 central to stress-adaptive remodeling (Gilkerson et al., 2024; review) (gilkerson2024oma1mediatedmitochondrialdynamics pages 1-2). Broader expert analyses emphasize cristae as dynamic compartments whose protein and lipid composition—including OPA1—govern bioenergetic capacity and signaling, reframing morphology-function relationships (Caron & Bertolin, 2024; Wai, 2024) (caron2024cristaeshapingand pages 1-4, wai2024ismitochondrialmorphology pages 1-4).

Relevant statistics and data (selected)
- Cristae metrics in eat-3 vs WT: total cristae length 1.21 mm vs 7.34 mm; inner boundary membrane 2.62 mm vs 5.38 mm (per mitochondrion; electron tomography quantitation). IMM septation frequency ~63% vs ~0.5% WT (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 4-5).
- Stress markers: Fe/Mn-SOD induction >2-fold in eat-3(ad426); paraquat hypersensitivity assays show strong sensitivity of eat-3 compared to WT and to fzo-1 mutants (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 8-9).
- Genetic rescue: Progeny reaching L4 increased from mean 10 to 30 upon eat-3 cDNA rescue (Kanazawa et al., 2008) (kanazawa2008thec.elegans pages 3-4).
- Dynamics and lifespan: Disruption of fusion/fission yields progressive motor/tissue deficits; reduced median but unchanged maximal lifespan indicates altered longevity distribution (Byrne et al., 2019) (byrne2019disruptionofmitochondrial pages 1-2).

Verification against potential symbol ambiguity
- The literature consistently identifies eat-3 in C. elegans (D2013.5) as the OPA1 ortholog encoding a mitochondrial dynamin-like GTPase with canonical dynamin domains, matching the UniProt Q18965 entry. No conflicting gene symbol usage was identified in other organisms within the evidence base consulted (Kanazawa et al., 2008; Byrne et al., 2019; reviews 2024) (kanazawa2008thec.elegans pages 1-2, byrne2019disruptionofmitochondrial pages 1-2, caron2024cristaeshapingand pages 1-4, wai2024ismitochondrialmorphology pages 1-4).

Embedded evidence summary table
| Aspect | Key Findings (1–3 sentences) | Model / organism | Year | Citation (authors / journal) | URL |
|---|---|---:|---:|---|---|
| Identity / orthology & domains | eat-3 (D2013.5) encodes the C. elegans ortholog of OPA1/Mgm1, a dynamin‑family GTPase with an N-terminal mitochondrial targeting sequence and conserved GTPase, middle and GED/assembly domains consistent with membrane-remodeling activity. | Caenorhabditis elegans | 2008 | Kanazawa et al., PLoS Genetics (kanazawa2008thec.elegans pages 2-3) | https://doi.org/10.1371/journal.pgen.1000022 |
| Subcellular localization | EAT-3 is targeted to mitochondria and localizes to the intermembrane space/inner mitochondrial membrane via an N-terminal leader sequence. | C. elegans | 2008 | Kanazawa et al., PLoS Genetics (kanazawa2008thec.elegans pages 1-2) | https://doi.org/10.1371/journal.pgen.1000022 |
| Molecular function | EAT-3/OPA1 is a dynamin-like GTPase required for inner mitochondrial membrane (IMM) fusion and membrane remodeling (cristae shaping); GTPase activity and oligomerization are central to its mechanistic role. | C. elegans; conserved in metazoans | 2008, 2023 | Kanazawa et al., PLoS Genetics; von der Malsburg et al., Nature (kanazawa2008thec.elegans pages 3-4, malsburg2023structuralmechanismof pages 1-4) | https://doi.org/10.1371/journal.pgen.1000022; https://doi.org/10.1038/s41586-023-06441-6 |
| Biological processes / pathways | EAT-3 mediates IMM fusion and cristae architecture, influences oxidative phosphorylation and mtDNA maintenance, and interfaces with mitochondrial dynamics (FZO-1/MFN, DRP-1/DRP1) and stress-response pathways. | C. elegans; relevance to metazoan OPA1 biology | 2008, 2024 | Kanazawa et al., PLoS Genetics; Caron & Bertolin, J Cell Sci (kanazawa2008thec.elegans pages 9-10, caron2024cristaeshapingand pages 1-4) | https://doi.org/10.1371/journal.pgen.1000022; https://doi.org/10.1242/jcs.260986 |
| Regulation (OMA1 / YME1L proteolysis) | OPA1 exists as long (l-) and short (s-) forms produced by proteolytic processing (OMA1/YME1L/Parl family); stress-activated cleavage (e.g., by OMA1) shifts the l/s balance, reducing fusion competence and promoting fragmentation. | Mammalian mechanistic studies (applicable to OPA1 orthologs) | 2024 | Gilkerson et al., Int J Mol Sci; Fry et al., EMBO J (gilkerson2024oma1mediatedmitochondrialdynamics pages 1-2, fry2024insituarchitecture pages 1-2) | https://doi.org/10.3390/ijms25084566; https://doi.org/10.1038/s44318-024-00027-2 |
| Key organismal phenotypes (C. elegans) | eat-3 loss-of-function animals are smaller, slow-growing, sluggish, have reduced brood sizes and fragmented mitochondria with disorganized inner membranes and internal septae; phenotypes include hypersensitivity to oxidative stress and genetic interactions with drp-1 and sod-2. | C. elegans eat-3(ad426), tm1107 alleles | 2008 | Kanazawa et al., PLoS Genetics (kanazawa2008thec.elegans pages 8-9, kanazawa2008thec.elegans pages 9-9) | https://doi.org/10.1371/journal.pgen.1000022 |
| Quantitative data (selected) | Ultrastructure: total cristae length reported 1.21 mm in eat-3 vs 7.34 mm in wildtype; inner boundary membrane length 2.62 mm vs 5.38 mm (per mitochondrion, reported n values provided). Septae/internal septation: ~63% of eat-3 mitochondria vs ~0.5% WT. SOD-2 expression induced >2-fold in eat-3(ad426). Broodsize rescue: progeny reaching L4 increased from mean 10 (SD=8, n=28) to 30 (SD=22, n=26) with transgenic rescue. | C. elegans (Kanazawa et al.) | 2008 | Kanazawa et al., PLoS Genetics (kanazawa2008thec.elegans pages 4-5, kanazawa2008thec.elegans pages 8-9, kanazawa2008thec.elegans pages 3-4) | https://doi.org/10.1371/journal.pgen.1000022 |
| Recent (2023–2024) advances | High-resolution structural studies (human OPA1) define membrane-remodeling mechanisms; in situ cryo-ET shows l- vs s-OPA1 balance governs cristae stacking and mitochondrial shape; OPA1 perturbation alters nucleoid distribution and mtDNA levels, linking cristae remodeling to nucleoid organization. | Human / mammalian studies (structural & cellular) with relevance to eat-3 function | 2023–2024 | von der Malsburg et al., Nature; Fry et al., EMBO J; Macuada et al., Cell Death & Disease (malsburg2023structuralmechanismof pages 1-4, fry2024insituarchitecture pages 1-2, macuada2024opa1anddiseasecausing pages 1-2) | https://doi.org/10.1038/s41586-023-06441-6; https://doi.org/10.1038/s44318-024-00027-2; https://doi.org/10.1038/s41419-024-07165-9 |
| Applications / implementations | eat-3 mutants and overexpression lines are used as worm models of inner-membrane fusion/cristae defects; ubiquitous overexpression of eat-3 (and fzo-1/drp-1) modulates stress resistance and extends lifespan despite increased fragmentation, providing tools for resilience and aging studies. | C. elegans experimental models (OE and loss-of-function) | 2024 (application study) | Traa et al., Aging Cell (traa2024overexpressionofmitochondrial pages 1-2) | https://doi.org/10.1111/acel.14262 |

Table: Compact, sourced summary of key molecular, cellular, quantitative, and recent findings for C. elegans eat-3 (UniProt Q18965), with citations to the provided evidence contexts for quick reference.

Key sources with URLs and dates
- Kanazawa T et al. The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals. PLoS Genetics. Feb 2008. https://doi.org/10.1371/journal.pgen.1000022 (kanazawa2008thec.elegans pages 1-2, kanazawa2008thec.elegans pages 4-5, kanazawa2008thec.elegans pages 8-9, kanazawa2008thec.elegans pages 3-4, kanazawa2008thec.elegans pages 9-10).
- Fry MY et al. In situ architecture of Opa1-dependent mitochondrial cristae remodeling. The EMBO Journal. Published online Jan 15, 2024. https://doi.org/10.1038/s44318-024-00027-2 (fry2024insituarchitecture pages 1-2).
- von der Malsburg A et al. Structural mechanism of mitochondrial membrane remodelling by human OPA1. Nature. Aug 2023. https://doi.org/10.1038/s41586-023-06441-6 (malsburg2023structuralmechanismof pages 1-4).
- Gilkerson R et al. OMA1-mediated mitochondrial dynamics balance organellar homeostasis upstream of cellular stress responses. Int J Mol Sci. Apr 22, 2024. https://doi.org/10.3390/ijms25084566 (gilkerson2024oma1mediatedmitochondrialdynamics pages 1-2).
- Caron C, Bertolin G. Cristae shaping and dynamics in mitochondrial function. J Cell Sci. Jan 2024. https://doi.org/10.1242/jcs.260986 (caron2024cristaeshapingand pages 1-4).
- Wai T. Is mitochondrial morphology important for cellular physiology? Trends Endocrinol Metab. Oct 2024. https://doi.org/10.1016/j.tem.2024.05.005 (wai2024ismitochondrialmorphology pages 1-4).
- Byrne JJ et al. Disruption of mitochondrial dynamics affects behaviour and lifespan in C. elegans. Cell Mol Life Sci. Mar 2019. https://doi.org/10.1007/s00018-019-03024-5 (byrne2019disruptionofmitochondrial pages 1-2).
- Traa A et al. Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity. Aging Cell. Jul 2024. https://doi.org/10.1111/acel.14262 (traa2024overexpressionofmitochondrial pages 1-2).

References

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(kanazawa2008thec.elegans pages 8-9): Takayuki Kanazawa, Mauro Zappaterra, Ayako Hasegawa, Ashley P Wright, Erin D Newman-Smith, Karolyn F Buttle, Kent L McDonald, Carmen Mannella, and Alex van der Bliek. The c. elegans opa1 homologue eat-3 is essential for resistance to free radicals. PLoS Genetics, 4:e39, Feb 2008. URL: https://doi.org/10.1371/journal.pgen.1000022, doi:10.1371/journal.pgen.1000022. This article has 193 citations and is from a domain leading peer-reviewed journal.
(kanazawa2008thec.elegans pages 4-5): Takayuki Kanazawa, Mauro Zappaterra, Ayako Hasegawa, Ashley P Wright, Erin D Newman-Smith, Karolyn F Buttle, Kent L McDonald, Carmen Mannella, and Alex van der Bliek. The c. elegans opa1 homologue eat-3 is essential for resistance to free radicals. PLoS Genetics, 4:e39, Feb 2008. URL: https://doi.org/10.1371/journal.pgen.1000022, doi:10.1371/journal.pgen.1000022. This article has 193 citations and is from a domain leading peer-reviewed journal.
(kanazawa2008thec.elegans pages 9-9): Takayuki Kanazawa, Mauro Zappaterra, Ayako Hasegawa, Ashley P Wright, Erin D Newman-Smith, Karolyn F Buttle, Kent L McDonald, Carmen Mannella, and Alex van der Bliek. The c. elegans opa1 homologue eat-3 is essential for resistance to free radicals. PLoS Genetics, 4:e39, Feb 2008. URL: https://doi.org/10.1371/journal.pgen.1000022, doi:10.1371/journal.pgen.1000022. This article has 193 citations and is from a domain leading peer-reviewed journal.

Citations

fry2024insituarchitecture pages 1-2
malsburg2023structuralmechanismof pages 1-4
traa2024overexpressionofmitochondrial pages 1-2
byrne2019disruptionofmitochondrial pages 1-2
caron2024cristaeshapingand pages 1-4
wai2024ismitochondrialmorphology pages 1-4
https://doi.org/10.1371/journal.pgen.1000022
https://doi.org/10.1371/journal.pgen.1000022;
https://doi.org/10.1038/s41586-023-06441-6
https://doi.org/10.1242/jcs.260986
https://doi.org/10.3390/ijms25084566;
https://doi.org/10.1038/s44318-024-00027-2
https://doi.org/10.1038/s41586-023-06441-6;
https://doi.org/10.1038/s44318-024-00027-2;
https://doi.org/10.1038/s41419-024-07165-9
https://doi.org/10.1111/acel.14262
https://doi.org/10.3390/ijms25084566
https://doi.org/10.1016/j.tem.2024.05.005
https://doi.org/10.1007/s00018-019-03024-5
https://doi.org/10.1371/journal.pgen.1000022,
https://doi.org/10.1038/s41586-023-06441-6,
https://doi.org/10.1007/s00018-019-03024-5,
https://doi.org/10.1242/jcs.260986,
https://doi.org/10.1016/j.tem.2024.05.005,
https://doi.org/10.1038/s44318-024-00027-2,
https://doi.org/10.3390/ijms25084566,
https://doi.org/10.1038/s41419-024-07165-9,
https://doi.org/10.1111/acel.14262,

📄 View Raw YAML

id: Q18965
gene_symbol: eat-3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: EAT-3 is the C. elegans ortholog of mammalian OPA1 and yeast Mgm1, 
  a dynamin-family large GTPase required for mitochondrial inner membrane fusion
  and cristae organization. The protein contains a mitochondrial targeting 
  sequence, a conserved GTPase domain, a middle domain, and a GED/assembly 
  domain characteristic of dynamin family members. EAT-3 is localized to the 
  mitochondrial inner membrane and intermembrane space where it mediates inner 
  membrane fusion. Loss of eat-3 function causes mitochondrial fragmentation 
  with characteristic inner membrane septae dividing the matrix, a phenotype 
  specifically indicative of defective inner membrane fusion. eat-3 mutants show
  reduced cristae content, slow growth, small body size, reduced brood size, and
  hypersensitivity to oxidative stress (paraquat), with compensatory induction 
  of mitochondrial SOD-2. The gene was originally identified in feeding behavior
  screens (Eating defective), likely reflecting the metabolic consequences of 
  mitochondrial dysfunction affecting pharyngeal muscle function.
existing_annotations:
  - term:
      id: GO:0003924
      label: GTPase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EAT-3 is a dynamin-like GTPase with a conserved GTPase domain 
        containing G1-G4 motifs. The primary eat-3(ad426) mutation affects a 
        residue near the G2 motif, and intragenic suppressors cluster around 
        GTPase domain residues (PMID:18454199).
      action: ACCEPT
      reason: GTPase activity is the core enzymatic function of EAT-3. The 
        protein contains canonical dynamin GTPase, middle, and GED domains. 
        Mutations in the GTPase domain cause loss of function, and second-site 
        suppressors restore GTPase function (PMID:18454199).
      additional_reference_ids:
        - file:worm/eat-3/eat-3-deep-research-falcon.md
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: 'Similar to yeast Mgm1 and mammalian Opa1, this C. elegans
            protein has a putative mitochondrial targeting sequence followed by domains
            that are typical of dynamin family members: a conserved GTPase domain,
            a middle domain and a GED or assembly domain'
        - reference_id: PMID:18454199
          supporting_text: The affected residue is just downstream of the G2 
            threonine in the effector binding loop of the dynamin-like GTPase, 
            where it may disrupt the GTPase cycle.
        - reference_id: file:worm/eat-3/eat-3-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is overly broad. EAT-3 localizes specifically to 
        mitochondria, not the general cytoplasm. While technically mitochondria 
        are within the cytoplasm, more specific localization terms are 
        available.
      action: MARK_AS_OVER_ANNOTATED
      reason: EAT-3 has a mitochondrial targeting sequence and localizes to 
        mitochondria. More specific compartment annotations (mitochondrial inner
        membrane, intermembrane space) are more informative. This IBA annotation
        likely derives from broader dynamin family members that have cytoplasmic
        localization.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0008053
      label: mitochondrial fusion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EAT-3 is required for mitochondrial fusion, specifically the 
        inner membrane fusion step. This is the core biological process function
        of the protein (PMID:18454199).
      action: ACCEPT
      reason: Mitochondrial fusion is the primary biological process function of
        EAT-3. Loss of eat-3 causes mitochondrial fragmentation that can be 
        suppressed by loss of the fission protein DRP-1, confirming a role in 
        fusion. The IBA annotation is well-supported by phylogenetic inference 
        from mammalian OPA1 and yeast Mgm1.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Evidence for the role of Opa1 in fusion between 
            mitochondrial inner membranes initially came from studies of the 
            yeast homologue of Opa1, which is called Mgm1.
        - reference_id: PMID:18454199
          supporting_text: Similar mitochondrial fragmentation is observed in 
            muscle cells of fzo-1(tm1133) mutants... The mitochondria of eat-3 
            and fzo-1 mutants are similarly fragmented consistent with their 
            roles in mitochondrial fusion.
  - term:
      id: GO:0031966
      label: mitochondrial membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EAT-3 is localized to mitochondrial membranes, specifically the 
        inner membrane. This annotation is acceptable but could be more 
        specific.
      action: ACCEPT
      reason: The annotation is correct - EAT-3 is a mitochondrial membrane 
        protein. More specific annotations to inner membrane and intermembrane 
        space are also present, making this a reasonable general annotation.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0016559
      label: peroxisome fission
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is questionable for EAT-3. While some dynamin 
        family members are involved in peroxisome fission, there is no direct 
        evidence for EAT-3 function in peroxisomes. EAT-3/OPA1 is specifically a
        mitochondrial protein.
      action: REMOVE
      reason: EAT-3 is specifically localized to mitochondria via its 
        mitochondrial targeting sequence and functions in mitochondrial inner 
        membrane fusion. There is no published evidence for peroxisomal 
        localization or function of EAT-3 in C. elegans. This IBA annotation 
        appears to be an over-extension from other dynamin family members (like 
        DRP1/DNM1) that do participate in peroxisome fission, but 
        OPA1/Mgm1/EAT-3 orthologs are mitochondria-specific.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0005758
      label: mitochondrial intermembrane space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EAT-3 localizes to the mitochondrial intermembrane space, 
        consistent with its ortholog OPA1/Mgm1 (PMID:18454199).
      action: ACCEPT
      reason: The protein contains a mitochondrial leader sequence that targets 
        it to the intermembrane space, and it functions at the inner membrane, 
        consistent with IMS localization. This is well-supported by studies of 
        the mammalian and yeast orthologs.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Biochemical analysis shows that yeast Mgm1 and 
            mammalian Opa1 are localized to the mitochondrial intermembrane 
            space
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0005874
      label: microtubule
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation appears to be an over-extension from other 
        dynamin family members. EAT-3 is a mitochondrial protein with no 
        evidence for microtubule localization.
      action: REMOVE
      reason: EAT-3/OPA1/Mgm1 are mitochondrial inner membrane/intermembrane 
        space proteins. There is no published evidence for EAT-3 localization to
        microtubules in C. elegans. This IBA annotation likely derives from 
        classical dynamins (like DYN-1) or DRP-1 which can associate with 
        microtubules, but this does not apply to the OPA1 subfamily.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0008017
      label: microtubule binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: This annotation is inappropriate for EAT-3. The protein is 
        localized to mitochondria and has no documented microtubule binding 
        activity.
      action: REMOVE
      reason: EAT-3 is a mitochondrial inner membrane/IMS protein with a 
        mitochondrial targeting sequence. There is no evidence that EAT-3 binds 
        microtubules. This IBA annotation appears to be an inappropriate 
        transfer from other dynamin family members (classical dynamins, not the 
        OPA1/Mgm1 subfamily).
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: EAT-3 is a GTPase that binds GTP/GDP. This annotation is correct 
        but very general; GTP binding is the more specific and informative 
        annotation.
      action: ACCEPT
      reason: As a GTPase, EAT-3 binds nucleotides (GTP and GDP). This is a 
        correct but general annotation derived from UniProt keyword mapping. The
        more specific GTP binding annotation is also present.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: 'Similar to yeast Mgm1 and mammalian Opa1, this C. elegans
            protein has a putative mitochondrial targeting sequence followed by domains
            that are typical of dynamin family members: a conserved GTPase domain'
  - term:
      id: GO:0003924
      label: GTPase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: GTPase activity is the core enzymatic function of EAT-3, derived 
        from InterPro domain annotation. This duplicates the IBA annotation 
        above.
      action: ACCEPT
      reason: The InterPro-based annotation correctly identifies GTPase activity
        based on the dynamin GTPase domain. This is a core function 
        well-supported by the protein structure and mutant analysis.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: 'Similar to yeast Mgm1 and mammalian Opa1, this C. elegans
            protein has a putative mitochondrial targeting sequence followed by domains
            that are typical of dynamin family members: a conserved GTPase domain'
  - term:
      id: GO:0005525
      label: GTP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EAT-3 is a GTPase that binds GTP. This is a core molecular 
        function annotation derived from domain analysis.
      action: ACCEPT
      reason: GTP binding is required for GTPase activity. The dynamin GTPase 
        domain contains conserved GTP binding motifs (G1-G4). The eat-3(ad426) 
        mutation near the G2 motif disrupts function, confirming the importance 
        of GTP binding.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: The affected residue is just downstream of the G2 
            threonine in the effector binding loop of the dynamin-like GTPase, 
            where it may disrupt the GTPase cycle.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EAT-3 is localized to the mitochondrial inner membrane, 
        consistent with its function in inner membrane fusion.
      action: ACCEPT
      reason: EAT-3 functions at the mitochondrial inner membrane where it 
        mediates inner membrane fusion. The UniProt subcellular location 
        annotation is well-supported by the biological function and ortholog 
        studies.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Electron microscopy shows that the matrices of 
            fragmented mitochondria in eat-3 mutants are divided by inner 
            membrane septae, suggestive of a specific defect in fusion of the 
            mitochondrial inner membrane.
  - term:
      id: GO:0005758
      label: mitochondrial intermembrane space
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EAT-3 is targeted to the mitochondrial intermembrane space. This 
        duplicates the IBA annotation but is derived from UniProt subcellular 
        location mapping.
      action: ACCEPT
      reason: The protein has a mitochondrial leader sequence that targets it to
        the intermembrane space, consistent with the localization of OPA1 and 
        Mgm1 orthologs.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 has a mitochondrial leader sequence (mls) that 
            targets the protein to the mitochondrial intermembrane space.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Mammalian OPA1 has an established anti-apoptotic function. 
        However, in C. elegans, eat-3 does not appear to function in canonical 
        apoptosis (PMID:18454199, PMID:18722182).
      action: REMOVE
      reason: While mammalian OPA1 has anti-apoptotic functions, the C. elegans 
        eat-3 mutant phenotypes are not suppressed by ced-3 or ced-4 mutations, 
        indicating that caspase-dependent cell death does not contribute to 
        eat-3 phenotypes. The annotation is derived from UniProt keyword mapping
        but is not supported by experimental evidence in C. elegans.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Although mammalian Opa1 is antiapoptotic, mutations 
            in the canonical C. elegans cell death genes ced-3 and ced-4 do not 
            suppress the slow growth and small broodsize phenotypes of eat-3 
            mutants.
        - reference_id: PMID:18722182
          supporting_text: Here we report that profusion genes fzo-1 and eat-3 
            or the profission gene drp-1 are not required for apoptosis 
            activation in C. elegans.
  - term:
      id: GO:0008289
      label: lipid binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: OPA1 family proteins interact with cardiolipin in the inner 
        membrane. This annotation from UniProt keyword mapping has some basis in
        the function.
      action: ACCEPT
      reason: OPA1/Mgm1 proteins are known to interact with cardiolipin, a lipid
        enriched in the mitochondrial inner membrane, which is important for 
        their membrane fusion function. While not directly demonstrated for C. 
        elegans EAT-3, this is a conserved feature of the protein family.
      additional_reference_ids:
        - PMID:23226476
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: EAT-3 is required for fusion of mitochondrial inner 
            membranes [implying membrane interaction]
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: GTPase activity is a form of hydrolase activity (hydrolyzes GTP 
        to GDP + Pi). This is a correct but very general annotation.
      action: ACCEPT
      reason: GTPases catalyze hydrolysis of GTP, making them hydrolases. This 
        annotation is correct but very general; the more specific GTPase 
        activity annotation is more informative.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: 'Similar to yeast Mgm1 and mammalian Opa1, this C. elegans
            protein has a putative mitochondrial targeting sequence followed by domains
            that are typical of dynamin family members: a conserved GTPase domain'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:21248201
    review:
      summary: EAT-3 localizes to mitochondria as demonstrated by 
        co-fractionation and protease protection experiments in PMID:21248201.
      action: ACCEPT
      reason: This IDA annotation is supported by experimental data showing 
        EAT-3 co-fractionates with mitochondria and is protected from protease 
        digestion in intact mitochondria, confirming mitochondrial localization.
      supported_by:
        - reference_id: PMID:21248201
          supporting_text: 'Subcellular distribution of MOMA-1 determined by differential
            centrifugation... The distributions were quantified with densitometry
            of P2 and S2 fractions: 88% of EAT-3, 12% of tubulin, and 98% of MOMA-1
            is in the mitochondrial pellet.'
        - reference_id: PMID:21248201
          supporting_text: Protease protection experiment to determine the 
            submitochondrial localization... MOMA-1 is digested when no 
            detergent is added, like MFF-1, while EAT-3 and F1beta are protease 
            protected.
  - term:
      id: GO:0002119
      label: nematode larval development
    evidence_type: IGI
    original_reference_id: PMID:18454199
    review:
      summary: eat-3 mutants have slow development and growth defects. This is a
        phenotypic consequence of mitochondrial dysfunction rather than a core 
        function.
      action: KEEP_AS_NON_CORE
      reason: While eat-3 mutants do have developmental defects (slow growth, 
        delayed development), these are secondary consequences of impaired 
        mitochondrial function rather than a direct role in development. The 
        core function is mitochondrial inner membrane fusion.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Worms injected with eat-3 dsRNA give viable progeny 
            but their brood size is reduced... The F1 worms remain small, are 
            sluggish and develop slowly.
  - term:
      id: GO:0040014
      label: regulation of multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: eat-3 mutants show growth defects, but this is a pleiotropic 
        consequence of mitochondrial dysfunction rather than a direct regulatory
        role in growth.
      action: KEEP_AS_NON_CORE
      reason: eat-3 loss of function causes slow growth and small body size, but
        this is due to impaired mitochondrial function (oxidative 
        phosphorylation defects) rather than a direct role in regulating 
        organismal growth. The growth defects are consistent with metabolic 
        insufficiency.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: eat-3 RNAi worms rarely reach 0.5 mm, consistent with
            a previous study showing that the eat-3(ad426) mutant also remains 
            small... developmental decisions are normal, but the rate of 
            development is greatly reduced as one might expect from a general 
            decrease in metabolic activity.
  - term:
      id: GO:0040014
      label: regulation of multicellular organism growth
    evidence_type: IGI
    original_reference_id: PMID:18454199
    review:
      summary: This is a duplicate annotation with IGI evidence, showing genetic
        interactions affecting growth. Same reasoning as above - secondary 
        phenotype.
      action: KEEP_AS_NON_CORE
      reason: Growth phenotype is a secondary consequence of mitochondrial 
        dysfunction, not a core regulatory function.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: the phenotypes of eat-3 mutants are consistent with 
            defects in oxidative phosphorylation.
  - term:
      id: GO:0008053
      label: mitochondrial fusion
    evidence_type: IMP
    original_reference_id: PMID:18722182
    review:
      summary: Experimental evidence from PMID:18722182 supporting mitochondrial
        fusion role.
      action: ACCEPT
      reason: This is direct experimental evidence from C. elegans showing eat-3
        is required for mitochondrial fusion. This is the core biological 
        process function.
      supported_by:
        - reference_id: PMID:18722182
          supporting_text: profusion genes fzo-1 and eat-3 or the profission 
            gene drp-1 are not required for apoptosis activation in C. elegans 
            [but are required for fusion/fission respectively]
  - term:
      id: GO:0000303
      label: response to superoxide
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: eat-3 mutants are hypersensitive to paraquat and show induction 
        of SOD-2. This is a stress response consequence of mitochondrial 
        dysfunction.
      action: KEEP_AS_NON_CORE
      reason: eat-3 mutants show hypersensitivity to paraquat (superoxide) and 
        compensatory induction of SOD-2, but this is a consequence of 
        mitochondrial dysfunction leading to increased ROS production, not a 
        primary function in oxidative stress response.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: eat-3 mutants are hypersensitive to paraquat, which 
            promotes damage by free radicals, and they are sensitive to loss of 
            the mitochondrial superoxide dismutase sod-2. We conclude that free 
            radicals contribute to the pathology of C. elegans eat-3 mutants.
        - reference_id: PMID:18454199
          supporting_text: Fe/Mn-SOD expression is induced more than two-fold in
            eat-3(ad426) animals... This induction is almost entirely 
            attributable to SOD-2
  - term:
      id: GO:0007005
      label: mitochondrion organization
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: EAT-3 is essential for proper mitochondrial organization, 
        particularly inner membrane and cristae organization.
      action: ACCEPT
      reason: EAT-3 is required for proper mitochondrial morphology and 
        organization. Loss of EAT-3 leads to fragmented mitochondria with 
        disorganized inner membranes and reduced cristae. This is a direct 
        function of the protein.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: "The eat-3 mitochondria had on average 1.21 µm total cristae
            length (n = 20, SD = 0.78), compared with 7.34 µm in wildtype mitochondria
            (n = 16, SD = 3.80)"
  - term:
      id: GO:0008053
      label: mitochondrial fusion
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: Primary experimental evidence for mitochondrial fusion function 
        from the foundational eat-3 study.
      action: ACCEPT
      reason: This is the core biological process function of EAT-3, 
        demonstrated by mitochondrial fragmentation in mutants and suppression 
        by drp-1 loss of function.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: We find that mutations in the C. elegans eat-3 locus 
            cause mitochondria to fragment in agreement with the mutant 
            phenotypes observed in yeast and mammalian cells. Electron 
            microscopy shows that the matrices of fragmented mitochondria in 
            eat-3 mutants are divided by inner membrane septae, suggestive of a 
            specific defect in fusion of the mitochondrial inner membrane.
        - reference_id: PMID:18454199
          supporting_text: DRP-1(K40A) gives rise to interconnected 
            mitochondria, regardless of whether it is expressed in a wildtype 
            background, with antisense eat-3, or in an eat-3 mutant... We 
            conclude that a functioning mitochondrial division apparatus is 
            required for the mitochondrial fragmentation induced by mutant 
            eat-3.
  - term:
      id: GO:0035264
      label: multicellular organism growth
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: eat-3 mutants show reduced body size and growth, a consequence of
        mitochondrial dysfunction.
      action: KEEP_AS_NON_CORE
      reason: Growth defects are a secondary phenotype of mitochondrial 
        dysfunction, not a core function of EAT-3.
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: The F1 worms remain small, are sluggish and develop 
            slowly... eat-3 RNAi worms rarely reach 0.5 mm
  - term:
      id: GO:1990627
      label: mitochondrial inner membrane fusion
    evidence_type: IMP
    original_reference_id: PMID:18454199
    review:
      summary: EAT-3 specifically mediates mitochondrial inner membrane fusion, 
        as demonstrated by the characteristic inner membrane septae phenotype in
        eat-3 mutants.
      action: NEW
      reason: The existing GO:0008053 (mitochondrial fusion) annotation is 
        correct but GO:1990627 (mitochondrial inner membrane fusion) is more 
        specific and accurately describes the precise function of EAT-3. The 
        inner membrane septae phenotype is diagnostic for inner membrane fusion 
        defects.
      proposed_replacement_terms:
        - id: GO:1990627
          label: mitochondrial inner membrane fusion
      supported_by:
        - reference_id: PMID:18454199
          supporting_text: Electron microscopy shows that the matrices of 
            fragmented mitochondria in eat-3 mutants are divided by inner 
            membrane septae, suggestive of a specific defect in fusion of the 
            mitochondrial inner membrane.
        - reference_id: PMID:18454199
          supporting_text: EAT-3 is required for fusion of mitochondrial inner 
            membranes.
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:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:18454199
    title: The C. elegans Opa1 homologue EAT-3 is essential for resistance to 
      free radicals.
    findings:
      - statement: EAT-3 is the C. elegans ortholog of OPA1/Mgm1, with conserved
          dynamin domains
        supporting_text: 'Similar to yeast Mgm1 and mammalian Opa1, this C. elegans
          protein has a putative mitochondrial targeting sequence followed by domains
          that are typical of dynamin family members: a conserved GTPase domain, a
          middle domain and a GED or assembly domain'
      - statement: eat-3 mutations cause mitochondrial fragmentation with inner 
          membrane septae
        supporting_text: We find that mutations in the C. elegans eat-3 locus 
          cause mitochondria to fragment in agreement with the mutant phenotypes
          observed in yeast and mammalian cells. Electron microscopy shows that 
          the matrices of fragmented mitochondria in eat-3 mutants are divided 
          by inner membrane septae, suggestive of a specific defect in fusion of
          the mitochondrial inner membrane.
      - statement: eat-3 mutants have reduced cristae content (66% reduction)
        supporting_text: "The eat-3 mitochondria had on average 1.21 µm total cristae
          length (n = 20, SD = 0.78), compared with 7.34 µm in wildtype mitochondria
          (n = 16, SD = 3.80)"
      - statement: eat-3 mutants are hypersensitive to paraquat and induce SOD-2
        supporting_text: eat-3 mutants are hypersensitive to paraquat, which 
          promotes damage by free radicals, and they are sensitive to loss of 
          the mitochondrial superoxide dismutase sod-2. We conclude that free 
          radicals contribute to the pathology of C. elegans eat-3 mutants.
      - statement: drp-1 mutations suppress eat-3 phenotypes
        supporting_text: DRP-1(K40A) gives rise to interconnected mitochondria, 
          regardless of whether it is expressed in a wildtype background, with 
          antisense eat-3, or in an eat-3 mutant... We conclude that a 
          functioning mitochondrial division apparatus is required for the 
          mitochondrial fragmentation induced by mutant eat-3.
      - statement: ced-3/ced-4 mutations do not suppress eat-3 phenotypes
        supporting_text: Although mammalian Opa1 is antiapoptotic, mutations in 
          the canonical C. elegans cell death genes ced-3 and ced-4 do not 
          suppress the slow growth and small broodsize phenotypes of eat-3 
          mutants.
  - id: PMID:18722182
    title: Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death 
      execution pathways downstream of ced-3 and independent of ced-9.
    findings:
      - statement: eat-3 and fzo-1 are not required for apoptosis activation in 
          C. elegans
        supporting_text: Here we report that profusion genes fzo-1 and eat-3 or 
          the profission gene drp-1 are not required for apoptosis activation in
          C. elegans.
  - id: PMID:21248201
    title: A novel mitochondrial outer membrane protein, MOMA-1, that affects 
      cristae morphology in Caenorhabditis elegans.
    findings:
      - statement: EAT-3 co-fractionates with mitochondria (88% in mitochondrial
          pellet)
        supporting_text: 'Subcellular distribution of MOMA-1 determined by differential
          centrifugation... The distributions were quantified with densitometry of
          P2 and S2 fractions: 88% of EAT-3, 12% of tubulin, and 98% of MOMA-1 is
          in the mitochondrial pellet.'
      - statement: EAT-3 is protease-protected in intact mitochondria
        supporting_text: Protease protection experiment to determine the 
          submitochondrial localization... MOMA-1 is digested when no detergent 
          is added, like MFF-1, while EAT-3 and F1beta are protease protected.
      - statement: EAT-3 used as IMS marker in protease protection experiments
        supporting_text: MOMA-1 is digested when no detergent is added, like 
          MFF-1, while EAT-3 and F1beta are protease protected.
  - id: file:worm/eat-3/eat-3-deep-research-falcon.md
    title: Deep research review of eat-3 gene function
    findings: []
core_functions:
  - molecular_function:
      id: GO:0003924
      label: GTPase activity
    description: EAT-3 contains a conserved dynamin-type GTPase domain. 
      Mutations near the G2 motif disrupt function, and intragenic suppressors 
      restore GTPase activity (PMID:18454199).
    directly_involved_in:
      - id: GO:1990627
        label: mitochondrial inner membrane fusion
    locations:
      - id: GO:0005743
        label: mitochondrial inner membrane
      - id: GO:0005758
        label: mitochondrial intermembrane space
suggested_questions:
  - question: Does EAT-3 have proteolytic processing similar to mammalian OPA1 
      (l-OPA1/s-OPA1 forms)?
  - question: What is the relationship between EAT-3 and cristae junction 
      formation?
  - question: Does EAT-3 interact with cardiolipin or other mitochondrial 
      lipids?
suggested_experiments:
  - description: Determine if EAT-3 exists in long and short forms like 
      mammalian OPA1
  - description: Test for physical interaction between EAT-3 and IMMT-1 
      (mitofilin)
  - description: Measure in vitro GTPase activity of purified EAT-3
tags:
  - caeel-mitophagy

eat-3

Gene Description

Existing Annotations Review

Core Functions

EAT-3 contains a conserved dynamin-type GTPase domain. Mutations near the G2 motif disrupt function, and intragenic suppressors restore GTPase activity (PMID:18454199).

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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