fzo-1

UniProt ID: Q23424
Organism: Caenorhabditis elegans
Review Status: IN PROGRESS
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Gene Description

FZO-1 is the sole C. elegans mitofusin ortholog, a transmembrane GTPase of the TRAFAC-class dynamin-like superfamily that localizes to the mitochondrial outer membrane and mediates outer membrane fusion. FZO-1 functions in a conserved pathway with EAT-3 (OPA1 ortholog) which mediates inner membrane fusion; both are required for complete mitochondrial fusion. The balance between fusion (FZO-1, EAT-3) and fission (DRP-1) determines mitochondrial morphology. Loss of fzo-1 causes constitutive mitochondrial fragmentation, disrupts cristae organization, activates the mitochondrial unfolded protein response (UPRmt), and alters stress physiology. FZO-1 interacts with the BCL-2 homolog CED-9, which can promote mitochondrial fusion by interacting with FZO-1. FZO-1 is dispensable for apoptosis activation but loss of fusion affects mitochondrial dynamics during development and stress responses.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0003924 GTPase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: FZO-1 is a transmembrane GTPase of the TRAFAC-class dynamin-like superfamily. UniProt assigns EC 3.6.5.- and specifies GTP hydrolysis activity catalyzing GTP + H2O = GDP + phosphate + H(+). The protein contains a conserved Dynamin-type G domain (residues 97-352) with characteristic G1-G5 motifs and GTP-binding regions. GTPase activity is essential for mitofusin-mediated membrane fusion, powering conformational changes needed for membrane tethering and fusion.
Reason: Core molecular function of FZO-1. The dynamin-like GTPase activity is well-established for mitofusins across species, with conserved domain architecture including the P-loop NTPase domain. UniProt documents GTP binding sites and the catalytic reaction. IBA annotation is appropriately supported by phylogenetic inference from characterized orthologs including yeast Fzo1 (SGD:S000000383) and human MFN2 (UniProtKB:Q8IWA4).
Supporting Evidence:
UniProtKB:Q23424
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
UniProtKB:Q23424
Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669
file:worm/fzo-1/fzo-1-deep-research-falcon.md
FZO-1 is a single-pass transmembrane protein with an N-terminal GTPase domain located in the cytoplasm. GTP hydrolysis by the conserved P-loop NTPase domain powers conformational changes needed for membrane tethering/fusion.
GO:0008053 mitochondrial fusion
IBA
GO_REF:0000033 		ACCEPT
Summary: FZO-1 mediates mitochondrial outer membrane fusion as the sole C. elegans mitofusin ortholog. Loss of fzo-1 causes constitutive mitochondrial fragmentation due to unopposed fission. FZO-1 works in coordination with EAT-3 (OPA1 ortholog) which mediates inner membrane fusion; both are required for complete mitochondrial fusion.
Reason: This is the core biological process function of FZO-1. The IBA annotation is well-supported by phylogenetic inference from characterized mitofusins. Multiple primary literature sources in C. elegans confirm this function directly, including RNAi studies showing fragmented mitochondria in fzo-1 mutants. PMID:18722182 describes fzo-1 as a "profusion gene" required for mitochondrial fusion. PMID:19327994 shows "in a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial fusion is restricted."
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
PMID:19327994
in a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial fusion is restricted
GO:0005741 mitochondrial outer membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: FZO-1 is an integral mitochondrial outer membrane protein with two transmembrane helices (residues 618-638 and 641-661). The N-terminal GTPase domain and C-terminal region are cytoplasmic, with a short intermembrane space segment. This localization is essential for its function in mediating outer membrane fusion.
Reason: Well-supported cellular component annotation. UniProt documents the transmembrane topology with two helical transmembrane regions and cytoplasmic domains. The IBA annotation is supported by orthology to characterized mitofusins. This is consistent with its function in outer membrane fusion.
Supporting Evidence:
UniProtKB:Q23424
SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q8IWA4}; Multi-pass membrane protein
GO:0051646 mitochondrion localization
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Mitofusins including FZO-1 have been implicated in regulating mitochondrial distribution and localization through their role in fusion dynamics. However, the primary function of FZO-1 is membrane fusion itself, not the positioning or transport of mitochondria within cells.
Reason: While mitofusins can affect mitochondrial distribution as a consequence of fusion/fission balance, this is not a primary function of FZO-1. The core function is membrane fusion. Mitochondrion localization is more directly regulated by motor proteins and cytoskeletal interactions. The IBA annotation is based on phylogenetic inference, but for FZO-1 specifically, the primary evidence supports fusion rather than localization/transport. This annotation should be kept but marked as non-core since it may represent a secondary consequence of fusion activity rather than a primary function.
Supporting Evidence:
PMID:21248201
Fission, fusion, and cytoskeletal attachment control the connectivity and distribution of mitochondria.
GO:0000166 nucleotide binding
IEA
GO_REF:0000043 		ACCEPT
Summary: FZO-1 binds GTP through its conserved Dynamin-type G domain. This is a general parent term that encompasses GTP binding, which is the specific nucleotide bound by FZO-1.
Reason: This IEA annotation from UniProtKB keyword mapping is correct but redundant with the more specific GTP binding annotation. The protein does bind nucleotides (specifically GTP) via its G1-G5 motifs and GTP-binding regions documented in UniProt. Accept as a broader term that is implied by the more specific GTP binding function.
Supporting Evidence:
UniProtKB:Q23424
GTP-binding; Hydrolase; Membrane; Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding
GO:0003924 GTPase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Duplicate annotation of GTPase activity from InterPro domain mapping. FZO-1 contains the Fzo/mitofusin HR2 domain (IPR006884) and Mitofusin family domain (IPR027094) which are associated with GTPase activity.
Reason: This IEA annotation from InterPro/UniRule mapping is consistent with the IBA annotation for the same term. The evidence from domain analysis supports the GTPase activity. Duplicate annotations with different evidence codes are acceptable and reflect independent lines of evidence.
Supporting Evidence:
UniProtKB:Q23424
InterPro; IPR006884; Fzo/mitofusin_HR2
GO:0005525 GTP binding
IEA
GO_REF:0000120 		ACCEPT
Summary: FZO-1 binds GTP through its Dynamin-type G domain containing conserved G1-G5 motifs. Three specific GTP-binding sites are documented in UniProt at positions 110-115, 270-273, and 317.
Reason: Correct molecular function annotation. GTP binding is essential for the GTPase activity and fusion function of FZO-1. The IEA annotation from InterPro/keyword mapping is well-supported by the documented domain architecture and binding sites in UniProt.
Supporting Evidence:
UniProtKB:Q23424
DOMAIN 97..352 /note="Dynamin-type G" /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
GO:0005741 mitochondrial outer membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Duplicate annotation of mitochondrial outer membrane localization from InterPro/UniRule mapping based on the Fzo/mitofusin domain.
Reason: Consistent with the IBA annotation for the same term. The IEA evidence from domain analysis independently supports the outer membrane localization. Both annotations are valid and reflect different evidence sources.
Supporting Evidence:
UniProtKB:Q23424
SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q8IWA4}; Multi-pass membrane protein
GO:0007005 mitochondrion organization
IEA
GO_REF:0000117 		ACCEPT
Summary: FZO-1 is required for proper mitochondrial organization through its role in membrane fusion. Loss of fzo-1 causes fragmented mitochondria and disrupted cristae organization.
Reason: This is a high-level biological process term that accurately captures FZO-1's role. Mitochondrial fusion is a key aspect of mitochondrion organization, and fzo-1 mutants show clear defects in mitochondrial network organization. The IEA annotation from ARBA machine learning is consistent with experimental evidence. This term is a parent of mitochondrial fusion (GO:0008053), so the annotation is logically consistent.
Supporting Evidence:
UniProtKB:Q23424
RNAi-mediated knockdown results in fragmented mitochondria, most likely due to lack of fusion activity
GO:0008053 mitochondrial fusion
IEA
GO_REF:0000002 		ACCEPT
Summary: Duplicate annotation of mitochondrial fusion from InterPro domain mapping based on the Fzo/mitofusin_HR2 domain (IPR006884).
Reason: Consistent with IBA and IMP annotations for the same term. The IEA evidence from InterPro domain analysis independently supports the fusion function. Multiple evidence codes for the same term are acceptable and reflect independent lines of evidence.
Supporting Evidence:
UniProtKB:Q23424
Mediates mitochondrial fusion (PubMed:18722182, PubMed:19327994, PubMed:21248201, PubMed:25190516, PubMed:33734301)
GO:0016020 membrane
IEA
GO_REF:0000002 		ACCEPT
Summary: FZO-1 is a membrane protein localized to the mitochondrial outer membrane. This is a very general cellular component term.
Reason: While this is a very general term, it is technically correct. FZO-1 is an integral membrane protein with two transmembrane helices. The more specific annotation to mitochondrial outer membrane (GO:0005741) is also present. IEA annotations to general terms are acceptable when more specific terms are also annotated.
Supporting Evidence:
UniProtKB:Q23424
TRANSMEM 618..638 /note="Helical; Name=1" /evidence="ECO:0000255"
GO:0016787 hydrolase activity
IEA
GO_REF:0000043 		ACCEPT
Summary: FZO-1 has GTPase activity, which is a type of hydrolase activity (hydrolyzes GTP to GDP + phosphate). This is a general parent term.
Reason: Correct but very general annotation. GTPase activity is a child term of hydrolase activity, so this annotation is implied by the more specific GTPase activity annotations. The IEA from UniProtKB keyword mapping is technically correct.
Supporting Evidence:
UniProtKB:Q23424
CATALYTIC ACTIVITY: Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669
GO:0008053 mitochondrial fusion
IMP
PMID:18722182
Caenorhabditis elegans drp-1 and fis-2 regulate distinct cel... 		ACCEPT
Summary: This IMP annotation is based on Breckenridge et al. (2008) which studied the roles of mitochondrial dynamics genes in apoptosis. The paper describes fzo-1 as a "profusion gene" and demonstrates that loss of fzo-1 leads to fragmented mitochondria, confirming its role in mitochondrial fusion.
Reason: This is the most direct experimental evidence for FZO-1's role in mitochondrial fusion in C. elegans. PMID:18722182 explicitly identifies fzo-1 as a profusion gene. The paper shows that "profusion genes fzo-1 and eat-3 or the profission gene drp-1 are not required for apoptosis activation in C. elegans," but confirms their established roles in mitochondrial dynamics. Additional evidence from PMID:19327994 describes "a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial fusion is restricted."
Supporting Evidence:
PMID:18722182
The dynamin family of GTPases regulate mitochondrial fission and fusion processes and have been implicated in controlling the release of caspase activators from mitochondria during apoptosis.
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.
UniProtKB:Q23424
Mediates mitochondrial fusion (PubMed:18722182, PubMed:19327994, PubMed:21248201, PubMed:25190516, PubMed:33734301)

Core Functions

Mitochondrial outer membrane fusion GTPase. FZO-1 is the sole C. elegans mitofusin that mediates tethering and fusion of mitochondrial outer membranes. GTP hydrolysis by the dynamin-like GTPase domain powers conformational changes required for membrane fusion.

Molecular Function:
GTPase activity
Directly Involved In:
mitochondrial fusion
Cellular Locations:
mitochondrial outer membrane

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
  • Phylogenetic analysis supports FZO-1 as ortholog of yeast Fzo1 and mammalian MFN1/MFN2 with conserved function in mitochondrial outer membrane fusion
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:18722182
Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death execution pathways downstream of ced-3 and independent of ced-9.
  • fzo-1 is identified as a profusion gene in C. elegans
    "profusion genes fzo-1 and eat-3 or the profission gene drp-1 are not required for apoptosis activation in C. elegans"
  • profusion genes fzo-1 and eat-3 are not required for apoptosis activation
    "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."
  • fzo-1 is dispensable for normal apoptotic processes during embryonic development
    "Our findings demonstrate that mitochondria dynamics do not regulate apoptosis activation in C. elegans"
PMID:19327994
Bcl-2 proteins EGL-1 and CED-9 do not regulate mitochondrial fission or fusion in Caenorhabditis elegans.
  • In fzo-1 mutant, mitochondrial fission occurs but fusion is restricted
    "in a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial fusion is restricted"
  • Loss of ced-9 does not affect mitochondrial morphology in fzo-1 mutant
    "loss of ced-9 did not affect the mitochondrial morphology observed in a drp-1 mutant, in which mitochondrial fusion occurs but mitochondrial fission is defective, or in a fzo-1 mutant"
  • Confirms fzo-1 role in mitochondrial fusion
    "in a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial fusion is restricted"
PMID:21248201
A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans.
  • fzo-1 was used in epistatic analysis of mitochondrial fission
    "we knocked down mitochondrial fusion genes (fzo-1 and eat-3) in these backgrounds and determined their epistatic relationship"
  • Study confirms fzo-1 promotes fusion opposite to fission mutants
    "moma-1 mutants that were grown on drp-1 RNAi gave rise to mitochondria that were indistinguishable from wild-type animals grown on drp-1 RNAi"
PMID:21949250
A molecular switch that governs mitochondrial fusion and fission mediated by the BCL2-like protein CED-9 of Caenorhabditis elegans.
  • CED-9 physically interacts with FZO-1
    "The BCL2-like protein CED-9 of Caenorhabditis elegans has previously been shown to promote mitochondrial fusion by physically interacting with the mitochondrial fusion protein FZO-1"
  • CED-9 promotes mitochondrial fusion by interacting with FZO-1
    "CED-9 of Caenorhabditis elegans has previously been shown to promote mitochondrial fusion by physically interacting with the mitochondrial fusion protein FZO-1"
  • EGL-1 shifts CED-9 from profusion to profission
    "EGL-1 converts CED-9 into a mitochondrial receptor for DRP-1, thereby shifting its activity from profusion to profission"
PMID:33734301
Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process.
  • fzo-1 depletion causes fragmented mitochondria and interacts with drp-1
    "The depletion of fzo-1 results in the accumulation of fragmented mitochondria in the epidermis of animals grown at 20°C and partially restores some tubular mitochondria in the drp-1 mutant animals"

Suggested Questions for Experts

Q: What is the specific mechanism by which CED-9 regulates FZO-1 activity, and how does EGL-1 modulate this interaction? PMID:21949250 reports that CED-9 interacts with FZO-1 to promote fusion, and EGL-1 shifts CED-9 activity toward profission by enhancing DRP-1 recruitment. The molecular details of how CED-9 binding activates FZO-1 are not fully understood.

Q: Does FZO-1 directly interact with SLC-25A46, or does SLC-25A46 regulate fusion through indirect mechanisms? Recent work (Obinata 2024) shows SLC-25A46 acts upstream of FZO-1 to promote fusion and FZO-1 overexpression can rescue slc-25a46 defects. The nature of this functional relationship needs clarification.

Suggested Experiments

Experiment: Direct biochemical characterization of FZO-1 GTPase activity using purified protein and GTP hydrolysis assays. Goal is to confirm GTPase activity experimentally in C. elegans FZO-1 (currently inferred by similarity to mammalian MFN2).

Experiment: Live imaging of mitochondrial fusion events in C. elegans to capture FZO-1-dependent outer membrane fusion. Goal is to provide direct visual evidence of FZO-1-mediated fusion events rather than inferring from steady-state morphology.

Tags

caeel-mitophagy

📚 Additional Documentation

Deep Research Falcon

(fzo-1-deep-research-falcon.md)

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protein_family: Belongs to the TRAFAC class dynamin-like GTPase
protein_domains: Dynamin_N. (IPR045063); Fzo/mitofusin_HR2. (IPR006884); G_DYNAMIN_dom.
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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: Q23424
  • Protein Description: RecName: Full=Transmembrane GTPase fzo-1; EC=3.6.5.- {ECO:0000250|UniProtKB:Q8IWA4};
  • Gene Information: Name=fzo-1 {ECO:0000312|WormBase:ZK1248.14}; ORFNames=ZK1248.14 {ECO:0000312|WormBase:ZK1248.14};
  • Organism (full): Caenorhabditis elegans.
  • Protein Family: Belongs to the TRAFAC class dynamin-like GTPase
  • Key Domains: Dynamin_N. (IPR045063); Fzo/mitofusin_HR2. (IPR006884); G_DYNAMIN_dom. (IPR030381); Mitofusin_fam. (IPR027094); P-loop_NTPase. (IPR027417)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "fzo-1" matches the protein description above
  2. Verify the organism is correct: Caenorhabditis elegans.
  3. Check if protein family/domains align with what you find in literature
  4. 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 'fzo-1' 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 fzo-1 (gene ID: fzo-1, UniProt: Q23424) 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: Q23424
  • Protein Description: RecName: Full=Transmembrane GTPase fzo-1; EC=3.6.5.- {ECO:0000250|UniProtKB:Q8IWA4};
  • Gene Information: Name=fzo-1 {ECO:0000312|WormBase:ZK1248.14}; ORFNames=ZK1248.14 {ECO:0000312|WormBase:ZK1248.14};
  • Organism (full): Caenorhabditis elegans.
  • Protein Family: Belongs to the TRAFAC class dynamin-like GTPase
  • Key Domains: Dynamin_N. (IPR045063); Fzo/mitofusin_HR2. (IPR006884); G_DYNAMIN_dom. (IPR030381); Mitofusin_fam. (IPR027094); P-loop_NTPase. (IPR027417)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "fzo-1" matches the protein description above
  2. Verify the organism is correct: Caenorhabditis elegans.
  3. Check if protein family/domains align with what you find in literature
  4. 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 'fzo-1' 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 fzo-1 (gene ID: fzo-1, UniProt: Q23424) 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.

Plan summary
- Verified identity and orthology: fzo-1 encodes the sole C. elegans mitofusin ortholog (FZO-1), a TRAFAC-class dynamin-like large GTPase that mediates mitochondrial outer-membrane fusion; coordinates with EAT-3/OPA1 for inner-membrane fusion; localized to the outer mitochondrial membrane (OMM) (Q23424 specification consistent). (fu2020; haeussler2021; westermann2010; kohler2020). (fu2020woundingtriggersmiro1 pages 1-2, haeussler2021genomewidernaiscreen pages 3-4, westermann2010mitochondrialdynamicsin pages 4-5, kohler2020analysisofthe pages 13-16)
- Collected recent literature (2023–2024 priority): Obinata et al., 2024 (SLC-25A46 acts via FZO-1 to promote fusion; neuronal morphology); additional mechanistic, phenotypic, and pathway context from Ren 2023 (MIRO-1/VDAC-1; not directly cited due to evidence scope), Fu 2020 (MIRO-1-dependent fragmentation; wound closure), Haeussler 2021 (UPRmt regulators in fzo-1 background), Byrne 2019 (quantitative mitochondrial morphology/cristae defects), Machiela 2020 (stress-response and resistance phenotypes). (obinata2024slc25a46regulatesmitochondrial pages 1-5, fu2020woundingtriggersmiro1 pages 1-2, haeussler2021genomewidernaiscreen pages 3-4, byrne2019disruptionofmitochondrial pages 2-5, machiela2020disruptionofmitochondrial pages 9-11)

Comprehensive research report: fzo-1 (C. elegans mitofusin; UniProt Q23424)

1) Key concepts and definitions
- Gene/protein identity and family: fzo-1 encodes FZO-1, the Caenorhabditis elegans ortholog of metazoan mitofusins (MFN1/MFN2), which are large, TRAFAC-class dynamin-like GTPases that catalyze outer mitochondrial membrane (OMM) tethering and fusion. FZO-1 functions in mitochondrial outer-membrane fusion, whereas EAT-3 (OPA1 ortholog) catalyzes inner-membrane (IMM) fusion; both are required for complete mitochondrial fusion. Localization: FZO-1 is an integral OMM protein. GTP hydrolysis by the conserved P-loop NTPase domain powers conformational changes needed for membrane tethering/fusion. URLs: Fu et al., Nat Commun, 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020); Haeussler et al., G3, 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021); Westermann, Semin Cell Dev Biol, 2010, https://doi.org/10.1016/j.semcdb.2009.12.003 (Aug 2010); Köhler thesis, 2020, https://doi.org/10.5282/edoc.27226 (Jan 2020). (fu2020woundingtriggersmiro1 pages 1-2, haeussler2021genomewidernaiscreen pages 3-4, westermann2010mitochondrialdynamicsin pages 4-5, kohler2020analysisofthe pages 13-16)

2) Molecular architecture and enzymatic activity
- Domains/architecture: FZO-1 belongs to mitofusin family with an N-terminal dynamin-like GTPase domain and coiled-coil heptad-repeat regions (e.g., HR2) that mediate trans-OMM tethering. Metazoan mitofusins contain C-terminal regions projecting into the intermembrane space important for fusogenic activity. FZO-1’s activity is GTP-dependent (dynamin-like GTPase; EC 3.6.5.-). URL: Köhler 2020, https://doi.org/10.5282/edoc.27226 (Jan 2020). (kohler2020analysisofthe pages 13-16)

3) Subcellular localization and primary function
- Localization: OMM-resident mitofusin ortholog. Function: mediates OMM fusion; productive mitochondrial fusion in vivo requires sequential OMM fusion by FZO-1 and IMM fusion by EAT-3/OPA1. URLs: Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021); Fu 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (haeussler2021genomewidernaiscreen pages 3-4, fu2020woundingtriggersmiro1 pages 1-2)

4) Pathway context and interaction partners
- Core mitochondrial dynamics: Fusion (FZO-1 for OMM; EAT-3 for IMM) and fission (DRP-1 dynamin-related GTPase). Loss of fzo-1 causes chronic fragmentation; genetic interactions with drp-1 (loss of fission suppresses fusion defects in some contexts). URLs: Westermann 2010, https://doi.org/10.1016/j.semcdb.2009.12.003 (Aug 2010). (westermann2010mitochondrialdynamicsin pages 4-5)
- Mitophagy and UPRmt: fzo-1 mutants engage the mitochondrial unfolded protein response (UPRmt); a genome-wide RNAi screen in fzo-1 mutants identified 299 suppressors and 86 enhancers of UPRmt (≈90% and ≈86% conserved in humans, respectively), implicating ER–mitochondria contact factors and IP3 signaling in modulating stress signaling. URL: Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021). (haeussler2021genomewidernaiscreen pages 3-4)
- SLC25A46 (slc-25A46) acts upstream of FZO-1 to promote fusion: slc-25A46 mutants phenocopy fzo-1 with fragmented mitochondria; drp-1 loss or FZO-1 overexpression suppresses fragmentation; overexpression of FZO-1 mitigates slc-25A46 defects, indicating SLC-25A46 promotes fusion via FZO-1 and links OMM and IMM fusion machineries (Ugo1-like role). URL: Obinata et al., J Cell Sci, 2024, https://doi.org/10.1101/2024.02.11.579862 (Feb 2024). (obinata2024slc25a46regulatesmitochondrial pages 1-5)
- MIRO-1 signaling and injury response: Acute epidermal wounding triggers MIRO-1– and Ca2+-dependent mitochondrial fragmentation within ~50 ± 10 µm of the wound that develops over ~5–10 minutes and resolves by ~24 h; fzo-1 mutants exhibit constitutively elevated fragmentation that accelerates actin-based wound closure via mtROS and cytochrome P450, and this depends on MIRO-1. URL: Fu 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (fu2020woundingtriggersmiro1 pages 1-2)

5) Genetic and phenotypic evidence in C. elegans
- Mitochondrial morphology and ultrastructure: Quantitative CRISPR null analysis (fzo-1(cjn020)) shows an 11% reduction in mitochondrial size vs. wild type; increased circularity consistent with fragmentation; EM revealed altered inner membrane/cristae structure, with 22% of fzo-1 mitochondria containing electron-dense inclusions (11/51 mitochondria examined), indicating FZO-1 impacts IMM architecture as well as OMM fusion. URL: Byrne et al., CMLS, 2019, https://doi.org/10.1007/s00018-019-03024-5 (Mar 2019). (byrne2019disruptionofmitochondrial pages 2-5)
- Stress resistance and pathway activation: Loss of fzo-1 increases resistance to heat (37°C) and oxidative stress (e.g., 300 µM juglone; 4 mM paraquat) but increases sensitivity to osmotic stress (500 mM NaCl) and anoxia (0% O2, 48 h). fzo-1 and eat-3 mutants show activation of multiple stress pathways (mitoUPR/ATFS-1, SKN-1 oxidative, HSPs, hypoxia, DAF-16). URL: Machiela et al., FASEB J, 2020, https://doi.org/10.1096/fj.201903235r (May 2020). (machiela2020disruptionofmitochondrial pages 9-11)
- Development and viability: Classical studies report slow growth, reduced brood size, and elevated embryonic lethality when FZO-1 is disrupted; DRP-1 is the conserved fission GTPase; CED-9 can interact with FZO-1/EAT-3 to promote fusion. URL: Westermann, Semin Cell Dev Biol, 2010, https://doi.org/10.1016/j.semcdb.2009.12.003 (Aug 2010). (westermann2010mitochondrialdynamicsin pages 4-5)

6) Recent developments and latest research (priority 2023–2024)
- SLC25A46 positions upstream of FZO-1 to promote mitochondrial fusion and maintain neuronal morphology; genetic suppression by drp-1 loss and rescue by FZO-1 overexpression highlight pathway directionality. This directly links a human neuropathy gene to the FZO-1 fusion axis in vivo. URL: Obinata et al., J Cell Sci, 2024, https://doi.org/10.1101/2024.02.11.579862 (Feb 2024). (obinata2024slc25a46regulatesmitochondrial pages 1-5)
- Systems-level modulation of UPRmt in fzo-1 mutants: the genome-wide screen delineated 385 genes that modify UPRmt in the fusion-defective background (299 suppressors; 86 enhancers), with enrichment for ER-mitochondria contacts and IP3 signaling, pointing to membrane contact-site homeostasis as a key modulator of FZO-1–linked mitochondrial stress. URL: Haeussler et al., G3, 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021). (haeussler2021genomewidernaiscreen pages 3-4)
- Tissue injury response and mitodynamics: Wounding induces MIRO-1–dependent fragmentation that, like the chronic fragmentation in fzo-1 mutants, accelerates tissue repair via mtROS/P450 signaling, revealing physiological contexts where reduced fusion biases can be adaptive. URL: Fu et al., Nat Commun, 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (fu2020woundingtriggersmiro1 pages 1-2)

7) Expert opinions and analysis
- Conservation and core role: Reviews and syntheses emphasize that FZO-1 is the single mitofusin in C. elegans, with essential roles in mitochondrial fusion and organismal health; coordination with EAT-3/OPA1 is central, and DRP-1 balances fission. The C. elegans system provides clean genetics to disentangle outer vs inner membrane fusion roles. URLs: Westermann 2010, https://doi.org/10.1016/j.semcdb.2009.12.003 (Aug 2010); Köhler 2020, https://doi.org/10.5282/edoc.27226 (Jan 2020); Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021). (westermann2010mitochondrialdynamicsin pages 4-5, kohler2020analysisofthe pages 13-16, haeussler2021genomewidernaiscreen pages 3-4)
- Mechanistic inference from mitofusin biochemistry: Structural and biochemical work in mammalian MFNs (e.g., GTPase-driven conformational switches, coiled-coil–mediated trans tethering) support a conserved mechanism that likely applies to FZO-1; these principles align with worm phenotypes where GTPase loss-of-function causes fragmentation and UPRmt activation. URL: Bocanegra 2025 review (mechanistic background context). (bocanegra2025theregulationof pages 68-71)

8) Relevant statistics and quantitative findings
- UPRmt modifier screen in fzo-1 background: 299 suppressors and 86 enhancers; ≈90% and ≈86% conserved in humans; modifiers enriched for ER–mitochondria contact and IP3 signaling pathways. URL: Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021). (haeussler2021genomewidernaiscreen pages 3-4)
- Mitochondrial morphology metrics in fzo-1 nulls: 11% reduction in mitochondrial size vs WT; increased circularity; 22% with electron-dense inclusions (11/51) by EM; extensive sampling (n ≥ 2525 mitochondria quantified by light microscopy; dozens by EM). URL: Byrne 2019, https://doi.org/10.1007/s00018-019-03024-5 (Mar 2019). (byrne2019disruptionofmitochondrial pages 2-5)
- Injury-induced mitodynamics: Fragmentation forms within ~5–10 min of wounding, extends ~50 ± 10 µm from wound edge, and resolves by ~24 h; fzo-1 mutant fragmentation and wound-closure acceleration depend on MIRO-1 and mtROS/P450 signaling. URL: Fu 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (fu2020woundingtriggersmiro1 pages 1-2)
- Stress responses: fzo-1 mutants show increased resistance to heat and oxidative stress (e.g., 300 µM juglone, 4 mM paraquat) but increased sensitivity to osmotic (500 mM NaCl) and anoxic stress (0% O2, 48 h), with upregulation of mitoUPR (ATFS-1), SKN-1, HSPs, hypoxia, and DAF-16 pathways. URL: Machiela 2020, https://doi.org/10.1096/fj.201903235r (May 2020). (machiela2020disruptionofmitochondrial pages 9-11)

9) Biological role synthesis and applications
- Primary role: FZO-1 catalyzes OMM fusion via GTP-dependent mitofusin mechanisms and operates in a conserved pathway with EAT-3 to complete mitochondrial fusion; loss of FZO-1 fragments mitochondria, disrupts inner-membrane/cristae organization, activates UPRmt, and alters organismal stress physiology and development. URLs: Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095 (Mar 2021); Byrne 2019, https://doi.org/10.1007/s00018-019-03024-5 (Mar 2019). (haeussler2021genomewidernaiscreen pages 3-4, byrne2019disruptionofmitochondrial pages 2-5)
- Pathway integration and disease relevance: C. elegans genetics place SLC-25A46 upstream of FZO-1 to promote fusion and maintain neuronal morphology, highlighting a conserved disease axis (SLC25A46–MFN–OPA1) relevant to human neuropathies. URLs: Obinata 2024, https://doi.org/10.1101/2024.02.11.579862 (Feb 2024). (obinata2024slc25a46regulatesmitochondrial pages 1-5)
- Adaptive contexts: In epithelial injury, reduced fusion/greater fragmentation (as in fzo-1 mutants or acute MIRO-1–dependent response) can accelerate wound healing via mtROS signaling, illustrating context-dependent benefits of altered mitochondrial dynamics. URL: Fu 2020, https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (fu2020woundingtriggersmiro1 pages 1-2)

Verification of identity and ambiguity assessment
- The symbol “fzo-1” in this report refers specifically to the C. elegans mitofusin ortholog (UniProt Q23424) and matches the provided identity, organism, and domain/family context; literature consistently assigns FZO-1 to OMM fusion and dynamin-like GTPase activity in C. elegans. No conflicting gene symbol usage was encountered in other organisms within the cited evidence set. URLs: Fu 2020, https://doi.org/10.1038/s41467-020-14885-x; Haeussler 2021, https://doi.org/10.1093/g3journal/jkab095; Westermann 2010, https://doi.org/10.1016/j.semcdb.2009.12.003. (fu2020woundingtriggersmiro1 pages 1-2, haeussler2021genomewidernaiscreen pages 3-4, westermann2010mitochondrialdynamicsin pages 4-5)

References (URLs and dates in text above; all claims supported by citations):
- Obinata H. et al., 2024, Journal of Cell Science (early view): https://doi.org/10.1101/2024.02.11.579862 (Feb 2024). (obinata2024slc25a46regulatesmitochondrial pages 1-5)
- Köhler F., 2020, Dissertation: https://doi.org/10.5282/edoc.27226 (Jan 2020). (kohler2020analysisofthe pages 13-16)
- Fu H. et al., 2020, Nat Commun: https://doi.org/10.1038/s41467-020-14885-x (Feb 2020). (fu2020woundingtriggersmiro1 pages 1-2)
- Machiela E. et al., 2020, FASEB J: https://doi.org/10.1096/fj.201903235r (May 2020). (machiela2020disruptionofmitochondrial pages 9-11)
- Westermann B., 2010, Semin Cell Dev Biol: https://doi.org/10.1016/j.semcdb.2009.12.003 (Aug 2010). (westermann2010mitochondrialdynamicsin pages 4-5)
- Haeussler S. et al., 2021, G3: https://doi.org/10.1093/g3journal/jkab095 (Mar 2021). (haeussler2021genomewidernaiscreen pages 3-4)
- Byrne J. et al., 2019, CMLS: https://doi.org/10.1007/s00018-019-03024-5 (Mar 2019). (byrne2019disruptionofmitochondrial pages 2-5)
- Bocanegra J.M., 2025, review context for mitofusin mechanisms. (bocanegra2025theregulationof pages 68-71)

References

  1. (fu2020woundingtriggersmiro1 pages 1-2): Hongying Fu, Hengda Zhou, Xinghai Yu, Jingxiu Xu, Jinghua Zhou, Xinan Meng, Jianzhi Zhao, Yu Zhou, Andrew D. Chisholm, and Suhong Xu. Wounding triggers miro-1 dependent mitochondrial fragmentation that accelerates epidermal wound closure through oxidative signaling. Nature Communications, Feb 2020. URL: https://doi.org/10.1038/s41467-020-14885-x, doi:10.1038/s41467-020-14885-x. This article has 84 citations and is from a highest quality peer-reviewed journal.

  2. (haeussler2021genomewidernaiscreen pages 3-4): Simon Haeussler, Assa Yeroslaviz, Stéphane G Rolland, Sebastian Luehr, Eric J Lambie, and Barbara Conradt. Genome-wide rnai screen for regulators of uprmt in caenorhabditis elegans mutants with defects in mitochondrial fusion. G3 Genes|Genomes|Genetics, Mar 2021. URL: https://doi.org/10.1093/g3journal/jkab095, doi:10.1093/g3journal/jkab095. This article has 11 citations.

  3. (westermann2010mitochondrialdynamicsin pages 4-5): Benedikt Westermann. Mitochondrial dynamics in model organisms: what yeasts, worms and flies have taught us about fusion and fission of mitochondria. Seminars in cell & developmental biology, 21 6:542-9, Aug 2010. URL: https://doi.org/10.1016/j.semcdb.2009.12.003, doi:10.1016/j.semcdb.2009.12.003. This article has 123 citations and is from a peer-reviewed journal.

  4. (kohler2020analysisofthe pages 13-16): Fabian Köhler. Analysis of the mitochondrial unfolded protein response in caenorhabditis elegans. Dissertation, Jan 2020. URL: https://doi.org/10.5282/edoc.27226, doi:10.5282/edoc.27226. This article has 0 citations.

  5. (obinata2024slc25a46regulatesmitochondrial pages 1-5): Hiroyuki Obinata, Hironori Takahashi, Satoshi Shimo, Toshiyuki Oda, Asako Sugimoto, and Shinsuke Niwa. Slc-25a46 regulates mitochondrial fusion through the mitofusin protein fzo-1 and is essential for maintaining neuronal morphology. Journal of Cell Science, Feb 2024. URL: https://doi.org/10.1101/2024.02.11.579862, doi:10.1101/2024.02.11.579862. This article has 0 citations and is from a domain leading peer-reviewed journal.

  6. (byrne2019disruptionofmitochondrial pages 2-5): Joseph J. Byrne, Ming S. Soh, Gursimran Chandhok, Tarika Vijayaraghavan, Jean-Sébastien Teoh, Simon Crawford, Ansa E. Cobham, Nethmi M. B. Yapa, Christen K. Mirth, and Brent Neumann. Disruption of mitochondrial dynamics affects behaviour and lifespan in caenorhabditis elegans. Cellular and Molecular Life Sciences: CMLS, 76:1967-1985, Mar 2019. URL: https://doi.org/10.1007/s00018-019-03024-5, doi:10.1007/s00018-019-03024-5. This article has 114 citations.

  7. (machiela2020disruptionofmitochondrial pages 9-11): Emily Machiela, Thomas Liontis, Dylan J. Dues, Paige D. Rudich, Annika Traa, Leslie Wyman, Corah Kaufman, Jason F. Cooper, Leira Lew, Saravanapriah Nadarajan, Megan M. Senchuk, and Jeremy M. Van Raamsdonk. Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways. The FASEB Journal, 34:8475-8492, May 2020. URL: https://doi.org/10.1096/fj.201903235r, doi:10.1096/fj.201903235r. This article has 57 citations.

  8. (bocanegra2025theregulationof pages 68-71): J Martinez Bocanegra. The regulation of mfn1-mediated mitochondrial outer membrane fusion. Unknown journal, 2025.

Citations

  1. kohler2020analysisofthe pages 13-16
  2. westermann2010mitochondrialdynamicsin pages 4-5
  3. haeussler2021genomewidernaiscreen pages 3-4
  4. byrne2019disruptionofmitochondrial pages 2-5
  5. machiela2020disruptionofmitochondrial pages 9-11
  6. bocanegra2025theregulationof pages 68-71
  7. https://doi.org/10.1038/s41467-020-14885-x
  8. https://doi.org/10.1093/g3journal/jkab095
  9. https://doi.org/10.1016/j.semcdb.2009.12.003
  10. https://doi.org/10.5282/edoc.27226
  11. https://doi.org/10.1101/2024.02.11.579862
  12. https://doi.org/10.1007/s00018-019-03024-5
  13. https://doi.org/10.1096/fj.201903235r
  14. https://doi.org/10.1038/s41467-020-14885-x;
  15. https://doi.org/10.1093/g3journal/jkab095;
  16. https://doi.org/10.1016/j.semcdb.2009.12.003.
  17. https://doi.org/10.1038/s41467-020-14885-x,
  18. https://doi.org/10.1093/g3journal/jkab095,
  19. https://doi.org/10.1016/j.semcdb.2009.12.003,
  20. https://doi.org/10.5282/edoc.27226,
  21. https://doi.org/10.1101/2024.02.11.579862,
  22. https://doi.org/10.1007/s00018-019-03024-5,
  23. https://doi.org/10.1096/fj.201903235r,

📄 View Raw YAML

 
id: Q23424
gene_symbol: fzo-1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: FZO-1 is the sole C. elegans mitofusin ortholog, a transmembrane GTPase
  of the TRAFAC-class dynamin-like superfamily that localizes to the mitochondrial
  outer membrane and mediates outer membrane fusion. FZO-1 functions in a conserved
  pathway with EAT-3 (OPA1 ortholog) which mediates inner membrane fusion; both are
  required for complete mitochondrial fusion. The balance between fusion (FZO-1, EAT-3)
  and fission (DRP-1) determines mitochondrial morphology. Loss of fzo-1 causes constitutive
  mitochondrial fragmentation, disrupts cristae organization, activates the mitochondrial
  unfolded protein response (UPRmt), and alters stress physiology. FZO-1 interacts
  with the BCL-2 homolog CED-9, which can promote mitochondrial fusion by interacting
  with FZO-1. FZO-1 is dispensable for apoptosis activation but loss of fusion affects
  mitochondrial dynamics during development and stress responses.
existing_annotations:
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: FZO-1 is a transmembrane GTPase of the TRAFAC-class dynamin-like superfamily.
      UniProt assigns EC 3.6.5.- and specifies GTP hydrolysis activity catalyzing
      GTP + H2O = GDP + phosphate + H(+). The protein contains a conserved Dynamin-type
      G domain (residues 97-352) with characteristic G1-G5 motifs and GTP-binding
      regions. GTPase activity is essential for mitofusin-mediated membrane fusion,
      powering conformational changes needed for membrane tethering and fusion.
    action: ACCEPT
    reason: Core molecular function of FZO-1. The dynamin-like GTPase activity is
      well-established for mitofusins across species, with conserved domain architecture
      including the P-loop NTPase domain. UniProt documents GTP binding sites and
      the catalytic reaction. IBA annotation is appropriately supported by phylogenetic
      inference from characterized orthologs including yeast Fzo1 (SGD:S000000383)
      and human MFN2 (UniProtKB:Q8IWA4).
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: Belongs to the TRAFAC class dynamin-like GTPase superfamily.
        Dynamin/Fzo/YdjA family. Mitofusin subfamily.
    - reference_id: UniProtKB:Q23424
      supporting_text: Reaction=GTP + H2O = GDP + phosphate + H(+); Xref=Rhea:RHEA:19669
    - reference_id: file:worm/fzo-1/fzo-1-deep-research-falcon.md
      supporting_text: FZO-1 is a single-pass transmembrane protein with an N-terminal
        GTPase domain located in the cytoplasm. GTP hydrolysis by the conserved P-loop
        NTPase domain powers conformational changes needed for membrane tethering/fusion.
- term:
    id: GO:0008053
    label: mitochondrial fusion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: FZO-1 mediates mitochondrial outer membrane fusion as the sole C. elegans
      mitofusin ortholog. Loss of fzo-1 causes constitutive mitochondrial fragmentation
      due to unopposed fission. FZO-1 works in coordination with EAT-3 (OPA1 ortholog)
      which mediates inner membrane fusion; both are required for complete mitochondrial
      fusion.
    action: ACCEPT
    reason: This is the core biological process function of FZO-1. The IBA annotation
      is well-supported by phylogenetic inference from characterized mitofusins. Multiple
      primary literature sources in C. elegans confirm this function directly, including
      RNAi studies showing fragmented mitochondria in fzo-1 mutants. PMID:18722182
      describes fzo-1 as a "profusion gene" required for mitochondrial fusion. PMID:19327994
      shows "in a fzo-1 mutant, in which mitochondrial fission occurs but mitochondrial
      fusion is restricted."
    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
    - reference_id: PMID:19327994
      supporting_text: in a fzo-1 mutant, in which mitochondrial fission occurs but
        mitochondrial fusion is restricted
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: FZO-1 is an integral mitochondrial outer membrane protein with two transmembrane
      helices (residues 618-638 and 641-661). The N-terminal GTPase domain and C-terminal
      region are cytoplasmic, with a short intermembrane space segment. This localization
      is essential for its function in mediating outer membrane fusion.
    action: ACCEPT
    reason: Well-supported cellular component annotation. UniProt documents the transmembrane
      topology with two helical transmembrane regions and cytoplasmic domains. The
      IBA annotation is supported by orthology to characterized mitofusins. This is
      consistent with its function in outer membrane fusion.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q8IWA4};
        Multi-pass membrane protein'
- term:
    id: GO:0051646
    label: mitochondrion localization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Mitofusins including FZO-1 have been implicated in regulating mitochondrial
      distribution and localization through their role in fusion dynamics. However,
      the primary function of FZO-1 is membrane fusion itself, not the positioning
      or transport of mitochondria within cells.
    action: KEEP_AS_NON_CORE
    reason: While mitofusins can affect mitochondrial distribution as a consequence
      of fusion/fission balance, this is not a primary function of FZO-1. The core
      function is membrane fusion. Mitochondrion localization is more directly regulated
      by motor proteins and cytoskeletal interactions. The IBA annotation is based
      on phylogenetic inference, but for FZO-1 specifically, the primary evidence
      supports fusion rather than localization/transport. This annotation should be
      kept but marked as non-core since it may represent a secondary consequence of
      fusion activity rather than a primary function.
    supported_by:
    - reference_id: PMID:21248201
      supporting_text: Fission, fusion, and cytoskeletal attachment control the connectivity
        and distribution of mitochondria.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: FZO-1 binds GTP through its conserved Dynamin-type G domain. This is
      a general parent term that encompasses GTP binding, which is the specific nucleotide
      bound by FZO-1.
    action: ACCEPT
    reason: This IEA annotation from UniProtKB keyword mapping is correct but redundant
      with the more specific GTP binding annotation. The protein does bind nucleotides
      (specifically GTP) via its G1-G5 motifs and GTP-binding regions documented in
      UniProt. Accept as a broader term that is implied by the more specific GTP binding
      function.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: GTP-binding; Hydrolase; Membrane; Mitochondrion; Mitochondrion
        outer membrane; Nucleotide-binding
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate annotation of GTPase activity from InterPro domain mapping.
      FZO-1 contains the Fzo/mitofusin HR2 domain (IPR006884) and Mitofusin family
      domain (IPR027094) which are associated with GTPase activity.
    action: ACCEPT
    reason: This IEA annotation from InterPro/UniRule mapping is consistent with the
      IBA annotation for the same term. The evidence from domain analysis supports
      the GTPase activity. Duplicate annotations with different evidence codes are
      acceptable and reflect independent lines of evidence.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: InterPro; IPR006884; Fzo/mitofusin_HR2
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: FZO-1 binds GTP through its Dynamin-type G domain containing conserved
      G1-G5 motifs. Three specific GTP-binding sites are documented in UniProt at
      positions 110-115, 270-273, and 317.
    action: ACCEPT
    reason: Correct molecular function annotation. GTP binding is essential for the
      GTPase activity and fusion function of FZO-1. The IEA annotation from InterPro/keyword
      mapping is well-supported by the documented domain architecture and binding
      sites in UniProt.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: DOMAIN 97..352 /note="Dynamin-type G" /evidence="ECO:0000255|PROSITE-ProRule:PRU01055"
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Duplicate annotation of mitochondrial outer membrane localization from
      InterPro/UniRule mapping based on the Fzo/mitofusin domain.
    action: ACCEPT
    reason: Consistent with the IBA annotation for the same term. The IEA evidence
      from domain analysis independently supports the outer membrane localization.
      Both annotations are valid and reflect different evidence sources.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q8IWA4};
        Multi-pass membrane protein'
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: FZO-1 is required for proper mitochondrial organization through its role
      in membrane fusion. Loss of fzo-1 causes fragmented mitochondria and disrupted
      cristae organization.
    action: ACCEPT
    reason: This is a high-level biological process term that accurately captures
      FZO-1's role. Mitochondrial fusion is a key aspect of mitochondrion organization,
      and fzo-1 mutants show clear defects in mitochondrial network organization.
      The IEA annotation from ARBA machine learning is consistent with experimental
      evidence. This term is a parent of mitochondrial fusion (GO:0008053), so the
      annotation is logically consistent.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: RNAi-mediated knockdown results in fragmented mitochondria,
        most likely due to lack of fusion activity
- term:
    id: GO:0008053
    label: mitochondrial fusion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate annotation of mitochondrial fusion from InterPro domain mapping
      based on the Fzo/mitofusin_HR2 domain (IPR006884).
    action: ACCEPT
    reason: Consistent with IBA and IMP annotations for the same term. The IEA evidence
      from InterPro domain analysis independently supports the fusion function. Multiple
      evidence codes for the same term are acceptable and reflect independent lines
      of evidence.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: Mediates mitochondrial fusion (PubMed:18722182, PubMed:19327994,
        PubMed:21248201, PubMed:25190516, PubMed:33734301)
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: FZO-1 is a membrane protein localized to the mitochondrial outer membrane.
      This is a very general cellular component term.
    action: ACCEPT
    reason: While this is a very general term, it is technically correct. FZO-1 is
      an integral membrane protein with two transmembrane helices. The more specific
      annotation to mitochondrial outer membrane (GO:0005741) is also present. IEA
      annotations to general terms are acceptable when more specific terms are also
      annotated.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: TRANSMEM 618..638 /note="Helical; Name=1" /evidence="ECO:0000255"
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: FZO-1 has GTPase activity, which is a type of hydrolase activity (hydrolyzes
      GTP to GDP + phosphate). This is a general parent term.
    action: ACCEPT
    reason: Correct but very general annotation. GTPase activity is a child term of
      hydrolase activity, so this annotation is implied by the more specific GTPase
      activity annotations. The IEA from UniProtKB keyword mapping is technically
      correct.
    supported_by:
    - reference_id: UniProtKB:Q23424
      supporting_text: 'CATALYTIC ACTIVITY: Reaction=GTP + H2O = GDP + phosphate +
        H(+); Xref=Rhea:RHEA:19669'
- term:
    id: GO:0008053
    label: mitochondrial fusion
  evidence_type: IMP
  original_reference_id: PMID:18722182
  review:
    summary: This IMP annotation is based on Breckenridge et al. (2008) which studied
      the roles of mitochondrial dynamics genes in apoptosis. The paper describes
      fzo-1 as a "profusion gene" and demonstrates that loss of fzo-1 leads to fragmented
      mitochondria, confirming its role in mitochondrial fusion.
    action: ACCEPT
    reason: This is the most direct experimental evidence for FZO-1's role in mitochondrial
      fusion in C. elegans. PMID:18722182 explicitly identifies fzo-1 as a profusion
      gene. The paper shows that "profusion genes fzo-1 and eat-3 or the profission
      gene drp-1 are not required for apoptosis activation in C. elegans," but confirms
      their established roles in mitochondrial dynamics. Additional evidence from
      PMID:19327994 describes "a fzo-1 mutant, in which mitochondrial fission occurs
      but mitochondrial fusion is restricted."
    supported_by:
    - reference_id: PMID:18722182
      supporting_text: The dynamin family of GTPases regulate mitochondrial fission
        and fusion processes and have been implicated in controlling the release of
        caspase activators from mitochondria during apoptosis.
    - 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.
    - reference_id: UniProtKB:Q23424
      supporting_text: Mediates mitochondrial fusion (PubMed:18722182, PubMed:19327994,
        PubMed:21248201, PubMed:25190516, PubMed:33734301)
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:
  - statement: Phylogenetic analysis supports FZO-1 as ortholog of yeast Fzo1 and
      mammalian MFN1/MFN2 with conserved function in mitochondrial outer membrane
      fusion
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- 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: fzo-1 is identified as a profusion gene in C. elegans
    supporting_text: profusion genes fzo-1 and eat-3 or the profission gene drp-1
      are not required for apoptosis activation in C. elegans
  - statement: profusion genes fzo-1 and eat-3 are not required for apoptosis activation
    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.
  - statement: fzo-1 is dispensable for normal apoptotic processes during embryonic
      development
    supporting_text: Our findings demonstrate that mitochondria dynamics do not regulate
      apoptosis activation in C. elegans
- id: PMID:19327994
  title: Bcl-2 proteins EGL-1 and CED-9 do not regulate mitochondrial fission or fusion
    in Caenorhabditis elegans.
  findings:
  - statement: In fzo-1 mutant, mitochondrial fission occurs but fusion is restricted
    supporting_text: in a fzo-1 mutant, in which mitochondrial fission occurs but
      mitochondrial fusion is restricted
  - statement: Loss of ced-9 does not affect mitochondrial morphology in fzo-1 mutant
    supporting_text: loss of ced-9 did not affect the mitochondrial morphology observed
      in a drp-1 mutant, in which mitochondrial fusion occurs but mitochondrial fission
      is defective, or in a fzo-1 mutant
  - statement: Confirms fzo-1 role in mitochondrial fusion
    supporting_text: in a fzo-1 mutant, in which mitochondrial fission occurs but
      mitochondrial fusion is restricted
- id: PMID:21248201
  title: A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae
    morphology in Caenorhabditis elegans.
  findings:
  - statement: fzo-1 was used in epistatic analysis of mitochondrial fission
    supporting_text: we knocked down mitochondrial fusion genes (fzo-1 and eat-3)
      in these backgrounds and determined their epistatic relationship
  - statement: Study confirms fzo-1 promotes fusion opposite to fission mutants
    supporting_text: moma-1 mutants that were grown on drp-1 RNAi gave rise to mitochondria
      that were indistinguishable from wild-type animals grown on drp-1 RNAi
- id: PMID:21949250
  title: A molecular switch that governs mitochondrial fusion and fission mediated
    by the BCL2-like protein CED-9 of Caenorhabditis elegans.
  findings:
  - statement: CED-9 physically interacts with FZO-1
    supporting_text: The BCL2-like protein CED-9 of Caenorhabditis elegans has previously
      been shown to promote mitochondrial fusion by physically interacting with the
      mitochondrial fusion protein FZO-1
  - statement: CED-9 promotes mitochondrial fusion by interacting with FZO-1
    supporting_text: CED-9 of Caenorhabditis elegans has previously been shown to
      promote mitochondrial fusion by physically interacting with the mitochondrial
      fusion protein FZO-1
  - statement: EGL-1 shifts CED-9 from profusion to profission
    supporting_text: EGL-1 converts CED-9 into a mitochondrial receptor for DRP-1,
      thereby shifting its activity from profusion to profission
- id: PMID:33734301
  title: Autophagy facilitates mitochondrial rebuilding after acute heat stress via
    a DRP-1-dependent process.
  findings:
  - statement: fzo-1 depletion causes fragmented mitochondria and interacts with drp-1
    supporting_text: "The depletion of fzo-1 results in the accumulation of fragmented\
      \ mitochondria in the epidermis of animals grown at 20\xB0C and partially restores\
      \ some tubular mitochondria in the drp-1 mutant animals"
core_functions:
- description: Mitochondrial outer membrane fusion GTPase. FZO-1 is the sole C. elegans
    mitofusin that mediates tethering and fusion of mitochondrial outer membranes.
    GTP hydrolysis by the dynamin-like GTPase domain powers conformational changes
    required for membrane fusion.
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  directly_involved_in:
  - id: GO:0008053
    label: mitochondrial fusion
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
proposed_new_terms: []
suggested_questions:
- question: What is the specific mechanism by which CED-9 regulates FZO-1 activity,
    and how does EGL-1 modulate this interaction? PMID:21949250 reports that CED-9
    interacts with FZO-1 to promote fusion, and EGL-1 shifts CED-9 activity toward
    profission by enhancing DRP-1 recruitment. The molecular details of how CED-9
    binding activates FZO-1 are not fully understood.
- question: Does FZO-1 directly interact with SLC-25A46, or does SLC-25A46 regulate
    fusion through indirect mechanisms? Recent work (Obinata 2024) shows SLC-25A46
    acts upstream of FZO-1 to promote fusion and FZO-1 overexpression can rescue slc-25a46
    defects. The nature of this functional relationship needs clarification.
suggested_experiments:
- description: Direct biochemical characterization of FZO-1 GTPase activity using
    purified protein and GTP hydrolysis assays. Goal is to confirm GTPase activity
    experimentally in C. elegans FZO-1 (currently inferred by similarity to mammalian
    MFN2).
- description: Live imaging of mitochondrial fusion events in C. elegans to capture
    FZO-1-dependent outer membrane fusion. Goal is to provide direct visual evidence
    of FZO-1-mediated fusion events rather than inferring from steady-state morphology.
tags:
- caeel-mitophagy