id: Q20291
gene_symbol: fis-1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  fis-1 (F41G3.4) is the Caenorhabditis elegans ortholog of FIS1, a small (143 aa)
  tail-anchored protein of the mitochondrial outer membrane. Like other FIS1-family
  members it has a cytosol-facing tetratricopeptide-repeat (TPR) fold and a single
  C-terminal transmembrane helix that anchors it in the outer membrane, with the
  TPR body exposed to the cytosol. C. elegans has a second FIS1 homolog, fis-2,
  which acts partly redundantly with fis-1. In mammals and fungi FIS1 proteins are
  receptor/adaptor factors that participate in recruiting the dynamin-related GTPase
  DRP1 to the outer membrane during mitochondrial (and peroxisomal) fission. In
  C. elegans, however, loss of fis-1 (and fis-2) does not detectably impair
  mitochondrial or peroxisomal fission or morphology; instead FIS-1 acts downstream
  of the DRP-1/MFF fission step to promote the orderly disposal of damaged
  mitochondria. Loss of fis-1/fis-2 causes stress-induced accumulation of large
  autophagic (LGG-1/LC3-positive) aggregates containing mitochondrial remnants, and
  fis-1 is required for removal of UV-C-induced mitochondrial DNA damage. FIS-1 thus
  couples stress-induced mitochondrial fission to mitophagic quality control at the
  mitochondrial outer membrane / ER-mitochondrial interface.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:21248201
  title: A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae
    morphology in Caenorhabditis elegans.
  findings:
  - statement: >-
      YFP::FIS-1 is used as a reference marker for a bona fide mitochondrial outer
      membrane protein in C. elegans muscle cells, supporting mitochondrial outer
      membrane localization of FIS-1.
    supporting_text: >-
      Fluorescence labeling showed a pattern similar to patterns observed with YFP
      fused to a bona fide mitochondrial OM protein (YFP::FIS-1)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PMC full text confirmed. The paper is about MOMA-1, but it experimentally uses
      YFP::FIS-1 as an established mitochondrial outer-membrane marker, which is the
      basis of the IDA localization annotation (assigned by WormBase).
- id: PMID:24196833
  title: Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
  findings:
  - statement: >-
      C. elegans fis-1/fis-2 single and double mutants have wild-type mitochondrial
      morphology; Fis1 homologs have no obvious effect on mitochondrial or
      peroxisomal fission, unlike Mff/Drp1.
    supporting_text: >-
      Our results show that fis-1 and fis-2 single and double mutants have wild-type
      mitochondrial morphologies, as also shown by others
  - statement: >-
      Loss of fis-1/fis-2 causes accumulation of large LGG-1 (LC3) autophagic
      aggregates containing mitochondrial remnants and DRP-1; FIS-1 acts downstream
      of DRP-1/MFF fission to guide mitophagic disposal.
    supporting_text: >-
      causing the formation of large aggregates containing LGG-1, DRP-1, and remnants
      of mitochondria
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PMC full text confirmed. Although the title emphasizes mammalian Fis1, the
      paper directly characterizes C. elegans fis-1 and fis-2 (deletion alleles,
      overexpression, LGG-1 aggregate assays, pink-1 epistasis). Establishes that
      worm FIS-1 is dispensable for fission but required for orderly disposal of
      defective mitochondria (mitophagy coupling).
- id: PMID:24058863
  title: Effects of mutations in mitochondrial dynamics-related genes on the mitochondrial
    response to ultraviolet C radiation in developing Caenorhabditis elegans.
  findings:
  - statement: >-
      RNAi knockdown of fis-1 blocks removal of UV-C-induced mitochondrial DNA
      damage, similarly to drp-1, whereas fis-1 knockout alone does not affect
      mitochondrial morphology or development.
    supporting_text: >-
      RNAi knockdown of fis-1 inhibited mtDNA damage removal similarly to drp-1
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PMC full text confirmed. Provides the experimental basis for a role of fis-1
      in removal of UV-C-induced mtDNA damage (UniProt DNA-damage keyword), using
      the fis-1(tm1867) allele and RNAi.
- 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: >-
      In C. elegans, minor pro-apoptotic roles for drp-1 and fis-2 (a FIS1 homolog)
      are revealed in sensitized backgrounds, acting downstream of the CED-3 caspase
      to promote elimination of mitochondria in dying cells.
    supporting_text: >-
      minor proapoptotic roles for drp-1 and fis-2, a homolog of human Fis1, are
      revealed in sensitized genetic backgrounds
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Cached record is abstract-only (full_text_available: false). The abstract
      foregrounds the fis-1 paralog fis-2, not fis-1 itself; UniProt cites this paper
      for the fis-1 disruption phenotype (normal mitochondrial connectivity). Used
      here only as background context for the family's redundant, non-core roles in
      cell death; not used to support a specific fis-1 GO annotation.
existing_annotations:
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Family-level phylogenetic (IBA) inference of a generic "lipid binding"
      molecular function. There is no C. elegans-specific evidence that FIS-1 binds
      lipid; its C-terminal transmembrane helix mediates membrane anchoring, which is
      not the same as a lipid-binding molecular function. This is a weak,
      uninformative over-propagation for this gene.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No experimental support in worm; the informative molecular function of FIS-1 is
      adaptor/receptor activity (GO:0060090), not lipid binding. Membrane anchoring
      via the tail-anchor TM helix does not justify a lipid-binding MF.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000326738
        source_label: FIS1 family node
        source_status: SOURCE_WEAK_OR_INFERRED
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Captures the core, informative molecular function of FIS1-family proteins:
      an outer-membrane receptor/adaptor that helps bring the fission GTPase DRP-1
      into the fission/degradation machinery. Consistent with C. elegans data showing
      FIS-1 is part of the DRP-1/MAM fission complex that couples fission to
      mitophagic disposal.
    action: ACCEPT
    reason: >-
      Best-supported and most informative MF term for this gene; consistent with the
      family function (Drp1 recruitment/adaptor) and with worm FIS-1 acting within the
      DRP-1-containing MAM fission complex.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: >-
        Recruitment of Drp1 to mitochondria is mediated by proteins that are anchored
        in the mitochondrial outer membrane
    - reference_id: PMID:24196833
      supporting_text: >-
        Fis1 is part of the MAM complex and contributes to a late stage of the removal
        process but is not required for entry of Drp1 into the MAM or fission
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Mitochondrial outer membrane is the well-established site of FIS-1 action,
      supported by direct C. elegans evidence (YFP::FIS-1 used as an OM marker),
      ISS from human FIS1, and the tail-anchor topology.
    action: ACCEPT
    reason: >-
      Strongly supported localization; core to FIS-1 function. Corroborated by the
      IDA annotation (PMID:21248201).
    supported_by:
    - reference_id: PMID:21248201
      supporting_text: >-
        Fluorescence labeling showed a pattern similar to patterns observed with YFP
        fused to a bona fide mitochondrial OM protein (YFP::FIS-1)
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Peroxisomal membrane localization is inferred from mammalian/plant FIS1
      homologs, which act in peroxisome fission. It is plausible for worm FIS-1 by
      homology but has not been directly demonstrated in C. elegans, and fis-1
      mutants have normal (punctate) peroxisomes. Retain as a non-core, homology-based
      localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      No direct worm evidence for peroxisomal localization or a peroxisomal role;
      family-level propagation. Not a core function of C. elegans fis-1.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: showing punctate peroxisomes in wild-type and Fis1 mutants
- term:
    id: GO:0000266
    label: mitochondrial fission
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Mitochondrial fission is the ancestral FIS1-family process, and worm FIS-1 is
      part of the fission machinery (overexpression drives fragmentation; FIS-1 is in
      the DRP-1/MAM fission complex). However, loss of fis-1/fis-2 in C. elegans does
      NOT impair mitochondrial fission or morphology, so this is not the core,
      essential fission determinant in worm (mff-1/mff-2 + drp-1 are). Retain as
      non-core: FIS-1 participates in, but is not required for, fission.
    action: KEEP_AS_NON_CORE
    reason: >-
      Defensible at the family/machinery level and via overexpression, but loss-of-
      function is phenotypically silent for fission in worm; the more specific,
      experimentally supported role is coupling fission to mitophagic disposal.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: >-
        Our results show that fis-1 and fis-2 single and double mutants have wild-type
        mitochondrial morphologies, as also shown by others
    - reference_id: PMID:24196833
      supporting_text: >-
        These dominant effects show that overexpressed Fis1 can affect mitochondrial
        fission even though C. elegans Fis1 proteins are not required for fission
- term:
    id: GO:0016559
    label: peroxisome fission
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Peroxisome fission is a documented FIS1 function in mammals and plants, but in
      C. elegans fis-1 mutants have normal punctate peroxisomes and only Mff/Drp1
      loss produces tubular (fission-defective) peroxisomes. Family-level propagation
      not supported by direct worm evidence; retain as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      No demonstrated peroxisome-fission role for worm fis-1; the worm data show
      normal peroxisomes in fis-1 mutants. Keep as homology-based, non-core.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: showing punctate peroxisomes in wild-type and Fis1 mutants
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      source_entities:
      - source_id: PANTHER:PTN000326738
        source_label: FIS1 family node
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
- term:
    id: GO:0000266
    label: mitochondrial fission
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Electronic InterPro2GO mapping of the Fis1 domain (IPR016543) to mitochondrial
      fission. Same considerations as the IBA mitochondrial-fission annotation:
      defensible at the family level but not the core essential fission role in worm.
    action: KEEP_AS_NON_CORE
    reason: >-
      Redundant with the IBA mitochondrial-fission annotation; family/domain-level
      inference. Non-core given the loss-of-function-silent fission phenotype in worm.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location mapping to mitochondrial outer membrane. Correct
      and corroborated by IDA and ISS evidence.
    action: ACCEPT
    reason: Well-supported core localization; redundant with IDA/ISS annotations.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location mapping to peroxisomal membrane, transferred from
      the mammalian FIS1 dual localization. Not directly shown in worm; non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homology-based peroxisomal localization; no direct C. elegans evidence. Retain
      as non-core.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer of mitochondrial outer membrane localization from human FIS1
      (Q9Y3D6). Consistent with worm IDA evidence.
    action: ACCEPT
    reason: Well-supported core localization; consistent with experimental worm data.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS transfer of peroxisomal membrane localization from human FIS1. Plausible by
      homology but not demonstrated in worm; non-core.
    action: KEEP_AS_NON_CORE
    reason: Homology-based; no direct worm evidence for peroxisomal localization.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:21248201
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) evidence: YFP::FIS-1 localizes to the mitochondrial
      outer membrane and is used as a reference OM marker in C. elegans muscle cells.
      This is the strongest evidence for FIS-1 localization and anchors the core
      cellular component.
    action: ACCEPT
    reason: >-
      Direct assay in C. elegans; the experimental basis for FIS-1 mitochondrial
      outer membrane localization.
    supported_by:
    - reference_id: PMID:21248201
      supporting_text: >-
        Fluorescence labeling showed a pattern similar to patterns observed with YFP
        fused to a bona fide mitochondrial OM protein (YFP::FIS-1)
- term:
    id: GO:0000423
    label: mitophagy
  evidence_type: IMP
  original_reference_id: PMID:24196833
  qualifier: involved_in
  review:
    summary: >-
      Proposed new annotation (not currently in GOA). Genetic loss of fis-1 (with
      fis-2) disrupts the orderly disposal of defective mitochondria: mitochondrial
      stress induces accumulation of large LGG-1/LC3-positive autophagic aggregates
      containing mitochondrial remnants and DRP-1, and these aggregates are suppressed
      by pink-1, mff, and drp-1 mutations. FIS-1 therefore acts within the mitophagy
      pathway, downstream of DRP-1/MFF-mediated fission, to guide fragmented
      mitochondria into autophagic degradation.
    action: NEW
    reason: >-
      Captures the core, experimentally supported biological process of C. elegans
      fis-1 (coupling stress-induced fission to mitophagic disposal), which is absent
      from the current GOA annotations.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: >-
        causing the formation of large aggregates containing LGG-1, DRP-1, and remnants
        of mitochondria
core_functions:
- description: >-
    FIS-1 is a tail-anchored mitochondrial outer membrane protein that acts as a
    receptor/adaptor coupling stress-induced mitochondrial fission to the orderly
    disposal (mitophagy) of damaged mitochondria. It functions downstream of the
    DRP-1/MFF fission step, within a DRP-1-containing complex at the
    ER-mitochondrial interface (MAM), to guide fragmented, defective mitochondria
    into autophagic (LGG-1/LC3-positive) degradation. Loss of fis-1 (with the
    paralog fis-2) does not impair fission but causes stalled, enlarged autophagic
    aggregates and blocks removal of UV-C-induced mitochondrial DNA damage.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0000423
    label: mitophagy
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:24196833
    supporting_text: >-
      Fis1 is part of the MAM complex and contributes to a late stage of the removal
      process but is not required for entry of Drp1 into the MAM or fission
  - reference_id: PMID:24196833
    supporting_text: >-
      causing the formation of large aggregates containing LGG-1, DRP-1, and remnants
      of mitochondria
  - reference_id: PMID:24058863
    supporting_text: >-
      RNAi knockdown of fis-1 inhibited mtDNA damage removal similarly to drp-1
knowledge_gaps:
- gap_statement: >-
    The molecular mechanism by which FIS-1 couples completed mitochondrial fission
    to mitophagic disposal is undefined. In C. elegans FIS-1 is not the essential
    Drp1 receptor for fission (MFF is), yet its loss stalls a late intermediate step
    of orderly mitochondrial disposal, and it is unknown whether it acts by a direct
    downstream autophagy/MAM partner, by remodeling the ER-mitochondrial interface,
    or by handing off DRP-1.
  boundary: >-
    Established: FIS-1 localizes to the mitochondrial outer membrane, is part of the
    DRP-1-containing MAM fission complex, and is required (redundantly with fis-2)
    for orderly disposal of defective mitochondria downstream of DRP-1/MFF and PINK-1.
    Unknown: the specific molecular activity/partner through which it enables the late
    degradation step.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: >-
    FIS1 has long been assumed to be a fission receptor; the worm (and mammalian)
    data reassign it to a mitophagy-coupling role whose mechanism is unresolved,
    directly relevant to PINK1/Parkin quality-control biology and neurodegeneration.
  provenance:
  - reference_id: PMID:24196833
    supporting_text: >-
      Fis1 is part of the MAM complex and contributes to a late stage of the removal
      process but is not required for entry of Drp1 into the MAM or fission
- gap_statement: >-
    Whether C. elegans fis-1 has any endogenous loss-of-function role in
    mitochondrial or peroxisomal fission is unresolved: loss of fis-1/fis-2 is
    phenotypically silent for organelle morphology, while FIS-1 overexpression is
    sufficient to fragment mitochondria.
  boundary: >-
    Established: fis-1/fis-2 mutants have wild-type mitochondrial and peroxisomal
    morphology; overexpressed FIS-1 drives fragmentation. Unknown: whether
    endogenous FIS-1 contributes measurably to fission under any physiological
    condition, or is entirely dispensable for fission with a dedicated role only in
    disposal.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  provenance:
  - reference_id: PMID:24196833
    supporting_text: >-
      These dominant effects show that overexpressed Fis1 can affect mitochondrial
      fission even though C. elegans Fis1 proteins are not required for fission
- gap_statement: >-
    The direct binding partners of C. elegans FIS-1 are unmapped. It is unknown
    whether worm FIS-1 uses adaptor proteins analogous to the yeast Mdv1/Caf4
    proteins, whether it binds DRP-1 directly under stress, and which downstream
    autophagy or MAM factors it engages to promote degradation.
  boundary: >-
    Established (in mammals): stress induces a Drp1-Fis1 co-immunoprecipitable
    complex that also contains ER/MAM proteins. Unknown (in worm): the direct FIS-1
    interactome and whether adaptor intermediates are required.
  gap_kind:
  - BIOLOGY
  - CURATION
  dark_aspect: MF_DARK
  status: OPEN
  provenance:
  - reference_id: PMID:24196833
    supporting_text: >-
      Recruitment of Drp1 to mitochondria is mediated by proteins that are anchored
      in the mitochondrial outer membrane
proposed_new_terms: []
suggested_questions:
- question: >-
    Does endogenous C. elegans FIS-1 physically interact with DRP-1 (directly or via
    an adaptor) during stress-induced fission, and what are its other outer-membrane
    or MAM partners?
- question: >-
    Is the fis-1 requirement for removal of UV-C-induced mtDNA damage a consequence
    of its mitophagy-coupling role, or a separable function?
suggested_experiments:
- hypothesis: >-
    FIS-1 acts at a late, degradation-committing step of mitophagy downstream of
    DRP-1/MFF-mediated fission.
  description: >-
    Perform stage-resolved mitophagy flux assays (e.g. mito-Rosella / mtKeima or
    LGG-1 puncta maturation) in fis-1, fis-2, fis-1;fis-2, mff, and drp-1 mutants
    after Paraquat or antimycin A, to place the fis-1-dependent step relative to
    autophagosome formation, cargo engulfment, and lysosomal fusion.
- hypothesis: >-
    Worm FIS-1 has direct or adaptor-mediated protein partners at the
    ER-mitochondrial interface.
  description: >-
    Use proximity labeling (TurboID) or co-immunoprecipitation of tagged FIS-1 from
    C. elegans under basal and stress conditions to identify DRP-1 and MAM/autophagy
    interactors and test for adaptor intermediates.