id: Q6AHP8
gene_symbol: fis-2
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  fis-2 (F13B9.8) is one of two Caenorhabditis elegans homologs of FIS1, a small
  (151 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. The worm genome encodes a
  second FIS1 homolog, fis-1, with which fis-2 acts partly redundantly. In
  mammals and fungi FIS1 proteins are receptor/adaptor factors implicated in
  recruiting the dynamin-related GTPase DRP1 to the outer membrane during
  mitochondrial (and peroxisomal) fission. In C. elegans, however, loss of fis-2
  (alone or together with fis-1) does not detectably impair mitochondrial or
  peroxisomal fission or morphology; the essential fission machinery is instead
  MFF/DRP-1. The functions demonstrated for fis-2 are downstream of, or parallel
  to, fission: it has a minor pro-apoptotic role in promoting the elimination of
  mitochondria in dying cells, acting downstream of the CED-3 caspase and
  independently of DRP-1 and CED-9, and it contributes (redundantly with fis-1)
  to the orderly disposal of damaged mitochondria, where loss of both paralogs
  causes stress-induced accumulation of large autophagic (LGG-1/LC3-positive)
  aggregates containing mitochondrial remnants. fis-2 is thus a mitochondrial
  outer membrane FIS1-family protein linked to mitochondrial quality control and
  cell-death execution rather than to the core fission reaction.
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: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16184190
  title: Genetic interactions due to constitutive and inducible gene regulation mediated
    by the unfolded protein response in C. elegans.
  findings:
  - statement: >-
      A genome-wide C. elegans UPR microarray study. fis-2 (F13B9.8) is not named
      in the abstract or main text; its identification as a UPR-regulated gene is
      in the supplementary microarray tables, which is the basis of the WormBase
      HEP annotation to IRE1-mediated UPR.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PMC full text confirmed (full_text_available: true). This is a
      transcriptional-profiling study of the C. elegans UPR; fis-2 appears only as
      a high-throughput expression-profiling (HEP) target in supplementary data.
      No verbatim fis-2 quote is available. Supports at most that fis-2 mRNA is
      UPR-responsive, not that fis-2 functions in the UPR; used to justify a
      non-core, expression-based annotation only.
- 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: >-
      fis-2 (a homolog of human Fis1) has a minor pro-apoptotic role revealed in
      sensitized genetic backgrounds, acting downstream of the CED-3 caspase and
      independently of DRP-1 and CED-9 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: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cached record is abstract-only (full_text_available: false). The abstract
      directly foregrounds fis-2 and is the source of the fis-2-specific IGI
      apoptosis annotation and (via full text not in cache) the IDA mitochondrion
      localization curated by WormBase. This is the ONLY paper demonstrating an
      individual (fis-2 single-gene) loss-of-function phenotype for fis-2.
- id: PMID:24196833
  title: Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
  findings:
  - statement: >-
      C. elegans fis-2 single and fis-1;fis-2 double mutants have wild-type
      mitochondrial (and peroxisomal) morphology; Fis1 homologs are not essential
      for fission or for DRP-1 recruitment, unlike MFF/DRP-1.
    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 both FIS1 paralogs (the fis-1;fis-2 "Fis1" double mutant) causes
      stress-induced accumulation of large LGG-1 autophagic aggregates containing
      mitochondrial remnants and DRP-1; drp-1 fis-1 fis-2 and pink-1 fis-1 fis-2
      triple mutants place fis-2 genetically in the mitophagic disposal pathway
      downstream of DRP-1/MFF and PINK-1.
    supporting_text: >-
      pink-1 single and pink-1 fis-1 fis-2 triple mutant animals had no colocalizing
      spots, as expected for a complete block of mitophagy
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PMC full text confirmed. Directly characterizes C. elegans fis-2 using the
      fis-1(tm1867); fis-2(gk414) double mutant (called the "Fis1 mutant"
      throughout) plus drp-1 fis-1 fis-2 and pink-1 fis-1 fis-2 triple mutants.
      Establishes that fis-2 is dispensable for fission and contributes REDUNDANTLY
      (only demonstrated in the double mutant) to orderly disposal of defective
      mitochondria. Not in the GOA seed set; added here because it is the primary
      loss-of-function characterization of worm fis-2.
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-2 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 inferred
      for FIS1-family proteins 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: >-
      The most informative molecular-function term available for a FIS1-family
      protein: an outer-membrane receptor/adaptor that helps bring the fission
      GTPase DRP-1 into the fission/degradation machinery. Consistent with fis-2
      being a tail-anchored mitochondrial outer membrane protein that acts within
      the DRP-1/MAM disposal machinery. Important caveat: this is entirely
      family-level inference — no worm FIS-2 protein has been shown to bind DRP-1,
      an adaptor, or any partner (see knowledge_gaps).
    action: ACCEPT
    reason: >-
      Best-supported and most informative MF term for this gene; consistent with
      the family function (Drp1 recruitment/adaptor). Retained as the representative
      molecular function while flagged as an MF-dark gap because it is undemonstrated
      for fis-2 specifically.
    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 expected site of action for a FIS1-family
      tail-anchored protein and is consistent with the fis-2 IDA mitochondrion
      localization (PMID:18722182) and ISS from human FIS1. Accept as the core
      cellular component, recognizing that OM-resolution localization of worm fis-2
      is inferred (homology + tail-anchor topology) rather than directly resolved.
    action: ACCEPT
    reason: >-
      Well-supported localization consistent with the family and with the
      experimental (IDA) mitochondrial annotation; core to FIS-2 function.
- 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. Plausible for worm fis-2 by
      homology but not directly demonstrated, and fis-1;fis-2 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-2.
    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, but in C. elegans
      loss of fis-2 (alone or with fis-1) does NOT impair mitochondrial fission or
      morphology, and Fis1 homologs are not essential for fission or DRP-1
      recruitment (MFF/DRP-1 are the essential factors). Retain as non-core: fis-2
      belongs to the fission machinery at the family level but is not required for
      fission in worm.
    action: KEEP_AS_NON_CORE
    reason: >-
      Defensible at the family level, but loss-of-function is phenotypically silent
      for fission in worm; this is not the core, essential fission determinant.
    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: >-
        Mff and Fis1 are not essential for fission or for Drp1 recruitment to
        mitochondria in C. elegans
- 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;fis-2 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-2; the worm data show
      normal peroxisomes in Fis1 mutants. Keep as homology-based, non-core.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: >-
        showing punctate peroxisomes in wild-type and Fis1 mutants and tubular
        peroxisomes in drp-1 mutant and Mff double 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/domain 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:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated electronic annotation to the mitochondrion. Correct and corroborated
      by the direct experimental (IDA) mitochondrial localization from PMID:18722182
      and by ISS from human FIS1.
    action: ACCEPT
    reason: >-
      Well-supported core localization; consistent with the experimental IDA
      annotation.
- 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,
      consistent with the FIS1 tail-anchor topology and ISS from human FIS1.
    action: ACCEPT
    reason: >-
      Well-supported core localization; redundant with the ISS annotation and
      consistent with the experimental mitochondrial localization.
- 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 the fis-2 IDA mitochondrial localization and the
      tail-anchor topology.
    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:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: HEP
  original_reference_id: PMID:16184190
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      High-throughput expression-profiling (HEP) annotation: fis-2 (F13B9.8) was
      identified as a UPR-regulated gene in a genome-wide microarray study of the
      C. elegans unfolded protein response. This reflects transcriptional
      co-regulation of fis-2 with the IRE1/XBP-1 UPR, not a demonstrated functional
      role of fis-2 within the UPR pathway. fis-2 is not named in the paper's text
      (the evidence is in supplementary tables), so no verbatim supporting quote is
      available.
    action: KEEP_AS_NON_CORE
    reason: >-
      Expression-based (HEP) association only; being a UPR target gene does not
      establish that fis-2 acts in the UPR. Retain as a peripheral, non-core
      annotation reflecting transcriptional responsiveness, not core function.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:18722182
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) mitochondrial localization of FIS-2 curated by
      WormBase from Breckenridge et al. 2008. This is the strongest, fis-2-specific
      evidence for FIS-2 localization and anchors the core cellular component. The
      cached record is abstract-only, so the localization figure is not quotable
      here; the annotation is retained on the WormBase curator's IDA assignment.
    action: ACCEPT
    reason: >-
      Direct experimental assay in C. elegans (WormBase IDA); the experimental basis
      for FIS-2 mitochondrial localization.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IGI
  original_reference_id: PMID:18722182
  qualifier: involved_in
  review:
    summary: >-
      The only individually demonstrated fis-2 function. Genetic-interaction (IGI)
      evidence: fis-2 has a minor pro-apoptotic role, revealed in sensitized
      genetic backgrounds, acting downstream of the CED-3 caspase and independently
      of DRP-1 and CED-9 to promote elimination of mitochondria in dying cells and
      facilitate cell-death execution. The effect is minor (fis-2 single mutants
      show only small changes in cell-corpse numbers), so this is a genuine but
      non-essential role.
    action: ACCEPT
    reason: >-
      Experimentally supported, fis-2-specific role in cell-death execution (IGI
      with ced-3). This is the best-characterized function of fis-2 and should be
      retained.
    supported_by:
    - reference_id: PMID:18722182
      supporting_text: >-
        minor proapoptotic roles for drp-1 and fis-2, a homolog of human Fis1, are
        revealed in sensitized genetic backgrounds
    - reference_id: PMID:18722182
      supporting_text: >-
        reveal distinct roles for drp-1 and fis-2 as mediators of cell-death
        execution downstream of caspase activation
- term:
    id: GO:0000423
    label: mitophagy
  evidence_type: IGI
  original_reference_id: PMID:24196833
  qualifier: involved_in
  review:
    summary: >-
      Proposed new annotation (not currently in GOA). Genetic loss of both FIS1
      paralogs (the fis-1;fis-2 double mutant) 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/mitophagosome spots are suppressed by drp-1,
      mff, and pink-1 mutations. fis-2 is genetically part of this pathway
      (drp-1 fis-1 fis-2 and pink-1 fis-1 fis-2 triple mutants). IMPORTANT: the
      disposal phenotype was only demonstrated in the fis-1;fis-2 double, so fis-2's
      contribution is redundant with fis-1, not shown to be fis-2-autonomous.
    action: NEW
    reason: >-
      Captures the experimentally supported biological process in which fis-2
      participates (coupling stress-induced fission to mitophagic disposal),
      currently absent from GOA. Annotated as IGI (redundancy with fis-1) to reflect
      that the phenotype requires loss of both paralogs.
    supported_by:
    - reference_id: PMID:24196833
      supporting_text: >-
        pink-1 single and pink-1 fis-1 fis-2 triple mutant animals had no colocalizing
        spots, as expected for a complete block of mitophagy
    - reference_id: PMID:24196833
      supporting_text: >-
        a drp-1 fis-1 fis-2 triple mutant strain also had reduced number and size of
        aggregates when treated with Paraquat
core_functions:
- description: >-
    FIS-2 is a tail-anchored mitochondrial outer membrane protein of the FIS1
    family that functions in the disposal of mitochondria rather than in the core
    fission reaction. Its individually demonstrated role is a minor pro-apoptotic
    (cell-death execution) function: acting downstream of the CED-3 caspase and
    independently of DRP-1 and CED-9, it promotes elimination of mitochondria in
    dying cells. Redundantly with the paralog fis-1, it also contributes to the
    orderly, PINK-1-dependent disposal of stress-damaged mitochondria downstream
    of MFF/DRP-1-mediated fission. Its molecular activity is inferred, at the
    family level only, to be that of a membrane adaptor/receptor.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  directly_involved_in:
  - id: GO:0006915
    label: apoptotic process
  - id: GO:0000423
    label: mitophagy
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:18722182
    supporting_text: >-
      minor proapoptotic roles for drp-1 and fis-2, a homolog of human Fis1, are
      revealed in sensitized genetic backgrounds
  - reference_id: PMID:24196833
    supporting_text: >-
      pink-1 single and pink-1 fis-1 fis-2 triple mutant animals had no colocalizing
      spots, as expected for a complete block of mitophagy
  - 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
knowledge_gaps:
- gap_statement: >-
    The molecular activity of FIS-2 is entirely undetermined experimentally. Its
    only molecular-function annotation ("molecular adaptor activity") is a
    phylogenetic (IBA) propagation from the FIS1 family; no C. elegans FIS-2
    protein has been shown to bind DRP-1, a fission adaptor, lipid, or any other
    partner, and no biochemical or structural study of worm FIS-2 exists.
  boundary: >-
    Established: FIS-2 is a FIS1-family tail-anchored protein of the mitochondrial
    outer membrane (IDA mitochondrion; ISS/tail-anchor topology) that participates
    genetically in mitochondrial disposal. Unknown: what FIS-2 actually does at the
    molecular level - its direct binding partner(s) and the biochemical activity,
    if any, beyond membrane anchoring.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: >-
    FIS1 has long been presumed a fission receptor; worm (and mammalian) data
    reassign the family to mitochondrial quality-control roles whose mechanism is
    unresolved. For the fis-2 paralog specifically, even the assumed adaptor
    activity is untested, making it a genuinely dark molecular function relevant to
    PINK1/Parkin quality-control biology.
  provenance:
  - reference_id: PMID:24196833
    supporting_text: >-
      Mff and Fis1 are not essential for fission or for Drp1 recruitment to
      mitochondria in C. elegans
- gap_statement: >-
    Whether FIS-2 has any non-redundant, fis-2-autonomous role in mitochondrial
    disposal/mitophagy is unresolved. Every mitophagy/LGG-1-aggregate phenotype
    was scored in the fis-1(tm1867); fis-2(gk414) double mutant (the "Fis1
    mutant"), and both single mutants have wild-type mitochondrial morphology, so
    the individual contribution of fis-2 to orderly disposal (versus complete
    redundancy with, or dispensability relative to, fis-1) has not been measured.
  boundary: >-
    Established: the fis-1;fis-2 double mutant accumulates stress-induced LGG-1
    aggregates and lies genetically downstream of MFF/DRP-1 and PINK-1. Unknown:
    what a fis-2 single loss-of-function does to mitophagic flux, and whether fis-2
    contributes anything the paralog fis-1 does not.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Distinguishing redundant from specialized paralog functions is required before
    fis-2 can be assigned a specific mitophagy role rather than a family-level one,
    and determines whether fis-2 is a distinct quality-control node or a fis-1
    backup.
  provenance:
  - 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
- gap_statement: >-
    The direct binding partners and interactome of C. elegans FIS-2 are unmapped.
    It is unknown whether FIS-2 binds DRP-1 (directly or via an adaptor
    intermediate analogous to yeast Mdv1/Caf4), whether it joins an
    ER-mitochondria (MAM) fission/disposal complex as mammalian FIS1 does under
    stress, and which downstream autophagy or apoptotic-machinery factors it
    engages.
  boundary: >-
    Established (in mammals): stress induces a DRP-1-FIS1 co-immunoprecipitable
    complex that also contains ER/MAM proteins. Unknown (for worm FIS-2): its
    physical interactors, and whether the mammalian complex applies to this
    paralog.
  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
- gap_statement: >-
    The mechanism and biological significance of the fis-2-specific pro-apoptotic
    role are unknown. fis-2 promotes elimination of mitochondria in dying cells
    downstream of CED-3 and independently of DRP-1/CED-9, but whether this uses the
    same membrane machinery as its (redundant) mitophagy role, why the effect is
    only detectable in sensitized backgrounds, and why this activity is
    foregrounded for fis-2 but not fis-1, are all unresolved.
  boundary: >-
    Established: in sensitized backgrounds fis-2 has a minor, CED-3-dependent,
    DRP-1/CED-9-independent pro-apoptotic effect on mitochondrial elimination.
    Unknown: the molecular basis of this activity and its relationship to the
    paralog-redundant mitophagy pathway.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  provenance:
  - reference_id: PMID:18722182
    supporting_text: >-
      drp-1 and fis-2 function independent of one another and the Bcl-2 homolog
      CED-9 and downstream of the CED-3 caspase to promote elimination of
      mitochondria in dying cells
proposed_new_terms: []
suggested_questions:
- question: >-
    Does a fis-2 single loss-of-function (independent of fis-1) measurably alter
    mitophagic flux or mitochondrial quality control, or is fis-2 fully redundant
    with fis-1?
- question: >-
    Does C. elegans FIS-2 physically interact with DRP-1 or MAM/ER-mitochondria
    components, and does it use an adaptor intermediate, as mammalian FIS1 does
    under stress?
- question: >-
    Do the two worm FIS1 paralogs partition functionally (fis-2 toward
    cell-death-execution disposal, fis-1 toward UVC/mtDNA-damage removal), or are
    they interchangeable?
suggested_experiments:
- hypothesis: >-
    FIS-2 makes a distinct, non-redundant contribution to stress-induced mitophagy
    that is masked by the paralog fis-1 in double-mutant analyses.
  description: >-
    Compare stage-resolved mitophagy flux (mito-Rosella / mtKeima or LGG-1 puncta
    maturation) after Paraquat or antimycin A across wild-type, fis-2 single,
    fis-1 single, and fis-1;fis-2 double mutants, with allele-specific rescue, to
    isolate any fis-2-autonomous step.
- hypothesis: >-
    Worm FIS-2 has direct or adaptor-mediated partners at the mitochondrial outer
    membrane / ER-mitochondrial interface.
  description: >-
    Use proximity labeling (TurboID) or co-immunoprecipitation of endogenously
    tagged FIS-2 from C. elegans under basal and mitochondrial-stress conditions to
    identify DRP-1, MAM, and autophagy/apoptosis interactors and to test for
    adaptor intermediates, comparing the FIS-2 and FIS-1 interactomes.