fis-1 (C. elegans) — Gene Review Notes

UniProt: Q20291 (FIS11_CAEEL); WormBase F41G3.4 / WBGene00001424; ORF F41G3.4.
Human ortholog: FIS1 (Q9Y3D6). Paralog in worm: fis-2 (a second FIS1 homologue).
Part of the flagship projects/CAEEL_MITOPHAGY.md project.

143 aa tail-anchored protein: cytosol-facing TPR-fold body + a single C-terminal
transmembrane helix (residues ~121–141) that anchors it in the mitochondrial outer
membrane. Belongs to the FIS1 family (PIRSF008835; CDD cd12212; PANTHER PTHR13247:SF1).

Deep research provenance

Falcon deep research (just deep-research-falcon worm fis-1 --fallback perplexity-lite) was
attempted TWICE (initial run stalled >15 min with zero output under heavy concurrent Edison
load; a bounded retry was killed by a 6-min timeout, exit 143). No -deep-research-falcon.md
file was produced, and the perplexity-lite fallback also did not yield a file. This review is
therefore grounded directly in UniProt (Q20291), GOA, and cached FULL-TEXT primary literature
(PMID:24196833, PMID:24058863, PMID:21248201 all have full text; PMID:18722182 abstract-only).
Because every existing annotation could be adjudicated from the cached full text, no UNDECIDED
calls were required.

Provenance sources

• UniProt Q20291 record (fis-1-uniprot.txt)
• GOA (fis-1-goa.tsv) — 12 annotations
• Primary literature (cached, full text unless noted):
• PMID:24196833 Shen et al. 2014 Mol Biol Cell — "Mutations in Fis1 disrupt orderly disposal of defective mitochondria" (full text; studies BOTH C. elegans fis-1/fis-2 AND mammalian FIS1)
• PMID:24058863 Bess et al. 2013 Worm — UVC / mtDNA damage removal (full text)
• PMID:21248201 Head et al. 2011 Mol Biol Cell — MOMA-1 paper (full text; uses YFP::FIS-1 as a bona fide mito OM marker)
• PMID:18722182 Breckenridge et al. 2008 Mol Cell — drp-1/fis-2 cell-death (ABSTRACT ONLY in cache; abstract foregrounds fis-2)

KNOWN (well supported)

Localization: mitochondrial outer membrane (KNOWN)

• YFP::FIS-1 is used as a reference mitochondrial outer-membrane marker in C. elegans.
  PMID:21248201
• Tail-anchored topology: cytosolic TPR body + single C-terminal TM helix (UniProt FT TRANSMEM 121..141; DOMAIN "The C-terminus is required for mitochondrial or peroxisomal localization, while the N-terminus is necessary for mitochondrial or peroxisomal fission").
• This underpins the IDA (PMID:21248201), ISS (from human Q9Y3D6), and IEA(SubCell) mito-OM annotations. Peroxisomal-membrane localization is by ISS/IBA from mammalian/plant homologues; NOT directly demonstrated in worm.

Molecular function: adaptor/receptor in the fission machinery (KNOWN at family level, consistent in worm)

• FIS1 family proteins are Drp1 recruitment/adaptor factors anchored in the OMM.
  PMID:24196833
• In worm, fission-inducing stress drives Drp1 into a complex with Fis1 (shown for mammalian cells; worm Fis1 is part of the MAM fission complex).
  PMID:24196833
• Supports GOA IBA GO:0060090 molecular adaptor activity (core MF).

Core role in C. elegans: orderly disposal of defective mitochondria / stress-induced mitophagy (KNOWN)

• fis-1;fis-2 (Fis1) mutants accumulate LGG-1 (worm LC3) autophagic aggregates, enlarged by mitochondrial stress (Paraquat/ROS, antimycin A).
  PMID:24196833
• Aggregates contain remnants of mitochondria + DRP-1 (and Parkin/ER).
  PMID:24196833
• Aggregate formation requires upstream Mff/Drp1 fission and Pink1 → fis-1 acts downstream, coupling fission to mitophagy. Model:
  PMID:24196833
• pink-1 fis-1 fis-2 triple mutant loses colocalizing mitophagosome spots ("as expected for a complete block of mitophagy") and has fewer/smaller LGG-1 aggregates than the Fis1 double.

Role in removal of UVC-induced mtDNA damage (KNOWN)

• RNAi knockdown of fis-1 blocks removal of UVC-induced mtDNA damage, like drp-1.
  PMID:24058863
• fis-1 knockout does not exacerbate UVC-induced larval arrest (redundancy/buffering by fusion).
  Figure legend: PMID:24058863
• This is the experimental basis for the UniProt "DNA damage" keyword (GO:0006974 DNA damage response, IEA-KW; no GOA annotation for it directly).

NOT known / important negatives

fis-1 is NOT required for mitochondrial fission in C. elegans (organism-specific negative)

• fis-1 and fis-2 single/double mutants have WILD-TYPE mitochondrial morphology; loss of function has no obvious fission defect.
  PMID:24196833
  PMID:24196833
• Corroborated by UVC paper: PMID:24058863
• BUT overexpressed FIS-1 can drive fragmentation, and it is part of the fission complex → the GO:0000266 "mitochondrial fission" IBA/IEA is defensible at the family/machinery level but is NOT the core essential fission determinant in worm (that is mff-1/mff-2 + drp-1). Treat as non-core.

fis-1 is NOT required for peroxisome fission in C. elegans (organism-specific negative)

• fis-1 mutants have normal (punctate) peroxisomes; only Mff/Drp1 loss gives tubular peroxisomes.
  PMID:24196833
• So GO:0016559 peroxisome fission (IBA) is a family-level propagation not supported by direct worm evidence; non-core.

lipid binding (GO:0008289, IBA) — weakly supported

• No worm-specific evidence that fis-1 binds lipid. The tail anchor inserts into membrane but that is membrane anchoring, not a "lipid binding" molecular function. Likely a generic family-level over-propagation; non-core / over-annotated.

Unknowns (candidate knowledge gaps)

1. The precise molecular activity by which Fis1 couples completed fission to the mitophagy/degradation machinery is undefined. It is not a Drp1 receptor essential for fission in worm (Mff is), yet its loss stalls an intermediate step of orderly disposal. Whether it acts by a direct partner (a downstream autophagy/MAM factor), by remodeling the ER–mitochondrial interface, or by handing off DRP-1, is unresolved.
   PMID:24196833
2. Whether C. elegans fis-1 has any endogenous (loss-of-function) role in mitochondrial or peroxisome fission at all, versus being entirely dispensable, is unresolved: LOF is phenotypically silent for morphology while overexpression is sufficient to fragment.
   PMID:24196833
3. The direct binding partners of worm FIS-1 (does it use adaptor proteins analogous to yeast Mdv1/Caf4? does it bind DRP-1 directly under stress?) have not been mapped in C. elegans.

Curation decisions summary (see fis-1-ai-review.yaml)

• ACCEPT (core): GO:0060090 molecular adaptor activity (IBA); GO:0005741 mitochondrial outer membrane (IDA/ISS/IEA/IBA).
• KEEP_AS_NON_CORE: GO:0000266 mitochondrial fission (IBA, IEA); GO:0005778 peroxisomal membrane (IBA/ISS/IEA); GO:0016559 peroxisome fission (IBA).
• MARK_AS_OVER_ANNOTATED: GO:0008289 lipid binding (IBA).
• Core biological role captured in core_functions = orderly disposal of defective mitochondria (stress-induced mitophagy coupling), MF = molecular adaptor activity at the mito OM.