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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008289 lipid binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. 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 Sources checked: PANTHER:PTN000326738 · FIS1 family node SOURCE WEAK OR INFERRED |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:24196833 Recruitment of Drp1 to mitochondria is mediated by proteins that are anchored in the mitochondrial outer membrane PMID:24196833 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 |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Strongly supported localization; core to FIS-1 function. Corroborated by the IDA annotation (PMID:21248201). Supporting Evidence: PMID:21248201 Fluorescence labeling showed a pattern similar to patterns observed with YFP fused to a bona fide mitochondrial OM protein (YFP::FIS-1) |
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: No direct worm evidence for peroxisomal localization or a peroxisomal role; family-level propagation. Not a core function of C. elegans fis-1. Supporting Evidence: PMID:24196833 showing punctate peroxisomes in wild-type and Fis1 mutants |
| GO:0000266 mitochondrial fission | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:24196833 Our results show that fis-1 and fis-2 single and double mutants have wild-type mitochondrial morphologies, as also shown by others PMID:24196833 These dominant effects show that overexpressed Fis1 can affect mitochondrial fission even though C. elegans Fis1 proteins are not required for fission |
| GO:0016559 peroxisome fission | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000326738 · FIS1 family node SUPPORTS SOURCE BUT NOT TARGET Supporting Evidence: PMID:24196833 showing punctate peroxisomes in wild-type and Fis1 mutants |
| GO:0000266 mitochondrial fission | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. Reason: Redundant with the IBA mitochondrial-fission annotation; family/domain-level inference. Non-core given the loss-of-function-silent fission phenotype in worm. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to mitochondrial outer membrane. Correct and corroborated by IDA and ISS evidence. Reason: Well-supported core localization; redundant with IDA/ISS annotations. |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to peroxisomal membrane, transferred from the mammalian FIS1 dual localization. Not directly shown in worm; non-core. Reason: Homology-based peroxisomal localization; no direct C. elegans evidence. Retain as non-core. |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of mitochondrial outer membrane localization from human FIS1 (Q9Y3D6). Consistent with worm IDA evidence. Reason: Well-supported core localization; consistent with experimental worm data. |
| GO:0005778 peroxisomal membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of peroxisomal membrane localization from human FIS1. Plausible by homology but not demonstrated in worm; non-core. Reason: Homology-based; no direct worm evidence for peroxisomal localization. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:21248201 A novel mitochondrial outer membrane protein, MOMA-1, that a... | ACCEPT | 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. Reason: Direct assay in C. elegans; the experimental basis for FIS-1 mitochondrial outer membrane localization. Supporting Evidence: PMID:21248201 Fluorescence labeling showed a pattern similar to patterns observed with YFP fused to a bona fide mitochondrial OM protein (YFP::FIS-1) |
| GO:0000423 mitophagy | IMP PMID:24196833 Mutations in Fis1 disrupt orderly disposal of defective mito... | NEW | 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. 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. Supporting Evidence: PMID:24196833 causing the formation of large aggregates containing LGG-1, DRP-1, and remnants of mitochondria |
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Download this section (compressed HTML)Q: 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?
Q: Is the fis-1 requirement for removal of UV-C-induced mtDNA damage a consequence of its mitophagy-coupling role, or a separable function?
Experiment: 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: FIS-1 acts at a late, degradation-committing step of mitophagy downstream of DRP-1/MFF-mediated fission.
Experiment: 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.
Hypothesis: Worm FIS-1 has direct or adaptor-mediated protein partners at the ER-mitochondrial interface.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: 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.
OPEN BIOLOGY MF_DARK
What is known: 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.
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 (the field's own admissions):
Gap: 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.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: 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.
Provenance (the field's own admissions):
Gap: 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.
OPEN BIOLOGYCURATION MF_DARK
What is known: 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.
Provenance (the field's own admissions):
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