MFF-1 is one of two Caenorhabditis elegans orthologs of mammalian mitochondrial fission factor (MFF), a tail-anchored mitochondrial outer membrane protein. It is a short (158 aa) protein with a cytosol-facing N-terminal domain and a single C-terminal transmembrane anchor, embedded in the mitochondrial outer membrane with part of the protein exposed to the cytosol. Together with its paralog MFF-2, MFF-1 is required for normal mitochondrial and peroxisomal fission; single mff-1 or mff-2 mutants have only weak defects, whereas the mff-1 mff-2 double mutant shows a strong mitochondrial fission defect approaching that of the fission dynamin drp-1, and tubular (unfission) peroxisomes. In this respect the worm Mff proteins differ markedly from the two worm Fis1 homologs (fis-1, fis-2), which have no obvious effect on fission. In mammals MFF is the principal receptor that recruits the dynamin-related GTPase DRP1/DNM1L to the mitochondrial surface; the worm proteins promote fission and contribute to stress-induced mitophagy, acting upstream of the Fis1-dependent step, but Mff is not strictly required for DRP-1 recruitment to worm mitochondria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000266 mitochondrial fission | IEA GO_REF:0000104 | ACCEPT | Summary: Mitochondrial fission is the core biological process for MFF-1. This UniRule IEA annotation is transferred from the characterized mammalian MFF ortholog and is directly supported by C. elegans genetics. Single mff-1 (and mff-2) mutants have weak effects owing to redundancy, but the mff-1 mff-2 double mutant has a strong mitochondrial fission defect approaching that of drp-1. Reason: Genuine, experimentally supported core function in worm. Unlike the worm Fis1 homologs (fis-1, fis-2), the Mff homologs have a real fission role. The IEA term is corroborated by direct mutant analysis (PMID:24196833). Supporting Evidence: PMID:24196833 mff-1 and mff-2 single mutants have weak effects, and that the Mff double mutant has a mitochondrial fission defect similar to but not as strong as the drp-1 defect |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: MFF-1 is a tail-anchored mitochondrial outer membrane protein (single C-terminal transmembrane helix, aa 139-156; cytosol-facing N-terminus). This SubCell IEA annotation is experimentally supported in worm, where anti-MFF-1 antibody serves as a mitochondrial outer membrane marker and MFF-1 is digested in protease-protection assays on intact mitochondria without detergent. Reason: Core localization, experimentally confirmed in C. elegans (PMID:21248201) and consistent with the canonical MFF topology and UniProt SubCell annotation. Supporting Evidence: PMID:21248201 MOMA-1 is digested when no detergent is added, like MFF-1, while EAT-3 and F1Ξ² are protease protected |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: MFF mediates peroxisomal as well as mitochondrial fission. In worm, the mff-1 mff-2 double mutant shows tubular (un-divided) peroxisomes, indicating a peroxisome fission defect, which supports a functional MFF role at peroxisomes. This IEA localization annotation is consistent with the peroxisome fission function. Reason: Supported by worm genetics (Mff double mutant to tubular peroxisomes, PMID:24196833) and by ortholog function, but peroxisome fission is a secondary role relative to the dominant mitochondrial fission function; retained as non-core. Supporting Evidence: PMID:24196833 We conclude that C. elegans Mff homologues affect mitochondrial and peroxisome fission, whereas Fis1 homologues have no obvious effects. |
| GO:0090141 positive regulation of mitochondrial fission | IEA GO_REF:0000104 | ACCEPT | Summary: MFF-1 promotes mitochondrial fission; its loss reduces fission (double mutant fission defect) and its function acts upstream in the fission pathway. This UniRule IEA annotation captures the positive-regulatory nature of the MFF receptor/adaptor role in driving fission. Reason: Consistent with the experimentally supported pro-fission role in worm (PMID:24196833). Appropriately specific positive-regulation term for a fission factor that promotes rather than executes membrane scission. Supporting Evidence: PMID:24196833 the Mff double mutant has a mitochondrial fission defect similar to but not as strong as the drp-1 defect |
| GO:0090314 positive regulation of protein targeting to membrane | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: This UniRule IEA term encodes the mammalian MFF function of recruiting the fission dynamin DRP1/DNM1L to the mitochondrial outer membrane. In C. elegans, however, Mff (mff-1/mff-2) is NOT strictly required for DRP-1 recruitment - CFP::DRP-1 still forms fission-marking spots and fractionates to mitochondria normally in Mff double and quadruple mutants, and worm lacks the MiD49/MiD51 receptors. Reason: The annotation is inferred from mammalian orthology and is only partially supported in worm. Because DRP-1 reaches worm mitochondria without Mff, this recruitment function is not firmly established as a worm activity; retained as non-core with an explicit caveat rather than removed (the mammalian ortholog function and the pro-fission role make it plausible, and it is not contradicted as a contributory rather than essential recruitment role). Supporting Evidence: PMID:24196833 Mff and Fis1 are not essential for fission or for Drp1 recruitment to mitochondria in C. elegans file:worm/mff-1/mff-1-deep-research-falcon.md MFF-1 functions as a membrane-anchored receptor/adaptor protein that recruits the dynamin-related GTPase DRP-1 from the cytosol to the mitochondrial outer membrane, thereby promoting mitochondrial fission |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Does C. elegans MFF-1 physically bind DRP-1, and is it a functional DRP-1 receptor given that DRP-1 recruitment to mitochondria is Mff-independent in worm?
Suggested experts: Alexander M. van der Bliek
Q: What is the functional division of labor between mff-1 and mff-2 (and relative to fis-1/fis-2) in worm mitochondrial versus peroxisomal fission?
Suggested experts: Alexander M. van der Bliek
Experiment: Co-immunoprecipitation and in vitro binding assays between MFF-1 (cytosolic domain) and DRP-1, combined with structure-guided mutagenesis and rescue of the mff-1 mff-2 double mutant.
Hypothesis: MFF-1 promotes fission by recruiting or organizing DRP-1 at the outer membrane even though DRP-1 can reach mitochondria independently of Mff.
Type: protein interaction / genetic rescue
Experiment: Paralog-specific fluorescent reporters and tissue-restricted rescue of the mff-1 mff-2 double mutant to dissect individual contributions at mitochondria versus peroxisomes.
Hypothesis: mff-1 and mff-2 have distinct tissue or organelle preferences.
Type: reporter expression / genetic rescue
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The specific molecular activity of C. elegans MFF-1 is uncharacterized: whether worm MFF-1 physically binds DRP-1 (and via which surface), whether it acts as a receptor/adaptor that recruits DRP-1 as in mammals, and whether it has any activity beyond scaffolding, are all undetermined. The GO molecular function is captured only by orthology-based IEA (positive regulation of protein targeting to membrane), not by a demonstrated worm activity.
OPEN BIOLOGY MF_DARK
What is known: It is firmly established that MFF-1 is a tail-anchored mitochondrial outer membrane protein (PMID:21248201) and that mff-1, redundantly with mff-2, is required for normal mitochondrial and peroxisomal fission (PMID:24196833). What is NOT established is the direct biochemical mechanism by which MFF-1 promotes fission in worm, because DRP-1 still localizes to mitochondria without Mff.
Significance: In mammals MFF is the principal DRP1 receptor, but the worm data show DRP-1 recruitment is Mff-independent, so the worm MFF-1 mechanism may differ from the textbook receptor model. Resolving it would clarify how metazoan fission-factor function is (or is not) conserved.
What would resolve it: Direct MFF-1-DRP-1 interaction assays (co-IP, in vitro binding), structure-guided mutagenesis of the cytosolic domain, and rescue of the mff-1 mff-2 double mutant with wild-type vs interaction-defective MFF-1.
Provenance (the field's own admissions):
Gap: The division of labor between mff-1 and mff-2 is unresolved: which paralog dominates, whether they are functionally interchangeable, whether they act in different tissues or at different targets (mitochondria vs peroxisomes), and whether they hetero-oligomerize are all unknown. Single-mutant phenotypes are weak, so the individual contribution of mff-1 has not been isolated.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: It is established that single mff-1 and single mff-2 mutants have only weak fission defects while the double mutant is strong, indicating substantial redundancy (PMID:24196833). The relative and tissue-specific contributions of each paralog are the gap.
Significance: Understanding mff-1 vs mff-2 (and their relation to fis-1/fis-2) division of labor is needed to build an accurate model of worm DRP-1 recruitment and mitochondrial fission, and to interpret single-gene perturbations in the mitophagy/aging pathway.
What would resolve it: Paralog-specific tagged reporters and tissue-restricted rescue of the mff-1 mff-2 double mutant, plus mff-1 vs mff-2 single- and cross-rescue experiments.
Provenance (the field's own admissions):
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)