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 F1β 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
|
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 — 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):
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The gene mff-1 (ORF name F11C1.2, CELE_F11C1.2) in Caenorhabditis elegans encodes Mitochondrial Fission Factor (MFF-1), a member of the Tango11 protein family containing the Mff/Tango-11 domain (InterPro IPR008518). C. elegans possesses two paralogs of this family: mff-1 (F11C1.2) and mff-2, both of which have been proposed as candidate DRP-1 receptors on the mitochondrial outer membrane (lu2011amolecularswitch pages 7-8). The protein is the C. elegans ortholog of mammalian MFF and Drosophila Tango11 (CG3404), which was originally identified through siRNA screening for genes that affect mitochondrial morphology in Drosophila S2 cells (singh2023mechanisticanalysisof pages 28-32). Importantly, the MFF/Tango11 family is metazoan-specific and absent in yeast, which instead utilizes a different set of adaptor proteins (Fis1/Mdv1/Caf4) for Dnm1-mediated mitochondrial fission (yu2020regulationofmammalian pages 6-7, singh2023mechanisticanalysisof pages 28-32).
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. This function is conserved from the well-characterized mammalian ortholog MFF. In mammalian cells, MFF is the principal DRP1 receptor and is essential for mitochondrial recruitment of DRP1; depletion of MFF severely inhibits mitochondrial fission and DRP1 recruitment, while overexpression extensively recruits DRP1 and induces mitochondrial fragmentation (otera2011discoveryofthe pages 1-3, yu2020regulationofmammalian pages 6-7). MFF binds DRP1 directly, although this interaction is transient and detectable only after chemical crosslinking (singh2023mechanisticanalysisof pages 28-32, singh2023mechanisticanalysisof pages 32-35). The interaction occurs through N-terminal repeat motifs (R1 and R2) in the first ~50 amino acids of MFF, which are essential for DRP1 binding (otera2011discoveryofthe pages 1-3, yu2020regulationofmammalian pages 6-7). Notably, MFF selectively recruits oligomerized, active forms of DRP1, distinguishing it from alternative DRP1 receptors such as MiD49/MiD51, which bind a wider range of DRP1 assembly states (yu2020regulationofmammalian pages 6-7).
In C. elegans, Lu et al. (2011) proposed that MFF-1 and MFF-2 serve as mitochondrial receptors for DRP-1, alongside the EGL-1–CED-9 complex. The rationale is that loss of egl-1 function only causes an approximately 20% increase in mitochondrial length, far less severe than the hyperfusion phenotype of drp-1 mutants, implying the existence of additional DRP-1 receptors such as MFF-1 and MFF-2 (lu2011amolecularswitch pages 7-8). Similarly, Qin et al. (2020) listed fis-2, mff-1, and mff-2 as candidate DRP-1 recruiters in C. elegans neurons (qin2020anendoplasmicreticulum pages 5-7).
MFF-1 is not an enzyme and does not catalyze a biochemical reaction. Rather, it functions as a structural adaptor that physically links cytosolic DRP-1 to the mitochondrial membrane, enabling the mechanochemical GTPase activity of DRP-1 to constrict and sever the outer mitochondrial membrane.
MFF-1 localizes to the mitochondrial outer membrane (MOM). This was directly demonstrated in C. elegans by Head et al. (2011), who used MFF-1 as an outer membrane marker in protease protection experiments on isolated mitochondria. They showed that MFF-1 is digested by proteinase K in intact mitochondria (similar to other cytoplasmically exposed MOM proteins), whereas inner membrane protein EAT-3 and matrix protein F1β remain protease-protected. This confirms that MFF-1 is embedded in the mitochondrial outer membrane with a substantial portion of the protein exposed to the cytosol (head2011anovelmitochondrial pages 5-6). This topology is fully consistent with the mammalian ortholog, which is a C-tail-anchored MOM protein with its N-terminal functional domain facing the cytosol (singh2023mechanisticanalysisof pages 28-32, otera2011discoveryofthe pages 1-3).
Based on conserved domain architecture from the mammalian ortholog, the MFF/Tango-11 domain (IPR008518) protein is predicted to contain: (1) N-terminal repeat regions that serve as the DRP1-binding interface; (2) a coiled-coil domain that mediates protein oligomerization; and (3) a C-terminal transmembrane domain that anchors the protein in the outer mitochondrial membrane in a tail-anchored configuration (singh2023mechanisticanalysisof pages 28-32). In mammalian MFF, the coiled-coil domain enables oligomerization, most likely as a trimer with a dissociation constant of approximately 10 μM in solution. This dynamic oligomerization is essential for DRP1 activation and is significantly more favorable when the protein is membrane-anchored (liu2021mffoligomerizationis pages 7-8, liu2021mffoligomerizationis pages 1-2). Oligomerization-defective MFF mutants fail to rescue mitochondrial division, DRP1 recruitment to mitochondria, and peroxisome division in MFF-knockout cells (liu2021mffoligomerizationis pages 1-2, liu2021mffoligomerizationis pages 6-7).
MFF-1 participates in the DRP1-mediated mitochondrial fission pathway. The current model, derived primarily from mammalian studies, proceeds as follows:
In C. elegans, the mitochondrial fission pathway additionally involves the EGL-1–CED-9 complex as a parallel DRP-1 receptor system. The BCL-2-like protein CED-9 can act as a molecular switch: in complex with the BH3-only protein EGL-1, it recruits GTP-bound DRP-1 to mitochondria and promotes fission, whereas CED-9 alone promotes FZO-1/EAT-3-dependent mitochondrial fusion (lu2011amolecularswitch pages 6-7, lu2011amolecularswitch pages 4-6, lu2011amolecularswitch pages 7-8). This dual-receptor system (EGL-1/CED-9 plus MFF-1/MFF-2) explains why loss of egl-1 alone only partially phenocopies drp-1 loss-of-function (lu2011amolecularswitch pages 7-8).
In mammalian cells, MFF is the sole DRP1 receptor essential for peroxisomal division. MFF-knockout cells display enlarged, elongated peroxisomes, and only wild-type MFF (but not oligomerization-deficient mutants) can rescue this phenotype (liu2021mffoligomerizationis pages 1-2, liu2021mffoligomerizationis pages 6-7, carmichael2022fissionimpossible(?)—new pages 9-10). Whether MFF-1 similarly participates in peroxisomal fission in C. elegans has not been directly tested in the retrieved literature, but this dual role is likely conserved given the family membership and the shared DRP1/MFF fission machinery.
Mammalian MFF is regulated by phosphorylation by AMP-activated protein kinase (AMPK), the master cellular energy sensor. Key phosphorylation sites include Ser146 (involved in regulating MAVS-mediated innate immune responses), as well as Ser155, Ser172, and Ser275, which collectively link energy status to mitochondrial fission activity (hanada2021mavsisenergized pages 9-10, hanada2021mavsisenergized pages 7-8, tabara2025molecularmechanismsof pages 9-10). Under conditions of mitochondrial dysfunction or energy stress, AMPK phosphorylates MFF to promote mitochondrial fission, thereby facilitating the segregation and removal of damaged mitochondria via mitophagy (hanada2021mavsisenergized pages 1-2, carmichael2022fissionimpossible(?)—new pages 9-10). Additionally, protein kinase D (PKD) phosphorylates MFF during mitosis to coordinate mitochondrial division with cell division (tabara2025molecularmechanismsof pages 9-10). Whether AMPK-mediated regulation of MFF-1 is conserved in C. elegans remains to be determined experimentally.
A remarkable non-canonical function of MFF was discovered in its regulation of mitochondrial antiviral signaling (MAVS). Hanada et al. (2020) demonstrated that MFF is required for the formation of active MAVS clusters on mitochondria, independent of its role in mitochondrial fission and independent of DRP1. Under energy-replete conditions, MFF promotes MAVS cluster formation and a robust antiviral response. Under energy-depleted conditions, AMPK phosphorylates MFF at Ser146, leading to disorganization of MAVS clusters and suppression of the acute antiviral response (hanada2021mavsisenergized pages 9-10, hanada2021mavsisenergized pages 7-8, hanada2021mavsisenergized pages 1-2). This dual role positions MFF as a critical link between mitochondrial metabolism and innate immunity.
The Tango11/MFF family is conserved across metazoa but absent from yeast. The Drosophila ortholog, Tango11 (CG3404), was identified through genome-wide siRNA screening, and its knockdown causes perinuclear clustering of mitochondria similar to DRP1 knockdown, confirming a conserved fission function (singh2023mechanisticanalysisof pages 28-32). C. elegans has expanded this family to include two paralogs, mff-1 and mff-2, possibly reflecting functional diversification or partial redundancy in DRP-1 recruitment (lu2011amolecularswitch pages 7-8). In mammals, the single MFF gene generates at least nine splice variants through alternative exon usage, producing proteins of 25.1–38.5 kDa (singh2023mechanisticanalysisof pages 28-32).
Loss-of-function mutations in human MFF cause encephalopathy due to mitochondrial and peroxisomal fission defect (OMIM 617086), an autosomal recessive disorder. Clinical features include Leigh-like encephalopathy, developmental delay, epileptic seizures, optic atrophy, peripheral neuropathy, microcephaly, and intellectual disability (carmichael2022fissionimpossible(?)—new pages 22-23, carmichael2022fissionimpossible(?)—new pages 9-10, carmichael2022fissionimpossible(?)—new pages 21-22, OpenTargets Search: -MFF). Mutations are typically nonsense mutations that cause truncation before the C-terminal transmembrane domain. At the cellular level, patient fibroblasts show elongated, hyper-fused mitochondria and peroxisomes, reflecting impaired organellar fission, while metabolic functions of these organelles often remain surprisingly normal (carmichael2022fissionimpossible(?)—new pages 9-10, carmichael2022fissionimpossible(?)—new pages 10-12). This underscores that the primary pathology derives from disrupted organellar dynamics and distribution rather than metabolic failure per se.
The following table provides a cross-species comparison of MFF-1/MFF/Tango11:
| Feature | C. elegans mff-1 | Human MFF | Drosophila Tango11 |
|---|---|---|---|
| Gene name | mff-1; ORF F11C1.2; UniProt Q19343 | MFF (mitochondrial fission factor) | Tango11 / CG3404; described as the Drosophila ortholog of MFF (lu2011amolecularswitch pages 7-8, singh2023mechanisticanalysisof pages 28-32) |
| Protein family | Tango11/MFF family; one of two C. elegans MFF paralogs (mff-1, mff-2) (lu2011amolecularswitch pages 7-8, singh2023mechanisticanalysisof pages 28-32) | Metazoan MFF/Tango11 family; major DRP1 receptor in mammals (otera2011discoveryofthe pages 1-3, yu2020regulationofmammalian pages 6-7) | Tango11/MFF family; conserved metazoan ortholog of mammalian MFF (singh2023mechanisticanalysisof pages 28-32) |
| Domain (IPR008518) | Mff/Tango-11 domain (IPR008518); consistent with assignment as mitochondrial fission factor family member | Mff/Tango-11 family domain with N-terminal DRP1-binding repeat region, coiled-coil segment, and C-terminal transmembrane anchor (singh2023mechanisticanalysisof pages 28-32, yu2020regulationofmammalian pages 6-7) | Conserved Tango11/MFF family domain inferred from orthology to mammalian MFF (singh2023mechanisticanalysisof pages 28-32) |
| Subcellular localization | Mitochondrial outer membrane; MFF-1 behaves as an outer membrane marker and is protease-sensitive in intact mitochondria, consistent with cytosolic exposure (head2011anovelmitochondrial pages 5-6) | C-tail-anchored outer mitochondrial membrane protein; also present on peroxisomal membranes (singh2023mechanisticanalysisof pages 28-32, otera2011discoveryofthe pages 1-3, liu2021mffoligomerizationis pages 1-2) | Functional ortholog implicated in mitochondrial morphology control; specific localization not directly shown in retrieved evidence, but inferred to act at mitochondria from orthology and phenotype (singh2023mechanisticanalysisof pages 28-32) |
| Primary function | Candidate DRP-1 receptor/adaptor for mitochondrial fission in worms; proposed to act alongside mff-2 as an additional DRP-1 receptor beyond EGL-1/CED-9 (lu2011amolecularswitch pages 7-8, qin2020anendoplasmicreticulum pages 5-7) | Core membrane adaptor/receptor that recruits cytosolic DRP1 to mitochondrial constriction sites and promotes mitochondrial division (otera2011discoveryofthe pages 1-3, singh2023mechanisticanalysisof pages 32-35, yu2020regulationofmammalian pages 6-7) | Required for normal mitochondrial morphology; knockdown causes perinuclear mitochondrial clustering similar to Drp1 knockdown, supporting a conserved fission role (singh2023mechanisticanalysisof pages 28-32) |
| DRP1 interaction | Proposed DRP-1 recruiter in C. elegans based on homology to mammalian MFF and worm mitochondrial dynamics studies (lu2011amolecularswitch pages 7-8, qin2020anendoplasmicreticulum pages 5-7) | Direct but transient DRP1-binding receptor; N-terminal repeats are required for recruitment, and MFF preferentially recruits oligomerized/active DRP1 (otera2011discoveryofthe pages 1-3, singh2023mechanisticanalysisof pages 32-35, yu2020regulationofmammalian pages 6-7) | Conserved Drp1-pathway component inferred from orthology and mitochondrial morphology phenotype after knockdown (singh2023mechanisticanalysisof pages 28-32) |
| Oligomerization | No direct oligomerization data found in retrieved worm-specific literature | Oligomerizes via coiled-coil domain, likely as a trimer; oligomerization is required for DRP1 activation, puncta formation, mitochondrial division, and peroxisomal division (liu2021mffoligomerizationis pages 7-8, liu2021mffoligomerizationis pages 1-2, liu2021mffoligomerizationis pages 6-7) | No direct oligomerization data found in retrieved evidence; likely conserved by family membership (singh2023mechanisticanalysisof pages 28-32) |
| Peroxisomal fission role | No direct worm-specific evidence found in retrieved literature | Essential for peroxisomal as well as mitochondrial fission; loss causes elongated/tubular peroxisomes (singh2023mechanisticanalysisof pages 28-32, liu2021mffoligomerizationis pages 1-2, carmichael2022fissionimpossible(?)—new pages 9-10) | No direct evidence found in retrieved literature |
| Key regulators (e.g., AMPK) | No direct worm-specific regulators identified in retrieved evidence | Regulated by AMPK phosphorylation; sites reported include S146 in innate immunity studies and S155, S172, S275 in broader mitochondrial dynamics reviews; phosphorylation links energy status to fission and MAVS signaling (hanada2021mavsisenergized pages 9-10, hanada2021mavsisenergized pages 7-8, tabara2025molecularmechanismsof pages 9-10, carmichael2022fissionimpossible(?)—new pages 9-10) | No direct regulator identified in retrieved evidence |
| Disease association | No specific disease association expected for worm gene | Biallelic loss-of-function mutations cause encephalopathy due to mitochondrial and peroxisomal fission defect / lethal encephalopathy, with developmental delay, optic atrophy, peripheral neuropathy, microcephaly, seizures, and elongated mitochondria/peroxisomes in patient cells (carmichael2022fissionimpossible(?)—new pages 22-23, carmichael2022fissionimpossible(?)—new pages 9-10, carmichael2022fissionimpossible(?)—new pages 21-22, OpenTargets Search: -MFF) | No human disease association applicable; useful as a comparative model gene (singh2023mechanisticanalysisof pages 28-32) |
Table: This table compares the key features of worm mff-1, human MFF, and Drosophila Tango11 to support functional annotation by orthology. It highlights what is directly shown in C. elegans versus what is inferred from better-characterized metazoan orthologs.
In summary, C. elegans MFF-1 (F11C1.2, UniProt Q19343) is a mitochondrial outer membrane protein belonging to the metazoan-specific Tango11/MFF family. It functions as a receptor/adaptor for the dynamin-related GTPase DRP-1, recruiting it from the cytosol to the mitochondrial surface to promote organellar fission. While direct functional studies on mff-1 in C. elegans are limited, its identification as a protease-sensitive outer mitochondrial membrane protein (head2011anovelmitochondrial pages 5-6), its classification within the Tango11 family (singh2023mechanisticanalysisof pages 28-32), and its proposal as a DRP-1 receptor alongside its paralog MFF-2 (lu2011amolecularswitch pages 7-8) strongly support functional conservation with the well-characterized mammalian MFF, which serves as the principal DRP1 adaptor for both mitochondrial and peroxisomal fission.
References
(lu2011amolecularswitch pages 7-8): Yun Lu, Stéphane G. Rolland, and Barbara Conradt. A molecular switch that governs mitochondrial fusion and fission mediated by the bcl2-like protein ced-9 of caenorhabditis elegans. Proceedings of the National Academy of Sciences, 108:E813-E822, Sep 2011. URL: https://doi.org/10.1073/pnas.1103218108, doi:10.1073/pnas.1103218108. This article has 48 citations and is from a highest quality peer-reviewed journal.
(singh2023mechanisticanalysisof pages 28-32): Abeer Prakash Singh. Mechanistic analysis of mitochondrial fission mediators. Text, Jan 2023. URL: https://doi.org/10.26181/21844440.v1, doi:10.26181/21844440.v1. This article has 0 citations and is from a peer-reviewed journal.
(yu2020regulationofmammalian pages 6-7): Rong Yu, Urban Lendahl, Monica Nistér, and Jian Zhao. Regulation of mammalian mitochondrial dynamics: opportunities and challenges. Frontiers in Endocrinology, Jun 2020. URL: https://doi.org/10.3389/fendo.2020.00374, doi:10.3389/fendo.2020.00374. This article has 222 citations.
(otera2011discoveryofthe pages 1-3): Hidenori Otera and Katsuyoshi Mihara. Discovery of the membrane receptor for mitochondrial fission gtpase drp1. Small GTPases, 2:167-172-51, May 2011. URL: https://doi.org/10.4161/sgtp.2.3.16486, doi:10.4161/sgtp.2.3.16486. This article has 108 citations and is from a peer-reviewed journal.
(singh2023mechanisticanalysisof pages 32-35): Abeer Prakash Singh. Mechanistic analysis of mitochondrial fission mediators. Text, Jan 2023. URL: https://doi.org/10.26181/21844440.v1, doi:10.26181/21844440.v1. This article has 0 citations and is from a peer-reviewed journal.
(qin2020anendoplasmicreticulum pages 5-7): Qing Qin, Ting Zhao, Wei Zou, Kang Shen, and Xiangming Wang. An endoplasmic reticulum atpase safeguards endoplasmic reticulum identity by removing ectopically localized mitochondrial proteins. Cell reports, 33 6:108363, Nov 2020. URL: https://doi.org/10.1016/j.celrep.2020.108363, doi:10.1016/j.celrep.2020.108363. This article has 48 citations and is from a highest quality peer-reviewed journal.
(head2011anovelmitochondrial pages 5-6): Brian P. Head, Miren Zulaika, Sergey Ryazantsev, and Alexander M. van der Bliek. A novel mitochondrial outer membrane protein, moma-1, that affects cristae morphology in caenorhabditis elegans. Molecular Biology of the Cell, 22:831-841, Mar 2011. URL: https://doi.org/10.1091/mbc.e10-07-0600, doi:10.1091/mbc.e10-07-0600. This article has 95 citations and is from a domain leading peer-reviewed journal.
(liu2021mffoligomerizationis pages 7-8): Ao Liu, Frieda Kage, and Henry N. Higgs. Mff oligomerization is required for drp1 activation and synergy with actin filaments during mitochondrial division. Oct 2021. URL: https://doi.org/10.1091/mbc.e21-04-0224, doi:10.1091/mbc.e21-04-0224. This article has 41 citations and is from a domain leading peer-reviewed journal.
(liu2021mffoligomerizationis pages 1-2): Ao Liu, Frieda Kage, and Henry N. Higgs. Mff oligomerization is required for drp1 activation and synergy with actin filaments during mitochondrial division. Oct 2021. URL: https://doi.org/10.1091/mbc.e21-04-0224, doi:10.1091/mbc.e21-04-0224. This article has 41 citations and is from a domain leading peer-reviewed journal.
(liu2021mffoligomerizationis pages 6-7): Ao Liu, Frieda Kage, and Henry N. Higgs. Mff oligomerization is required for drp1 activation and synergy with actin filaments during mitochondrial division. Oct 2021. URL: https://doi.org/10.1091/mbc.e21-04-0224, doi:10.1091/mbc.e21-04-0224. This article has 41 citations and is from a domain leading peer-reviewed journal.
(lu2011amolecularswitch pages 6-7): Yun Lu, Stéphane G. Rolland, and Barbara Conradt. A molecular switch that governs mitochondrial fusion and fission mediated by the bcl2-like protein ced-9 of caenorhabditis elegans. Proceedings of the National Academy of Sciences, 108:E813-E822, Sep 2011. URL: https://doi.org/10.1073/pnas.1103218108, doi:10.1073/pnas.1103218108. This article has 48 citations and is from a highest quality peer-reviewed journal.
(lu2011amolecularswitch pages 4-6): Yun Lu, Stéphane G. Rolland, and Barbara Conradt. A molecular switch that governs mitochondrial fusion and fission mediated by the bcl2-like protein ced-9 of caenorhabditis elegans. Proceedings of the National Academy of Sciences, 108:E813-E822, Sep 2011. URL: https://doi.org/10.1073/pnas.1103218108, doi:10.1073/pnas.1103218108. This article has 48 citations and is from a highest quality peer-reviewed journal.
(carmichael2022fissionimpossible(?)—new pages 9-10): Ruth E. Carmichael, Markus Islinger, and Michael Schrader. Fission impossible (?)—new insights into disorders of peroxisome dynamics. Cells, 11:1922, Jun 2022. URL: https://doi.org/10.3390/cells11121922, doi:10.3390/cells11121922. This article has 28 citations.
(hanada2021mavsisenergized pages 9-10): Yuki Hanada, Naotada Ishihara, Lixiang Wang, Hidenori Otera, Takaya Ishihara, Takumi Koshiba, Katsuyoshi Mihara, Yoshihiro Ogawa, and Masatoshi Nomura. Mavs is energized by mff which senses mitochondrial metabolism via ampk for acute antiviral immunity. Nature Communications, Nov 2020. URL: https://doi.org/10.1038/s41467-020-19287-7, doi:10.1038/s41467-020-19287-7. This article has 79 citations and is from a highest quality peer-reviewed journal.
(hanada2021mavsisenergized pages 7-8): Yuki Hanada, Naotada Ishihara, Lixiang Wang, Hidenori Otera, Takaya Ishihara, Takumi Koshiba, Katsuyoshi Mihara, Yoshihiro Ogawa, and Masatoshi Nomura. Mavs is energized by mff which senses mitochondrial metabolism via ampk for acute antiviral immunity. Nature Communications, Nov 2020. URL: https://doi.org/10.1038/s41467-020-19287-7, doi:10.1038/s41467-020-19287-7. This article has 79 citations and is from a highest quality peer-reviewed journal.
(tabara2025molecularmechanismsof pages 9-10): Luis-Carlos Tábara, Mayuko Segawa, and Julien Prudent. Molecular mechanisms of mitochondrial dynamics. Nature reviews. Molecular cell biology, 26:123-146, Oct 2025. URL: https://doi.org/10.1038/s41580-024-00785-1, doi:10.1038/s41580-024-00785-1. This article has 390 citations.
(hanada2021mavsisenergized pages 1-2): Yuki Hanada, Naotada Ishihara, Lixiang Wang, Hidenori Otera, Takaya Ishihara, Takumi Koshiba, Katsuyoshi Mihara, Yoshihiro Ogawa, and Masatoshi Nomura. Mavs is energized by mff which senses mitochondrial metabolism via ampk for acute antiviral immunity. Nature Communications, Nov 2020. URL: https://doi.org/10.1038/s41467-020-19287-7, doi:10.1038/s41467-020-19287-7. This article has 79 citations and is from a highest quality peer-reviewed journal.
(carmichael2022fissionimpossible(?)—new pages 22-23): Ruth E. Carmichael, Markus Islinger, and Michael Schrader. Fission impossible (?)—new insights into disorders of peroxisome dynamics. Cells, 11:1922, Jun 2022. URL: https://doi.org/10.3390/cells11121922, doi:10.3390/cells11121922. This article has 28 citations.
(carmichael2022fissionimpossible(?)—new pages 21-22): Ruth E. Carmichael, Markus Islinger, and Michael Schrader. Fission impossible (?)—new insights into disorders of peroxisome dynamics. Cells, 11:1922, Jun 2022. URL: https://doi.org/10.3390/cells11121922, doi:10.3390/cells11121922. This article has 28 citations.
(OpenTargets Search: -MFF): Open Targets Query (-MFF, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(carmichael2022fissionimpossible(?)—new pages 10-12): Ruth E. Carmichael, Markus Islinger, and Michael Schrader. Fission impossible (?)—new insights into disorders of peroxisome dynamics. Cells, 11:1922, Jun 2022. URL: https://doi.org/10.3390/cells11121922, doi:10.3390/cells11121922. This article has 28 citations.
UniProt: Q19343 (Q19343_CAEEL, unreviewed/TrEMBL). WormBase: WBGene00008691, F11C1.2.
Gene: mff-1. Human ortholog: MFF (mitochondrial fission factor). 158 aa.
mff-1 {ECO:0000313|WormBase:F11C1.2}, ORF F11C1.2, "Mitochondrial fission factor",just deep-research-falcon worm mff-1 --fallback perplexity-lite).Genuine falcon report. Confirms and extends the primary-literature picture. Key points:
- Confirms identity: mff-1 = ORF F11C1.2, UniProt Q19343, Tango11/MFF family (metazoan-specific, absent
in yeast). Two worm paralogs mff-1 and mff-2.
- Cites Head et al. 2011 (PMID:21248201) for the OM/protease-protection localization result (matches my
read of that paper).
- Cites Lu, Rolland, Conradt 2011 (PNAS; = PMID:21949250, already cached) proposing MFF-1/MFF-2 as
candidate DRP-1 receptors alongside the EGL-1–CED-9 complex — this is a PROPOSAL/inference, not a
direct MFF-1 mechanism test.
- Mammalian MFF biology (by orthology only, NOT worm): N-terminal R1/R2 repeats bind DRP1; MFF is the
principal DRP1 receptor; MFF mediates peroxisome fission; AMPK phosphorylates MFF (S146, S155, S172,
S275); MFF-MAVS/innate-immunity role; human MFF LoF → encephalopathy (OMIM 617086). None of these are
demonstrated for worm mff-1.
- Falcon did NOT retrieve Shen et al. 2014 (PMID:24196833) — so it states worm peroxisome fission "has
not been directly tested". My review has the stronger direct evidence (Shen 2014: Mff double mutant →
tubular peroxisomes), so I rely on the primary paper, not the falcon inference, for the peroxisome and
the Mff-independent-DRP-1-recruitment points.
Net: my review is anchored on the two direct experimental worm papers (PMID:24196833, PMID:21248201).
Falcon confirms identity + localization and provides mammalian/ortholog context. No falcon-only claim is
used as primary evidence; all supporting_text quotes are from cached PMIDs.
id: Q19343
gene_symbol: mff-1
aliases:
- F11C1.2
- Mitochondrial fission factor
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: >-
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.
references:
- 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:0000104
title: Electronic Gene Ontology annotations created by transferring manual GO annotations
between related proteins based on shared sequence features
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:24196833
title: Mutations in Fis1 disrupt orderly disposal of defective mitochondria.
findings:
- statement: >-
C. elegans has two Mff homologues (mff-1, mff-2); the Mff double mutant has a
mitochondrial fission defect approaching that of drp-1, whereas single mutants
are weak (indicating functional redundancy between mff-1 and mff-2)
supporting_text: 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
- statement: >-
Worm Mff homologues affect both mitochondrial and peroxisome fission, unlike the
Fis1 homologues
supporting_text: We conclude that C. elegans Mff homologues affect mitochondrial
and peroxisome fission, whereas Fis1 homologues have no obvious effects.
- statement: >-
In worm, Mff is not essential for DRP-1 recruitment to mitochondria (a divergence
from the mammalian paradigm)
supporting_text: We conclude that Mff affects fission, but Mff and Fis1 are not
essential for fission or for Drp1 recruitment to mitochondria in C. elegans.
- statement: >-
Loss of Mff reduces the number of mitophagosomes; Mff acts upstream of the
Fis1-dependent step in the fission-mitophagy sequence
supporting_text: significantly reduced number of spots in Mff double and Fis1 Mff
quadruple mutant strains
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full-text PMC paper (van der Bliek lab). Directly assays C. elegans mff-1 (allele
tm2955) with its paralog mff-2 (tm3041): establishes the fission role, peroxisome
fission role, mitophagy contribution, and the worm-specific finding that Mff is
not required for DRP-1 recruitment. Primary experimental source for this gene.
- id: PMID:21248201
title: A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae
morphology in Caenorhabditis elegans.
findings:
- statement: >-
mff-1 corresponds to ORF F11C1.2; C. elegans has two Mff homologues encoded by
mff-1(F11C1.2) and mff-2(F55F8.6)
supporting_text: two Mff homologues, encoded by mff-1(F11C1.2) and mff-2(F55F8.6)
- statement: >-
MFF-1 is a mitochondrial outer membrane protein, used as an outer membrane marker
supporting_text: antibodies for EAT-3 (an inner membrane marker), MOMA-1, MFF-1
(an outer membrane marker), and F1β subunit of the ATP synthase complex
- statement: >-
In protease-protection of intact mitochondria, MFF-1 is digested without
detergent, i.e. it is exposed to the cytosol / anchored in the outer membrane
supporting_text: MOMA-1 is digested when no detergent is added, like MFF-1, while
EAT-3 and F1β are protease protected
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full-text PMC paper (van der Bliek lab). Confirms gene identity (mff-1 = F11C1.2)
and provides experimental support for mitochondrial outer membrane localization
of MFF-1 (used as OM marker; digested in protease protection without detergent,
indicating cytosol-exposed OM anchoring).
- id: file:worm/mff-1/mff-1-deep-research-falcon.md
title: Deep research report for C. elegans mff-1 (falcon/Edison)
findings:
- statement: >-
By orthology to the well-characterized mammalian MFF, MFF-1 is a membrane-anchored
receptor/adaptor that recruits DRP-1 to the mitochondrial outer membrane to promote
fission; direct functional tests in worm are limited
supporting_text: 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
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Genuine falcon/Edison deep-research report (1059 s, 26 citations). Confirms gene
identity (mff-1 = F11C1.2, Q19343) and the Head et al. 2011 OM localization result,
and supplies mammalian/ortholog context (DRP1 receptor role, peroxisome fission,
AMPK regulation, disease). The receptor/adaptor claim for worm is orthology-based
inference, not a direct worm assay; used only as supporting/contextual evidence.
existing_annotations:
- term:
id: GO:0000266
label: mitochondrial fission
evidence_type: IEA
original_reference_id: GO_REF:0000104
qualifier: involved_in
review:
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.
action: ACCEPT
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).
supported_by:
- reference_id: PMID:24196833
supporting_text: 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
- term:
id: GO:0005741
label: mitochondrial outer membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
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.
action: ACCEPT
reason: >-
Core localization, experimentally confirmed in C. elegans (PMID:21248201) and
consistent with the canonical MFF topology and UniProt SubCell annotation.
supported_by:
- reference_id: PMID:21248201
supporting_text: MOMA-1 is digested when no detergent is added, like MFF-1, while
EAT-3 and F1β are protease protected
- term:
id: GO:0005777
label: peroxisome
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:24196833
supporting_text: We conclude that C. elegans Mff homologues affect mitochondrial
and peroxisome fission, whereas Fis1 homologues have no obvious effects.
- term:
id: GO:0090141
label: positive regulation of mitochondrial fission
evidence_type: IEA
original_reference_id: GO_REF:0000104
qualifier: involved_in
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:24196833
supporting_text: the Mff double mutant has a mitochondrial fission defect similar
to but not as strong as the drp-1 defect
- term:
id: GO:0090314
label: positive regulation of protein targeting to membrane
evidence_type: IEA
original_reference_id: GO_REF:0000104
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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).
supported_by:
- reference_id: PMID:24196833
supporting_text: Mff and Fis1 are not essential for fission or for Drp1 recruitment
to mitochondria in C. elegans
- reference_id: file:worm/mff-1/mff-1-deep-research-falcon.md
supporting_text: 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
core_functions:
- description: >-
MFF-1 is a tail-anchored mitochondrial outer membrane adaptor that, redundantly
with its paralog MFF-2, promotes mitochondrial (and peroxisomal) fission - the
mff-1 mff-2 double mutant has a strong fission defect approaching that of the
fission dynamin drp-1.
molecular_function:
id: GO:0060090
label: molecular adaptor activity
directly_involved_in:
- id: GO:0000266
label: mitochondrial fission
locations:
- id: GO:0005741
label: mitochondrial outer membrane
supported_by:
- reference_id: PMID:24196833
supporting_text: 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
- reference_id: PMID:21248201
supporting_text: antibodies for EAT-3 (an inner membrane marker), MOMA-1, MFF-1
(an outer membrane marker), and F1β subunit of the ATP synthase complex
knowledge_gaps:
- gap_statement: >-
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.
boundary: >-
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.
gap_kind:
- BIOLOGY
dark_aspect: MF_DARK
status: OPEN
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.
resolution: >-
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:
- 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: >-
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.
boundary: >-
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.
gap_kind:
- BIOLOGY
dark_aspect: RESIDUAL_SUBGAP
status: OPEN
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.
resolution: >-
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:
- reference_id: PMID:24196833
supporting_text: 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
proposed_new_terms: []
suggested_questions:
- question: >-
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?
experts:
- Alexander M. van der Bliek
- question: >-
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?
experts:
- Alexander M. van der Bliek
suggested_experiments:
- 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.
description: >-
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.
experiment_type: protein interaction / genetic rescue
- hypothesis: mff-1 and mff-2 have distinct tissue or organelle preferences.
description: >-
Paralog-specific fluorescent reporters and tissue-restricted rescue of the mff-1
mff-2 double mutant to dissect individual contributions at mitochondria versus
peroxisomes.
experiment_type: reporter expression / genetic rescue
tags:
- caeel-mitophagy