{"gene":"DNM1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2010,"finding":"Cryo-EM structural analysis of yeast Dnm1 in a GTP-bound state revealed it adopts a unique helical assembly distinct from dynamin. Upon GTP hydrolysis, Dnm1 constricted liposomes with a substantially larger conformational change than dynamin, and subsequently dissociated from the lipid bilayer, supporting a mechanochemical role during mitochondrial division.","method":"Cryo-EM 3D structure determination; liposome constriction assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus in vitro functional reconstitution with liposomes, multiple orthogonal methods in one rigorous study","pmids":["21170049"],"is_preprint":false},{"year":2001,"finding":"Yeast Net2p (Mdv1/Caf4 homolog) was identified as a Dnm1p-interacting protein required for mitochondrial fission. Net2p localizes to dot-like structures on the mitochondrial surface that colocalize with Dnm1p, preferentially at constriction sites along mitochondrial tubules.","method":"Yeast two-hybrid; co-localization by fluorescence and immunoelectron microscopy; genetic disruption with mitochondrial morphology readout","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and imaging evidence, multiple orthogonal methods (two-hybrid, fluorescence microscopy, immunoelectron microscopy), independently replicated in subsequent studies","pmids":["11179417"],"is_preprint":false},{"year":2005,"finding":"Structure-function analysis of Mdv1 showed that dynamic interactions between Mdv1 and assembled Dnm1 regulate Dnm1 self-assembly at the mitochondrial outer membrane, and that Mdv1 functions as an adaptor linking Fis1 with Dnm1 to promote mitochondrial division.","method":"Structure-function mutagenesis of Mdv1; co-immunoprecipitation; yeast genetics with mitochondrial morphology readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and structure-function analysis in a single lab with multiple orthogonal methods","pmids":["16272155"],"is_preprint":false},{"year":2007,"finding":"S. cerevisiae Fis1 directly binds Dnm1 via the concave surface of its tetratricopeptide repeat-like domain. The Fis1 N-terminal arm acts in an autoinhibitory manner, decreasing Fis1-Dnm1 binding affinity by more than 100-fold, suggesting regulated access to the Dnm1 binding site.","method":"In vitro binding assays; site-directed mutagenesis of Fis1; quantitative binding measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution with mutagenesis and quantitative affinity measurements, single lab but multiple orthogonal methods","pmids":["17884824"],"is_preprint":false},{"year":2006,"finding":"The minimum oligomeric form of cytoplasmic Dnm1p is a dimer. Dimeric Dnm1G385Dp stably interacts with Mdv1p on the outer mitochondrial membrane independently of higher-order assembly, but multimerization of Dnm1p is required to reorganize Mdv1p from uniform mitochondrial localization into punctate fission complexes. Fis1p is present in assembled fission complexes.","method":"In vivo and in vitro oligomerization assays; co-immunoprecipitation; fluorescence microscopy; genetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, in vitro assembly, live imaging), single lab, mechanistic dissection of assembly steps","pmids":["16601120"],"is_preprint":false},{"year":2012,"finding":"A novel motif in the Insert B domain of yeast Dnm1 is required for association with the mitochondrial adaptor Mdv1. Mutation of this motif specifically disrupts Dnm1-Mdv1 interactions, blocking Dnm1 recruitment to mitochondria and mitochondrial fission. Suppressor mutations in Mdv1 identified potential binding interfaces on the Mdv1 β-propeller domain.","method":"Site-directed mutagenesis; suppressor screen; co-immunoprecipitation; fluorescence microscopy; yeast genetics","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus genetic suppressor screen plus Co-IP, multiple orthogonal methods, single lab","pmids":["23148233"],"is_preprint":false},{"year":2015,"finding":"Epileptic encephalopathy-causing de novo mutations in human DNM1 (A177P, K206N, G359A) impair endocytosis in a dominant-negative manner. K206N decreased protein levels; G359A disrupted higher-order DNM1 oligomerization; all three mutations caused vesicle defects consistent with impaired vesicle scission activity.","method":"Transferrin endocytosis assay in transfected HeLa/COS-7 cells; high-content imaging; Western blotting; electron microscopy of transfected cells and Dnm1-Ftfl mouse brain","journal":"Neurology. Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional endocytosis assay, oligomerization analysis, EM), validated in both cell lines and mouse model, single group","pmids":["27066543"],"is_preprint":false},{"year":2017,"finding":"Synchrotron small-angle X-ray scattering (SAXS) revealed that Dnm1 restructures membranes into phases rich in negative Gaussian curvature (saddle-shaped curvature found at scission necks), inducing a fission neck of ~12.6 nm diameter. A helical domain of Dnm1 identified by machine learning was shown to be responsible for this membrane curvature generation. Fis1 inhibits this pro-fission membrane activity of Dnm1.","method":"Synchrotron SAXS; machine learning (SVM) identification of membrane-restructuring domain; in silico mutagenesis; phylogenetic analysis","journal":"ACS central science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — SAXS structural data with functional domain prediction, single lab, no reciprocal mutagenesis validation in cells","pmids":["29202017"],"is_preprint":false},{"year":2014,"finding":"Proteasomes associated with the Blm10 activator protein degrade Dnm1, thereby antagonizing mitochondrial fission. In the absence of BLM10, Dnm1 degradation is impaired in vitro and in vivo, leading to elevated Dnm1 levels, increased mitochondrial fragmentation, and mitochondrial dysfunction.","method":"In vitro and in vivo proteasome degradation assays; yeast genetics; mitochondrial morphology analysis; respiratory capacity measurements","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo degradation assays with genetic validation, single lab, multiple orthogonal methods","pmids":["24604417"],"is_preprint":false},{"year":2019,"finding":"In fission yeast, association of mitochondria with microtubules physically impedes the assembly of Dnm1 around mitochondria, thereby inhibiting mitochondrial fission. Disruption of microtubule dynamics (via kinesin-like protein deletions) alters mitochondrial lengths by modulating Dnm1 assembly, and increased mitochondrial fission upon mitotic spindle formation reduces partitioning errors during mitochondrial segregation.","method":"Gene deletions of kinesin-like proteins; high-resolution and time-lapse fluorescence microscopy; live-cell imaging of Dnm1 assembly","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic and imaging approaches, single lab","pmids":["30602572"],"is_preprint":false},{"year":2009,"finding":"In fission yeast, Dnm1 mediates mitochondrial fission in a microtubule-dependent manner. Dnm1-YFP localizes to foci at sites of mitochondrial severing at interfaces between adjacent nucleoids. Microtubule depolymerization causes mitochondrial fragmentation only when Dnm1 is present; mitochondrial fusion is microtubule-independent.","method":"Gene deletion; fluorescence microscopy with YFP-tagged Dnm1; microtubule depolymerization experiments","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion combined with live fluorescence imaging and pharmacological perturbation, single lab","pmids":["19373772"],"is_preprint":false},{"year":2007,"finding":"In Cyanidioschyzon merolae, Dnm1 co-purifies with the WD40/coiled-coil protein Mda1 as the two major proteins in the purified mitochondrial division machinery from M-phase arrested cells. Mda1 forms a ring on the mitochondrial outer surface preceding Dnm1 recruitment; Dnm1 colocalizes with Mda1 only in late division stages. Addition of GTP to the purified machinery releases Dnm1 independently, suggesting Mda1 forms a stable homo-oligomeric core structure.","method":"Biochemical purification of mitochondrial division machinery; immunofluorescence and immunoelectron microscopy; GTP-induced disassembly assay; sedimentation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical purification plus structural imaging plus functional GTP assay, single lab","pmids":["17360593"],"is_preprint":false},{"year":2019,"finding":"In fission yeast, glucose starvation promotes Dnm1 localization to mitochondria and increases mitochondrial fission frequency. Low PKA activity enhances glucose starvation-induced mitochondrial fragmentation, while high PKA activity confers resistance. AMPK is not involved in this process.","method":"Live-cell fluorescence microscopy; genetic manipulation of PKA and AMPK; profusion chamber experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with live imaging, single lab, multiple pathway components tested","pmids":["31562247"],"is_preprint":false},{"year":2023,"finding":"The R237W mutation in human DNM1 (most prevalent pathogenic variant) disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. Neurons from heterozygous R237W knock-in mice display dysfunctional endocytosis, altered excitatory neurotransmission, and seizure-like phenotypes. Treatment with BMS-204352, which accelerates endocytosis, corrects these phenotypes at cell, circuit, and in vivo levels.","method":"Knock-in mouse model; electrophysiology; endocytosis assays in neurons; in vivo pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (endocytosis, electrophysiology, in vivo), pharmacological rescue validation, strong mechanistic dissection","pmids":["37648685"],"is_preprint":false},{"year":2022,"finding":"A recurrent de novo splice site variant (c.1197-8G>A) in DNM1 intron 9 causes insertion of two amino acids predicted to impair oligomerization-dependent activity, acting through a dominant-negative mechanism. Neuropathological samples show accumulation of enlarged synaptic vesicles adherent to the plasma membrane, consistent with impaired vesicular fission. The brain predominantly expresses the exon 10a-containing isoform (DNM1A), and variants affecting this isoform cause more severe disease.","method":"RNA sequencing of pediatric brain samples; RT-PCR and Sanger sequencing of patient fibroblast cDNA; neuropathological electron microscopy; functional variant analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-seq isoform analysis, functional splice assay, neuropathological EM, multiple orthogonal methods in one study","pmids":["36413998"],"is_preprint":false},{"year":2021,"finding":"In mouse cortical neurons carrying the Dnm1-Ftfl dominant-negative variant, miniature and spontaneous EPSCs and IPSCs are larger but less frequent at all synapse types, with reduced excitatory and inhibitory synaptic vesicle markers. Baseline evoked transmission is reduced specifically at inhibitory synapses onto excitatory neurons due to a smaller pool of releasable synaptic vesicles.","method":"Paired whole-cell electrophysiology recordings from cultured cortical neurons; synaptic vesicle marker quantification","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with genetic model, single lab, multiple connection types characterized","pmids":["33372033"],"is_preprint":false},{"year":2024,"finding":"Atg44 (mitofissin) is required to complete Dnm1-mediated mitochondrial fission in yeast. In Atg44-deficient cells, Dnm1 accumulates at mitochondrial constriction sites where both outer and inner membranes remain continuous, indicating Dnm1 cannot complete fission without Atg44. Atg44 and Dnm1 cooperatively execute fission from inside (IMS) and outside (cytoplasm) the mitochondria, respectively.","method":"Yeast genetics (atg44 deletion); correlative light and electron microscopy (CLEM); live fluorescence microscopy of Dnm1 localization","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion combined with CLEM structural analysis, single lab","pmids":["38818923"],"is_preprint":false},{"year":2023,"finding":"Two GTPase domain residues of yeast Dnm1, T62 (G2 motif) and S277 (G5 motif), are functionally important: non-phosphorylatable and phosphomimetic variants of both residues abolished GTPase activity and mitochondrial fission function without altering secondary structure. S277 variants act in a dominant-negative manner without altering Dnm1 localization, while T62 variants alter localization. Both residues are putatively phosphorylated.","method":"Site-directed mutagenesis; in vivo and in vitro GTPase activity assays; yeast genetics with mitochondrial morphology readout; fluorescence microscopy","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assays plus in vivo genetic analysis, single lab, multiple orthogonal methods","pmids":["37838106"],"is_preprint":false},{"year":2025,"finding":"In yeast, Dnm1 is required for the focal clustering of Fis1 on the mitochondrial outer membrane: Fis1 appears as discrete puncta dependent on Dnm1 presence, in addition to diffuse signal. This reveals a feedback mechanism where the downstream effector Dnm1 influences the spatial distribution of its upstream receptor Fis1.","method":"CRISPR-Cas9 endogenous mNeonGreen tagging of Fis1; fluorescence microscopy; dnm1 deletion analysis","journal":"microPublication biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic experiment with live imaging, single lab, single method","pmids":["40910107"],"is_preprint":false},{"year":1995,"finding":"Yeast DNM1 encodes a dynamin-related GTPase that participates in receptor-mediated endocytosis at a post-internalization step before fusion with the vacuole (late endosome). Disruption of DNM1 increased the half-life of the Ste3p pheromone receptor 2-3 fold and impeded delivery of internalized receptor to the vacuole during ligand-induced endocytosis, without affecting initial internalization or vacuolar protein sorting.","method":"Gene disruption; receptor half-life assay; ligand internalization assay; vacuolar protein sorting assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with multiple biochemical readouts positioning the protein in a specific endocytic step, single lab","pmids":["7622557"],"is_preprint":false},{"year":2024,"finding":"In a mouse model of DNM1 disease expressing a patient-based GABAergic neuron variant, AAV9-based bivalent knockdown-replace (RNAi + codon-optimized Dnm1 cDNA) corrected synaptic transmission alterations from inhibitory to excitatory neurons and abrogated disease-associated transcriptomic changes. RNAi or cDNA alone were insufficient, demonstrating that the dominant-negative mutant DNM1 must be eliminated and replaced with wild-type for rescue.","method":"AAV9 gene therapy in mouse model; electrophysiological recordings of cortical neurons; RNA sequencing and functional annotation clustering","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene therapy with synaptic electrophysiology and transcriptomics, single lab, multiple orthogonal methods","pmids":["39127888"],"is_preprint":false},{"year":2020,"finding":"Purified S. cerevisiae Dnm1 exhibits assembly-stimulated hydrolysis of GTP, consistent with other fission dynamins. The yeast-purified enzyme shows different kinetics compared to enzyme isolated from non-native sources.","method":"Protein purification from native yeast source; in vitro GTPase activity assay","journal":"Methods in molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution, single lab, single method","pmids":["32529359"],"is_preprint":false},{"year":2024,"finding":"In fission yeast, Mfi2 (mitofissin 2), a mitochondrial outer membrane microprotein, independently facilitates mitochondrial fission during mitophagy alongside Dnm1. Mfi2 binds lipid membranes and mediates membrane fission in vitro, and overexpression of a C-terminally truncated form of Mfi2 partially restores mitophagy in atg44Δ cells. Genetic analyses reveal Mfi2 and Dnm1 function independently in mitophagy-associated fission.","method":"In vitro membrane fission assay; yeast genetics; fluorescence microscopy; genetic epistasis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, genetic and in vitro data for Dnm1's independent role but primarily about Mfi2","pmids":[],"is_preprint":true},{"year":2024,"finding":"In fission yeast, cellular redox state (controlled by electron entry into the ETC) controls mitochondrial morphology through Dnm1: conditions causing oxidized cytosol lead to rapid mitochondrial fragmentation, and Dnm1 fission machinery responds within minutes to redox state changes, preceding the change in mitochondrial form.","method":"Live-cell fluorescence microscopy; genetic manipulation of ETC components; pharmacological redox manipulation; time-lapse imaging of Dnm1","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, live imaging evidence for Dnm1 as redox sensor","pmids":[],"is_preprint":true},{"year":2024,"finding":"Human DNM1 promotes endocytic recycling of N-cadherin in ovarian cancer cells, maintaining a mesenchymal state. DNM1 upregulates N-cadherin by promoting its endocytosis and recycling, inducing cell polarization and motility. Loss of DNM1 suppresses peritoneal metastatic colonization in vivo.","method":"Master regulators algorithm; molecular assays (endocytosis/recycling); ATAC-seq and RNA-seq; in vivo metastasis model with DNM1 depletion","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, functional readout but mechanistic detail of DNM1's direct role in recycling is limited in abstract","pmids":[],"is_preprint":true},{"year":2026,"finding":"MDA5 regulates actin polymerization in B cells via an MDA5-NF-κB-DNM1 axis; impaired BCR signaling in Mda5 KO B cells can be rescued by treatment with the dynamin 1 (DNM1) activator Bis-T-23, placing DNM1 downstream of MDA5-NF-κB signaling in cytoskeletal dynamics regulation.","method":"Mda5 knockout B cells; pharmacological rescue with Bis-T-23; actin polymerization assay; BCR signaling assay","journal":"Cellular & molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological rescue experiment identifies DNM1 in pathway but direct mechanistic link is inferred","pmids":["41476189"],"is_preprint":false}],"current_model":"DNM1 (dynamin-1) is a large mechanochemical GTPase that self-assembles into helical/ring-like oligomeric structures on membranes, couples GTP hydrolysis to membrane constriction and vesicle scission, and functions in two primary contexts: (1) at presynaptic nerve terminals it mediates clathrin-dependent synaptic vesicle endocytosis (with dominant-negative mutations causing epileptic encephalopathy by impairing vesicle fission), and (2) as a conserved mitochondrial fission factor (yeast Dnm1) it is recruited to the outer mitochondrial membrane via direct interactions with Fis1 and the adaptor Mdv1/Net2p, where it assembles into multimeric fission complexes—regulated by GTP hydrolysis, Insert B-Mdv1 contacts, Fis1 autoinhibition, and cooperation with inner membrane factor Atg44—to execute mitochondrial division."},"narrative":{"mechanistic_narrative":"DNM1 (dynamin-1) is a self-assembling mechanochemical GTPase that couples GTP hydrolysis to membrane constriction and scission, acting both in synaptic vesicle endocytosis in neurons and, in its yeast ortholog Dnm1, as the core mitochondrial fission GTPase [PMID:21170049, PMID:27066543]. In the mitochondrial fission context, the protein assembles into a unique helical lattice that, upon GTP hydrolysis, constricts liposomes and then dissociates from the bilayer [PMID:21170049]; assembly-stimulated GTP hydrolysis and conserved GTPase-domain residues (G2 motif T62, G5 motif S277) are required for both catalytic activity and fission function [PMID:32529359, PMID:37838106]. Dnm1 generates the negative Gaussian (saddle) curvature characteristic of scission necks, narrowing the membrane to a ~12.6 nm neck via a helical membrane-restructuring domain [PMID:29202017]. Its minimal cytoplasmic unit is a dimer, and higher-order multimerization is needed to reorganize the adaptor into punctate fission complexes [PMID:16601120]. Recruitment to the outer mitochondrial membrane proceeds through the receptor Fis1 — which binds Dnm1 via the concave face of its TPR-like domain and is held under N-terminal autoinhibition — and the adaptor Mdv1/Net2p, which links Fis1 to Dnm1 and regulates Dnm1 self-assembly; an Insert B motif in Dnm1 mediates the Mdv1 contact [PMID:17884824, PMID:11179417, PMID:16272155, PMID:23148233]. Completion of division requires cooperation with the intermembrane-space factor Atg44, with Dnm1 acting from the cytosolic face and Atg44 from inside [PMID:38818923]. Dnm1 levels and fission output are tuned by Blm10-proteasome degradation and by inputs including microtubule association, glucose/PKA signaling, and cell-cycle cues [PMID:24604417, PMID:30602572, PMID:31562247]. In humans, dominant-negative de novo DNM1 mutations cause epileptic encephalopathy: variants such as A177P, K206N, G359A, R237W and a recurrent splice variant impair oligomerization and vesicle scission, producing accumulation of enlarged synaptic vesicles and altered synaptic transmission, with the brain-predominant exon-10a isoform (DNM1A) associated with more severe disease [PMID:27066543, PMID:37648685, PMID:36413998, PMID:33372033].","teleology":[{"year":1995,"claim":"Established that the yeast DNM1 gene product is a dynamin-related GTPase acting in a defined endocytic step, anchoring its role in membrane trafficking before its fission function was known.","evidence":"Gene disruption with receptor half-life, ligand internalization, and vacuolar sorting assays in yeast","pmids":["7622557"],"confidence":"Medium","gaps":["Did not identify the membrane-scission mechanism","No structural or biochemical characterization of GTPase activity"]},{"year":2001,"claim":"Identified the adaptor Net2p/Mdv1 as a Dnm1-interacting fission factor that localizes to constriction sites, revealing how Dnm1 is recruited to mitochondria.","evidence":"Yeast two-hybrid, fluorescence and immunoelectron microscopy, genetic disruption with morphology readout","pmids":["11179417"],"confidence":"High","gaps":["Molecular interfaces of the interaction not defined","Order of recruitment relative to Fis1 unresolved"]},{"year":2006,"claim":"Defined the assembly hierarchy showing the cytoplasmic Dnm1 dimer as the minimal unit and that multimerization is required to convert diffuse Mdv1 into punctate fission complexes.","evidence":"In vivo/in vitro oligomerization assays, Co-IP, fluorescence microscopy, genetics in yeast","pmids":["16601120"],"confidence":"High","gaps":["Stoichiometry of the assembled complex not determined","Trigger for multimerization on the membrane unclear"]},{"year":2007,"claim":"Mapped the direct Fis1-Dnm1 interaction to the Fis1 TPR concave surface and identified N-terminal autoinhibition as a regulatory switch controlling Dnm1 access.","evidence":"In vitro binding assays, site-directed mutagenesis, quantitative affinity measurements","pmids":["17884824"],"confidence":"High","gaps":["What relieves Fis1 autoinhibition in vivo not identified","Direct vs adaptor-mediated Fis1-Dnm1 contact in the complex not fully resolved"]},{"year":2007,"claim":"Showed in a divergent alga that a distinct WD40/coiled-coil protein (Mda1) forms a pre-existing ring recruiting Dnm1 late in division, demonstrating conserved late-stage Dnm1 action and GTP-dependent release.","evidence":"Biochemical purification of the division machinery, immuno-EM, GTP-induced disassembly and sedimentation","pmids":["17360593"],"confidence":"Medium","gaps":["Relationship of Mda1 to Mdv1/Fis1 adaptors unclear","Mechanism of Dnm1 release upon GTP addition not structurally defined"]},{"year":2010,"claim":"Provided the structural basis for fission, showing Dnm1 forms a unique helix that drives large GTP-hydrolysis-coupled liposome constriction followed by membrane dissociation.","evidence":"Cryo-EM 3D structure and liposome constriction assay","pmids":["21170049"],"confidence":"High","gaps":["In-cell constriction dimensions not directly measured","Coupling between conformational change and scission completion incomplete"]},{"year":2012,"claim":"Pinpointed the Insert B motif of Dnm1 as the structural determinant for Mdv1 binding, explaining how Dnm1 is physically tethered to the mitochondrial adaptor.","evidence":"Site-directed mutagenesis, suppressor screen, Co-IP, fluorescence microscopy in yeast","pmids":["23148233"],"confidence":"High","gaps":["Exact Mdv1 beta-propeller contact residues only inferred from suppressors","Whether Insert B contacts other partners not addressed"]},{"year":2014,"claim":"Identified Blm10-proteasome degradation of Dnm1 as a homeostatic brake on fission, linking Dnm1 protein levels to mitochondrial integrity.","evidence":"In vitro and in vivo degradation assays, yeast genetics, mitochondrial morphology and respiration measurements","pmids":["24604417"],"confidence":"Medium","gaps":["Signals targeting Dnm1 for Blm10-dependent turnover unknown","Whether degradation is regulated during the cell cycle unclear"]},{"year":2015,"claim":"Demonstrated that human epileptic-encephalopathy DNM1 mutations act dominant-negatively by impairing oligomerization and endocytic vesicle scission, establishing the disease mechanism.","evidence":"Transferrin endocytosis assays, oligomerization analysis, EM in cells and Dnm1-Ftfl mouse brain","pmids":["27066543"],"confidence":"High","gaps":["Synapse-level consequences not yet measured","Therapeutic correction not addressed"]},{"year":2017,"claim":"Defined the biophysical mechanism of scission, showing Dnm1 generates negative Gaussian curvature to form a ~12.6 nm fission neck via a helical membrane-restructuring domain, with Fis1 inhibiting this activity.","evidence":"Synchrotron SAXS, machine-learning domain identification, in silico mutagenesis","pmids":["29202017"],"confidence":"Medium","gaps":["Helical domain function not validated by in-cell mutagenesis","How Fis1 inhibits membrane restructuring mechanistically unclear"]},{"year":2019,"claim":"Connected cytoskeletal and metabolic cues to fission, showing microtubule association impedes Dnm1 assembly while glucose starvation and low PKA promote Dnm1 recruitment.","evidence":"Kinesin and pathway gene deletions, live-cell and time-lapse imaging of Dnm1 in fission yeast","pmids":["30602572","31562247"],"confidence":"Medium","gaps":["Molecular link between PKA activity and Dnm1 recruitment not defined","Whether microtubule effect is steric or signaled is unresolved"]},{"year":2023,"claim":"Defined GTPase-domain residues T62 and S277 as essential for catalysis and fission, with S277 variants acting dominant-negatively, and modeled the prevalent human R237W mutation in a knock-in mouse rescued pharmacologically.","evidence":"Site-directed mutagenesis with GTPase assays in yeast; R237W knock-in mouse with electrophysiology, endocytosis assays, and BMS-204352 rescue","pmids":["37838106","37648685"],"confidence":"High","gaps":["Physiological kinases for T62/S277 not identified","Long-term durability of pharmacological rescue unknown"]},{"year":2024,"claim":"Showed fission completion requires the intermembrane-space factor Atg44 cooperating with cytosolic Dnm1, and that Dnm1 in turn drives focal clustering of its receptor Fis1, revealing reciprocal spatial organization.","evidence":"atg44 deletion with CLEM and live imaging; CRISPR endogenous Fis1 tagging with dnm1 deletion in yeast","pmids":["38818923","40910107"],"confidence":"Medium","gaps":["How inner- and outer-membrane scission events are coordinated mechanistically unclear","Molecular basis of Dnm1-dependent Fis1 clustering not defined"]},{"year":2024,"claim":"Established the disease isoform and a corrective gene-therapy principle, identifying the brain-predominant DNM1A isoform and showing that combined knockdown-replace is required to rescue the dominant-negative mutant.","evidence":"Brain RNA-seq isoform analysis with splice variant functional assay and neuropathological EM; AAV9 bivalent knockdown-replace in mouse with electrophysiology and transcriptomics","pmids":["36413998","39127888","33372033"],"confidence":"High","gaps":["Isoform-specific structural differences not resolved","Clinical translation of knockdown-replace not established"]},{"year":null,"claim":"How DNM1's dual roles in synaptic endocytosis and mitochondrial fission are coordinated within a cell, and whether proposed roles in redox sensing, B-cell actin dynamics, and cancer cell N-cadherin recycling reflect direct DNM1 mechanisms, remain open.","evidence":"Not yet established","pmids":[],"confidence":"Low","gaps":["Redox-sensing and cancer/immune roles rest on Low-confidence or preprint evidence","Direct molecular mechanism in these contexts not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,17,21]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,21]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,10,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,19]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,13,14]}],"complexes":["mitochondrial division machinery (Dnm1-Mdv1-Fis1)"],"partners":["FIS1","MDV1","ATG44","BLM10","MDA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q05193","full_name":"Dynamin-1","aliases":["Dynamin","Dynamin I"],"length_aa":864,"mass_kda":97.4,"function":"Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission and participates in many forms of endocytosis, such as clathrin-mediated endocytosis or synaptic vesicle endocytosis as well as rapid endocytosis (RE) (PubMed:15703209, PubMed:20428113, PubMed:29668686, PubMed:8101525, PubMed:8910402, PubMed:9362482). Associates to the membrane, through lipid binding, and self-assembles into rings and stacks of interconnected rings through oligomerization to form a helical polymer around the vesicle membrane leading to constriction of invaginated coated pits around their necks (PubMed:30069048, PubMed:7877694, PubMed:9922133). Self-assembly of the helical polymer induces membrane tubules narrowing until the polymer reaches a length sufficient to trigger GTP hydrolysis (PubMed:19084269). Depending on the curvature imposed on the tubules, membrane detachment from the helical polymer upon GTP hydrolysis can cause spontaneous hemifission followed by complete fission (PubMed:19084269). May play a role in regulating early stages of clathrin-mediated endocytosis in non-neuronal cells through its activation by dephosphorylation via the signaling downstream of EGFR (PubMed:29668686). Controls vesicle size at a step before fission, during formation of membrane pits, at hippocampal synapses (By similarity). Controls plastic adaptation of the synaptic vesicle recycling machinery to high levels of activity (By similarity). Mediates rapid endocytosis (RE), a Ca(2+)-dependent and clathrin- and K(+)-independent process in chromaffin cells (By similarity). Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP (By similarity). Through its interaction with DNAJC6, acts during the early steps of clathrin-coated vesicle (CCV) formation (PubMed:12791276)","subcellular_location":"Cell membrane; Membrane, clathrin-coated pit; Cytoplasmic vesicle; Presynapse; Cytoplasmic vesicle, secretory vesicle, chromaffin granule","url":"https://www.uniprot.org/uniprotkb/Q05193/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNM1","classification":"Not Classified","n_dependent_lines":80,"n_total_lines":1208,"dependency_fraction":0.06622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000106976","cell_line_id":"CID000523","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"DNM3","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"DNM2","stoichiometry":0.2},{"gene":"SNX9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000523","total_profiled":1310},"omim":[{"mim_id":"620352","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 31B; 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Upon GTP hydrolysis, Dnm1 constricted liposomes with a substantially larger conformational change than dynamin, and subsequently dissociated from the lipid bilayer, supporting a mechanochemical role during mitochondrial division.\",\n      \"method\": \"Cryo-EM 3D structure determination; liposome constriction assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus in vitro functional reconstitution with liposomes, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"21170049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Yeast Net2p (Mdv1/Caf4 homolog) was identified as a Dnm1p-interacting protein required for mitochondrial fission. Net2p localizes to dot-like structures on the mitochondrial surface that colocalize with Dnm1p, preferentially at constriction sites along mitochondrial tubules.\",\n      \"method\": \"Yeast two-hybrid; co-localization by fluorescence and immunoelectron microscopy; genetic disruption with mitochondrial morphology readout\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and imaging evidence, multiple orthogonal methods (two-hybrid, fluorescence microscopy, immunoelectron microscopy), independently replicated in subsequent studies\",\n      \"pmids\": [\"11179417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Structure-function analysis of Mdv1 showed that dynamic interactions between Mdv1 and assembled Dnm1 regulate Dnm1 self-assembly at the mitochondrial outer membrane, and that Mdv1 functions as an adaptor linking Fis1 with Dnm1 to promote mitochondrial division.\",\n      \"method\": \"Structure-function mutagenesis of Mdv1; co-immunoprecipitation; yeast genetics with mitochondrial morphology readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and structure-function analysis in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16272155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S. cerevisiae Fis1 directly binds Dnm1 via the concave surface of its tetratricopeptide repeat-like domain. The Fis1 N-terminal arm acts in an autoinhibitory manner, decreasing Fis1-Dnm1 binding affinity by more than 100-fold, suggesting regulated access to the Dnm1 binding site.\",\n      \"method\": \"In vitro binding assays; site-directed mutagenesis of Fis1; quantitative binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution with mutagenesis and quantitative affinity measurements, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17884824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The minimum oligomeric form of cytoplasmic Dnm1p is a dimer. Dimeric Dnm1G385Dp stably interacts with Mdv1p on the outer mitochondrial membrane independently of higher-order assembly, but multimerization of Dnm1p is required to reorganize Mdv1p from uniform mitochondrial localization into punctate fission complexes. Fis1p is present in assembled fission complexes.\",\n      \"method\": \"In vivo and in vitro oligomerization assays; co-immunoprecipitation; fluorescence microscopy; genetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, in vitro assembly, live imaging), single lab, mechanistic dissection of assembly steps\",\n      \"pmids\": [\"16601120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A novel motif in the Insert B domain of yeast Dnm1 is required for association with the mitochondrial adaptor Mdv1. Mutation of this motif specifically disrupts Dnm1-Mdv1 interactions, blocking Dnm1 recruitment to mitochondria and mitochondrial fission. Suppressor mutations in Mdv1 identified potential binding interfaces on the Mdv1 β-propeller domain.\",\n      \"method\": \"Site-directed mutagenesis; suppressor screen; co-immunoprecipitation; fluorescence microscopy; yeast genetics\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus genetic suppressor screen plus Co-IP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23148233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Epileptic encephalopathy-causing de novo mutations in human DNM1 (A177P, K206N, G359A) impair endocytosis in a dominant-negative manner. K206N decreased protein levels; G359A disrupted higher-order DNM1 oligomerization; all three mutations caused vesicle defects consistent with impaired vesicle scission activity.\",\n      \"method\": \"Transferrin endocytosis assay in transfected HeLa/COS-7 cells; high-content imaging; Western blotting; electron microscopy of transfected cells and Dnm1-Ftfl mouse brain\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional endocytosis assay, oligomerization analysis, EM), validated in both cell lines and mouse model, single group\",\n      \"pmids\": [\"27066543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Synchrotron small-angle X-ray scattering (SAXS) revealed that Dnm1 restructures membranes into phases rich in negative Gaussian curvature (saddle-shaped curvature found at scission necks), inducing a fission neck of ~12.6 nm diameter. A helical domain of Dnm1 identified by machine learning was shown to be responsible for this membrane curvature generation. Fis1 inhibits this pro-fission membrane activity of Dnm1.\",\n      \"method\": \"Synchrotron SAXS; machine learning (SVM) identification of membrane-restructuring domain; in silico mutagenesis; phylogenetic analysis\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — SAXS structural data with functional domain prediction, single lab, no reciprocal mutagenesis validation in cells\",\n      \"pmids\": [\"29202017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Proteasomes associated with the Blm10 activator protein degrade Dnm1, thereby antagonizing mitochondrial fission. In the absence of BLM10, Dnm1 degradation is impaired in vitro and in vivo, leading to elevated Dnm1 levels, increased mitochondrial fragmentation, and mitochondrial dysfunction.\",\n      \"method\": \"In vitro and in vivo proteasome degradation assays; yeast genetics; mitochondrial morphology analysis; respiratory capacity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo degradation assays with genetic validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24604417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In fission yeast, association of mitochondria with microtubules physically impedes the assembly of Dnm1 around mitochondria, thereby inhibiting mitochondrial fission. Disruption of microtubule dynamics (via kinesin-like protein deletions) alters mitochondrial lengths by modulating Dnm1 assembly, and increased mitochondrial fission upon mitotic spindle formation reduces partitioning errors during mitochondrial segregation.\",\n      \"method\": \"Gene deletions of kinesin-like proteins; high-resolution and time-lapse fluorescence microscopy; live-cell imaging of Dnm1 assembly\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic and imaging approaches, single lab\",\n      \"pmids\": [\"30602572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In fission yeast, Dnm1 mediates mitochondrial fission in a microtubule-dependent manner. Dnm1-YFP localizes to foci at sites of mitochondrial severing at interfaces between adjacent nucleoids. Microtubule depolymerization causes mitochondrial fragmentation only when Dnm1 is present; mitochondrial fusion is microtubule-independent.\",\n      \"method\": \"Gene deletion; fluorescence microscopy with YFP-tagged Dnm1; microtubule depolymerization experiments\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion combined with live fluorescence imaging and pharmacological perturbation, single lab\",\n      \"pmids\": [\"19373772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Cyanidioschyzon merolae, Dnm1 co-purifies with the WD40/coiled-coil protein Mda1 as the two major proteins in the purified mitochondrial division machinery from M-phase arrested cells. Mda1 forms a ring on the mitochondrial outer surface preceding Dnm1 recruitment; Dnm1 colocalizes with Mda1 only in late division stages. Addition of GTP to the purified machinery releases Dnm1 independently, suggesting Mda1 forms a stable homo-oligomeric core structure.\",\n      \"method\": \"Biochemical purification of mitochondrial division machinery; immunofluorescence and immunoelectron microscopy; GTP-induced disassembly assay; sedimentation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical purification plus structural imaging plus functional GTP assay, single lab\",\n      \"pmids\": [\"17360593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In fission yeast, glucose starvation promotes Dnm1 localization to mitochondria and increases mitochondrial fission frequency. Low PKA activity enhances glucose starvation-induced mitochondrial fragmentation, while high PKA activity confers resistance. AMPK is not involved in this process.\",\n      \"method\": \"Live-cell fluorescence microscopy; genetic manipulation of PKA and AMPK; profusion chamber experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with live imaging, single lab, multiple pathway components tested\",\n      \"pmids\": [\"31562247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The R237W mutation in human DNM1 (most prevalent pathogenic variant) disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. Neurons from heterozygous R237W knock-in mice display dysfunctional endocytosis, altered excitatory neurotransmission, and seizure-like phenotypes. Treatment with BMS-204352, which accelerates endocytosis, corrects these phenotypes at cell, circuit, and in vivo levels.\",\n      \"method\": \"Knock-in mouse model; electrophysiology; endocytosis assays in neurons; in vivo pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with multiple orthogonal readouts (endocytosis, electrophysiology, in vivo), pharmacological rescue validation, strong mechanistic dissection\",\n      \"pmids\": [\"37648685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A recurrent de novo splice site variant (c.1197-8G>A) in DNM1 intron 9 causes insertion of two amino acids predicted to impair oligomerization-dependent activity, acting through a dominant-negative mechanism. Neuropathological samples show accumulation of enlarged synaptic vesicles adherent to the plasma membrane, consistent with impaired vesicular fission. The brain predominantly expresses the exon 10a-containing isoform (DNM1A), and variants affecting this isoform cause more severe disease.\",\n      \"method\": \"RNA sequencing of pediatric brain samples; RT-PCR and Sanger sequencing of patient fibroblast cDNA; neuropathological electron microscopy; functional variant analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq isoform analysis, functional splice assay, neuropathological EM, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36413998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In mouse cortical neurons carrying the Dnm1-Ftfl dominant-negative variant, miniature and spontaneous EPSCs and IPSCs are larger but less frequent at all synapse types, with reduced excitatory and inhibitory synaptic vesicle markers. Baseline evoked transmission is reduced specifically at inhibitory synapses onto excitatory neurons due to a smaller pool of releasable synaptic vesicles.\",\n      \"method\": \"Paired whole-cell electrophysiology recordings from cultured cortical neurons; synaptic vesicle marker quantification\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with genetic model, single lab, multiple connection types characterized\",\n      \"pmids\": [\"33372033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Atg44 (mitofissin) is required to complete Dnm1-mediated mitochondrial fission in yeast. In Atg44-deficient cells, Dnm1 accumulates at mitochondrial constriction sites where both outer and inner membranes remain continuous, indicating Dnm1 cannot complete fission without Atg44. Atg44 and Dnm1 cooperatively execute fission from inside (IMS) and outside (cytoplasm) the mitochondria, respectively.\",\n      \"method\": \"Yeast genetics (atg44 deletion); correlative light and electron microscopy (CLEM); live fluorescence microscopy of Dnm1 localization\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion combined with CLEM structural analysis, single lab\",\n      \"pmids\": [\"38818923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two GTPase domain residues of yeast Dnm1, T62 (G2 motif) and S277 (G5 motif), are functionally important: non-phosphorylatable and phosphomimetic variants of both residues abolished GTPase activity and mitochondrial fission function without altering secondary structure. S277 variants act in a dominant-negative manner without altering Dnm1 localization, while T62 variants alter localization. Both residues are putatively phosphorylated.\",\n      \"method\": \"Site-directed mutagenesis; in vivo and in vitro GTPase activity assays; yeast genetics with mitochondrial morphology readout; fluorescence microscopy\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assays plus in vivo genetic analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37838106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In yeast, Dnm1 is required for the focal clustering of Fis1 on the mitochondrial outer membrane: Fis1 appears as discrete puncta dependent on Dnm1 presence, in addition to diffuse signal. This reveals a feedback mechanism where the downstream effector Dnm1 influences the spatial distribution of its upstream receptor Fis1.\",\n      \"method\": \"CRISPR-Cas9 endogenous mNeonGreen tagging of Fis1; fluorescence microscopy; dnm1 deletion analysis\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic experiment with live imaging, single lab, single method\",\n      \"pmids\": [\"40910107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast DNM1 encodes a dynamin-related GTPase that participates in receptor-mediated endocytosis at a post-internalization step before fusion with the vacuole (late endosome). Disruption of DNM1 increased the half-life of the Ste3p pheromone receptor 2-3 fold and impeded delivery of internalized receptor to the vacuole during ligand-induced endocytosis, without affecting initial internalization or vacuolar protein sorting.\",\n      \"method\": \"Gene disruption; receptor half-life assay; ligand internalization assay; vacuolar protein sorting assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with multiple biochemical readouts positioning the protein in a specific endocytic step, single lab\",\n      \"pmids\": [\"7622557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a mouse model of DNM1 disease expressing a patient-based GABAergic neuron variant, AAV9-based bivalent knockdown-replace (RNAi + codon-optimized Dnm1 cDNA) corrected synaptic transmission alterations from inhibitory to excitatory neurons and abrogated disease-associated transcriptomic changes. RNAi or cDNA alone were insufficient, demonstrating that the dominant-negative mutant DNM1 must be eliminated and replaced with wild-type for rescue.\",\n      \"method\": \"AAV9 gene therapy in mouse model; electrophysiological recordings of cortical neurons; RNA sequencing and functional annotation clustering\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene therapy with synaptic electrophysiology and transcriptomics, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39127888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Purified S. cerevisiae Dnm1 exhibits assembly-stimulated hydrolysis of GTP, consistent with other fission dynamins. The yeast-purified enzyme shows different kinetics compared to enzyme isolated from non-native sources.\",\n      \"method\": \"Protein purification from native yeast source; in vitro GTPase activity assay\",\n      \"journal\": \"Methods in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution, single lab, single method\",\n      \"pmids\": [\"32529359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In fission yeast, Mfi2 (mitofissin 2), a mitochondrial outer membrane microprotein, independently facilitates mitochondrial fission during mitophagy alongside Dnm1. Mfi2 binds lipid membranes and mediates membrane fission in vitro, and overexpression of a C-terminally truncated form of Mfi2 partially restores mitophagy in atg44Δ cells. Genetic analyses reveal Mfi2 and Dnm1 function independently in mitophagy-associated fission.\",\n      \"method\": \"In vitro membrane fission assay; yeast genetics; fluorescence microscopy; genetic epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, genetic and in vitro data for Dnm1's independent role but primarily about Mfi2\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In fission yeast, cellular redox state (controlled by electron entry into the ETC) controls mitochondrial morphology through Dnm1: conditions causing oxidized cytosol lead to rapid mitochondrial fragmentation, and Dnm1 fission machinery responds within minutes to redox state changes, preceding the change in mitochondrial form.\",\n      \"method\": \"Live-cell fluorescence microscopy; genetic manipulation of ETC components; pharmacological redox manipulation; time-lapse imaging of Dnm1\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, live imaging evidence for Dnm1 as redox sensor\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human DNM1 promotes endocytic recycling of N-cadherin in ovarian cancer cells, maintaining a mesenchymal state. DNM1 upregulates N-cadherin by promoting its endocytosis and recycling, inducing cell polarization and motility. Loss of DNM1 suppresses peritoneal metastatic colonization in vivo.\",\n      \"method\": \"Master regulators algorithm; molecular assays (endocytosis/recycling); ATAC-seq and RNA-seq; in vivo metastasis model with DNM1 depletion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, functional readout but mechanistic detail of DNM1's direct role in recycling is limited in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MDA5 regulates actin polymerization in B cells via an MDA5-NF-κB-DNM1 axis; impaired BCR signaling in Mda5 KO B cells can be rescued by treatment with the dynamin 1 (DNM1) activator Bis-T-23, placing DNM1 downstream of MDA5-NF-κB signaling in cytoskeletal dynamics regulation.\",\n      \"method\": \"Mda5 knockout B cells; pharmacological rescue with Bis-T-23; actin polymerization assay; BCR signaling assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological rescue experiment identifies DNM1 in pathway but direct mechanistic link is inferred\",\n      \"pmids\": [\"41476189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNM1 (dynamin-1) is a large mechanochemical GTPase that self-assembles into helical/ring-like oligomeric structures on membranes, couples GTP hydrolysis to membrane constriction and vesicle scission, and functions in two primary contexts: (1) at presynaptic nerve terminals it mediates clathrin-dependent synaptic vesicle endocytosis (with dominant-negative mutations causing epileptic encephalopathy by impairing vesicle fission), and (2) as a conserved mitochondrial fission factor (yeast Dnm1) it is recruited to the outer mitochondrial membrane via direct interactions with Fis1 and the adaptor Mdv1/Net2p, where it assembles into multimeric fission complexes—regulated by GTP hydrolysis, Insert B-Mdv1 contacts, Fis1 autoinhibition, and cooperation with inner membrane factor Atg44—to execute mitochondrial division.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNM1 (dynamin-1) is a self-assembling mechanochemical GTPase that couples GTP hydrolysis to membrane constriction and scission, acting both in synaptic vesicle endocytosis in neurons and, in its yeast ortholog Dnm1, as the core mitochondrial fission GTPase [#0, #6]. In the mitochondrial fission context, the protein assembles into a unique helical lattice that, upon GTP hydrolysis, constricts liposomes and then dissociates from the bilayer [#0]; assembly-stimulated GTP hydrolysis and conserved GTPase-domain residues (G2 motif T62, G5 motif S277) are required for both catalytic activity and fission function [#21, #17]. Dnm1 generates the negative Gaussian (saddle) curvature characteristic of scission necks, narrowing the membrane to a ~12.6 nm neck via a helical membrane-restructuring domain [#7]. Its minimal cytoplasmic unit is a dimer, and higher-order multimerization is needed to reorganize the adaptor into punctate fission complexes [#4]. Recruitment to the outer mitochondrial membrane proceeds through the receptor Fis1 — which binds Dnm1 via the concave face of its TPR-like domain and is held under N-terminal autoinhibition — and the adaptor Mdv1/Net2p, which links Fis1 to Dnm1 and regulates Dnm1 self-assembly; an Insert B motif in Dnm1 mediates the Mdv1 contact [#3, #1, #2, #5]. Completion of division requires cooperation with the intermembrane-space factor Atg44, with Dnm1 acting from the cytosolic face and Atg44 from inside [#16]. Dnm1 levels and fission output are tuned by Blm10-proteasome degradation and by inputs including microtubule association, glucose/PKA signaling, and cell-cycle cues [#8, #9, #12]. In humans, dominant-negative de novo DNM1 mutations cause epileptic encephalopathy: variants such as A177P, K206N, G359A, R237W and a recurrent splice variant impair oligomerization and vesicle scission, producing accumulation of enlarged synaptic vesicles and altered synaptic transmission, with the brain-predominant exon-10a isoform (DNM1A) associated with more severe disease [#6, #13, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that the yeast DNM1 gene product is a dynamin-related GTPase acting in a defined endocytic step, anchoring its role in membrane trafficking before its fission function was known.\",\n      \"evidence\": \"Gene disruption with receptor half-life, ligand internalization, and vacuolar sorting assays in yeast\",\n      \"pmids\": [\"7622557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the membrane-scission mechanism\", \"No structural or biochemical characterization of GTPase activity\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the adaptor Net2p/Mdv1 as a Dnm1-interacting fission factor that localizes to constriction sites, revealing how Dnm1 is recruited to mitochondria.\",\n      \"evidence\": \"Yeast two-hybrid, fluorescence and immunoelectron microscopy, genetic disruption with morphology readout\",\n      \"pmids\": [\"11179417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interfaces of the interaction not defined\", \"Order of recruitment relative to Fis1 unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the assembly hierarchy showing the cytoplasmic Dnm1 dimer as the minimal unit and that multimerization is required to convert diffuse Mdv1 into punctate fission complexes.\",\n      \"evidence\": \"In vivo/in vitro oligomerization assays, Co-IP, fluorescence microscopy, genetics in yeast\",\n      \"pmids\": [\"16601120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the assembled complex not determined\", \"Trigger for multimerization on the membrane unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped the direct Fis1-Dnm1 interaction to the Fis1 TPR concave surface and identified N-terminal autoinhibition as a regulatory switch controlling Dnm1 access.\",\n      \"evidence\": \"In vitro binding assays, site-directed mutagenesis, quantitative affinity measurements\",\n      \"pmids\": [\"17884824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What relieves Fis1 autoinhibition in vivo not identified\", \"Direct vs adaptor-mediated Fis1-Dnm1 contact in the complex not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed in a divergent alga that a distinct WD40/coiled-coil protein (Mda1) forms a pre-existing ring recruiting Dnm1 late in division, demonstrating conserved late-stage Dnm1 action and GTP-dependent release.\",\n      \"evidence\": \"Biochemical purification of the division machinery, immuno-EM, GTP-induced disassembly and sedimentation\",\n      \"pmids\": [\"17360593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of Mda1 to Mdv1/Fis1 adaptors unclear\", \"Mechanism of Dnm1 release upon GTP addition not structurally defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis for fission, showing Dnm1 forms a unique helix that drives large GTP-hydrolysis-coupled liposome constriction followed by membrane dissociation.\",\n      \"evidence\": \"Cryo-EM 3D structure and liposome constriction assay\",\n      \"pmids\": [\"21170049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell constriction dimensions not directly measured\", \"Coupling between conformational change and scission completion incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Pinpointed the Insert B motif of Dnm1 as the structural determinant for Mdv1 binding, explaining how Dnm1 is physically tethered to the mitochondrial adaptor.\",\n      \"evidence\": \"Site-directed mutagenesis, suppressor screen, Co-IP, fluorescence microscopy in yeast\",\n      \"pmids\": [\"23148233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact Mdv1 beta-propeller contact residues only inferred from suppressors\", \"Whether Insert B contacts other partners not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Blm10-proteasome degradation of Dnm1 as a homeostatic brake on fission, linking Dnm1 protein levels to mitochondrial integrity.\",\n      \"evidence\": \"In vitro and in vivo degradation assays, yeast genetics, mitochondrial morphology and respiration measurements\",\n      \"pmids\": [\"24604417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals targeting Dnm1 for Blm10-dependent turnover unknown\", \"Whether degradation is regulated during the cell cycle unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that human epileptic-encephalopathy DNM1 mutations act dominant-negatively by impairing oligomerization and endocytic vesicle scission, establishing the disease mechanism.\",\n      \"evidence\": \"Transferrin endocytosis assays, oligomerization analysis, EM in cells and Dnm1-Ftfl mouse brain\",\n      \"pmids\": [\"27066543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synapse-level consequences not yet measured\", \"Therapeutic correction not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the biophysical mechanism of scission, showing Dnm1 generates negative Gaussian curvature to form a ~12.6 nm fission neck via a helical membrane-restructuring domain, with Fis1 inhibiting this activity.\",\n      \"evidence\": \"Synchrotron SAXS, machine-learning domain identification, in silico mutagenesis\",\n      \"pmids\": [\"29202017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Helical domain function not validated by in-cell mutagenesis\", \"How Fis1 inhibits membrane restructuring mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected cytoskeletal and metabolic cues to fission, showing microtubule association impedes Dnm1 assembly while glucose starvation and low PKA promote Dnm1 recruitment.\",\n      \"evidence\": \"Kinesin and pathway gene deletions, live-cell and time-lapse imaging of Dnm1 in fission yeast\",\n      \"pmids\": [\"30602572\", \"31562247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PKA activity and Dnm1 recruitment not defined\", \"Whether microtubule effect is steric or signaled is unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined GTPase-domain residues T62 and S277 as essential for catalysis and fission, with S277 variants acting dominant-negatively, and modeled the prevalent human R237W mutation in a knock-in mouse rescued pharmacologically.\",\n      \"evidence\": \"Site-directed mutagenesis with GTPase assays in yeast; R237W knock-in mouse with electrophysiology, endocytosis assays, and BMS-204352 rescue\",\n      \"pmids\": [\"37838106\", \"37648685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological kinases for T62/S277 not identified\", \"Long-term durability of pharmacological rescue unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed fission completion requires the intermembrane-space factor Atg44 cooperating with cytosolic Dnm1, and that Dnm1 in turn drives focal clustering of its receptor Fis1, revealing reciprocal spatial organization.\",\n      \"evidence\": \"atg44 deletion with CLEM and live imaging; CRISPR endogenous Fis1 tagging with dnm1 deletion in yeast\",\n      \"pmids\": [\"38818923\", \"40910107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How inner- and outer-membrane scission events are coordinated mechanistically unclear\", \"Molecular basis of Dnm1-dependent Fis1 clustering not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the disease isoform and a corrective gene-therapy principle, identifying the brain-predominant DNM1A isoform and showing that combined knockdown-replace is required to rescue the dominant-negative mutant.\",\n      \"evidence\": \"Brain RNA-seq isoform analysis with splice variant functional assay and neuropathological EM; AAV9 bivalent knockdown-replace in mouse with electrophysiology and transcriptomics\",\n      \"pmids\": [\"36413998\", \"39127888\", \"33372033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific structural differences not resolved\", \"Clinical translation of knockdown-replace not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNM1's dual roles in synaptic endocytosis and mitochondrial fission are coordinated within a cell, and whether proposed roles in redox sensing, B-cell actin dynamics, and cancer cell N-cadherin recycling reflect direct DNM1 mechanisms, remain open.\",\n      \"evidence\": \"Not yet established\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Redox-sensing and cancer/immune roles rest on Low-confidence or preprint evidence\", \"Direct molecular mechanism in these contexts not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 17, 21]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [1, 4, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 19]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 13, 14]}\n    ],\n    \"complexes\": [\"mitochondrial division machinery (Dnm1-Mdv1-Fis1)\"],\n    \"partners\": [\"FIS1\", \"MDV1\", \"ATG44\", \"BLM10\", \"MDA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}