{"gene":"DNM1L","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1992,"finding":"VPS1 (yeast ortholog of DNM1L) encodes a GTPase that binds and hydrolyzes GTP; the N-terminal domain provides GTP-binding/hydrolysis activity required for vacuolar protein sorting, while the C-terminal domain mediates association with sorting apparatus components; dominant-negative mutations mapped exclusively to the N-terminal half, and recessive mutations produced truncated/unstable proteins.","method":"In vitro GTP binding/hydrolysis assay, hydroxylamine mutagenesis, deletion analysis, subcellular fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay combined with domain-deletion mutagenesis and dominant-negative analysis; foundational mechanistic paper replicated conceptually across many subsequent studies","pmids":["1429836"],"is_preprint":false},{"year":1993,"finding":"Vps1p associates with the membrane fraction in subcellular fractionation experiments; the C-terminal half of Vps1p is important for this membrane association.","method":"Subcellular fractionation","journal":"Ciba Foundation symposium","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single fractionation experiment, single lab, corroborates 1992 paper but adds membrane-association detail","pmids":["8299420"],"is_preprint":false},{"year":1995,"finding":"Vps1p (yeast DNM1L ortholog) is an 80-kDa GTPase associated with the Golgi apparatus and is required for retention of late Golgi membrane proteins; in vps1Δ cells, Golgi and vacuolar membrane proteins are re-routed to the plasma membrane via the secretory pathway rather than the prevacuolar compartment, demonstrating Vps1p is required for vesicle formation from the late Golgi toward the prevacuolar compartment.","method":"Genetic epistasis (vps1Δ sec4-ts and vps1Δ end4-ts double mutants), protease protection assay, temperature-sensitive mutant analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with two independent temperature-sensitive mutations, protease-protection biochemical assay, consistent model across multiple markers","pmids":["7698993"],"is_preprint":false},{"year":1995,"finding":"MVP1 genetically interacts with VPS1; overproduction of Mvp1p suppresses multiple dominant vps1 alleles in a wild-type Vps1p-dependent manner, and Mvp1p co-localizes with Vps1p at late Golgi/prevacuolar compartments, indicating they act in concert to promote membrane traffic to the vacuole.","method":"Multicopy suppressor screen, genetic epistasis, fluorescence co-localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — suppressor screen plus co-localization, single lab, two complementary methods","pmids":["7862158"],"is_preprint":false},{"year":1997,"finding":"A dominant-negative Vps1p A293D point mutation (downstream of the GTP-binding motif) causes missorting of carboxypeptidase Y; expression of wild-type Vps1p partially suppresses this, consistent with competition for a shared sorting factor binding site.","method":"Point mutagenesis, CPY sorting assay, dominant-negative complementation","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single mutagenesis study, single lab, functional sorting assay","pmids":["9372190"],"is_preprint":false},{"year":1998,"finding":"Human DYMPLE (DNM1L/DRP1) was cloned; it encodes an 80-kDa dynamin-family GTPase lacking a proline-rich C-terminal domain; overexpressed wild-type protein shows a punctate perinuclear cytoplasmic pattern, while an N-terminal deletion mutant forms large aggregates bounded by a trans-Golgi network marker; three tissue-specific alternative splice forms produce in-frame deletions.","method":"cDNA cloning, overexpression with subcellular localization by fluorescence microscopy, Northern blot for splice variants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by overexpression microscopy plus splice-variant characterization; single lab","pmids":["9422767"],"is_preprint":false},{"year":2010,"finding":"A C452F missense mutation in the M (middle/stalk) domain of mouse Dnm1l causes dominant dilated cardiomyopathy; heterozygous mutant fibroblasts show abnormal mitochondrial and peroxisomal morphology; hearts show reduced mitochondrial enzyme complexes and ATP depletion; homozygosity is embryonic lethal; the mutation alters protein–protein interactions in a yeast two-hybrid assay, suggesting disrupted intramolecular interactions within the Dnm1l monomer.","method":"ENU mutagenesis screen, yeast two-hybrid protein interaction assay, mitochondrial morphology (fluorescence microscopy), enzymatic activity assays for respiratory chain complexes, ATP measurement","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, organelle morphology, biochemical enzyme/ATP assays) in a single rigorous study with defined dominant phenotype","pmids":["20585624"],"is_preprint":false},{"year":2010,"finding":"Yeast Vps1 transiently localizes to endocytic sites and facilitates endocytic membrane invagination; the C-terminal self-assembly domain is required for endocytic function but not for other membrane fission events (e.g., Golgi-to-vacuole sorting).","method":"Live-cell imaging of endocytic reporters, electron microscopy, biochemical approaches, domain-mutant analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging, EM, and biochemical approaches in one study; localization tied to functional consequence via domain mutants","pmids":["20841380"],"is_preprint":false},{"year":2010,"finding":"Loss of Vps1 disrupts assembly and maturation of endocytic vesicles at the plasma membrane (increased lifespan of cortical endocytic complexes), impairs directed post-internalization vesicle motility toward the vacuole, and causes severe disruption of actin cables; both the GTPase and GED domains are required for endocytic function.","method":"Time-lapse fluorescence live-cell imaging with particle tracking, GFP-tagged endocytic markers in vps1 null cells","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with particle tracking plus domain mutants, single lab","pmids":["20189679"],"is_preprint":false},{"year":2011,"finding":"Vps1 and the amphiphysin Rvs167 interact via Vps1's single type I SH3-binding motif and the Rvs167 SH3 domain; this interaction is specifically required for endocytic scission but not for other Vps1 membrane functions; in vitro, the Rvs161/Rvs167 heterodimer can disassemble Vps1 oligomers.","method":"Co-immunoprecipitation, in vitro oligomer disassembly assay, site-directed mutagenesis of SH3-binding motif, live-cell imaging, electron microscopy","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal interaction confirmed biochemically, in vitro disassembly assay, mutagenesis showing specificity, EM of endocytic invaginations","pmids":["22082017"],"is_preprint":false},{"year":2011,"finding":"The self-assembly-defective Vps1 I649K mutation causes formation of elongated endocytic invaginations (equivalent to I690K in human Dyn1), demonstrating that Vps1 self-assembly and consequent GTPase stimulation are critical for the vesicle scission/pinching-off step of endocytosis.","method":"Electron microscopy of endocytic invaginations in cells expressing Vps1-I649K","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EM provides direct structural evidence, single lab, single method","pmids":["21509199"],"is_preprint":false},{"year":2013,"finding":"Vps1 localizes to late endosomes and is required for efficient late endosome-to-vacuole transport; loss of Vps1 disrupts HOPS tethering complex integrity by mislocalizing Vps39 to the cytoplasm; double mutants of VPS1 with individual ESCRT I, II, or III genes show synthetic lethality.","method":"Fluorescence microscopy (FM4-64 pulse-chase, GFP-tagged markers), subcellular localization analysis, genetic epistasis (synthetic lethality)","journal":"Journal of biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple fluorescence markers plus genetic epistasis, single lab","pmids":["23385815"],"is_preprint":false},{"year":2013,"finding":"Vps1 functions in early endosome-to-late Golgi recycling of GFP-Snc1; the GTPase and GED domains of Vps1 are essential for this recycling function; loss of Vps1 also causes Vps51 (GARP component) mislocalization from the late Golgi and severe disruption of actin cables.","method":"Fluorescence microscopy of GFP-Snc1, genetic interaction analysis, domain mutant analysis","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — fluorescence microscopy plus domain mutants, single lab","pmids":["24219288"],"is_preprint":false},{"year":2014,"finding":"Vps1 promotes fission of retromer SNX-BAR-coated tubules from yeast endosomes; Mvp1 (SNX8 homolog) recruits Vps1 to the endosome in vivo and has potent membrane-remodeling activity in vitro; cargo export completely fails in vps1-null cells but is only delayed in mvp1-null cells.","method":"In vitro membrane remodeling assay (Mvp1), in vivo Vps1 endosomal localization, cargo export assays in null mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro membrane remodeling, in vivo recruitment assay, null mutant cargo export with distinct phenotypic endpoints","pmids":["24567361"],"is_preprint":false},{"year":2014,"finding":"Retromer, Vps1, and the Rab7 GTPase Ypt7 cooperate to retrieve transmembrane receptor Vps10 from vacuoles; retromer and Vps1 leave the vacuole with the cargo while Ypt7 remains, indicating Ypt7 has a regulatory role; both retromer and Vps1 are essential for vacuole membrane organization.","method":"In vitro vacuole recycling assay, cargo co-fractionation, fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay with co-fractionation and microscopy, single lab","pmids":["25512334"],"is_preprint":false},{"year":2014,"finding":"DNM1L (DRP1) interacts with kinesin light chain 1 (KLC1) through KLC1's tetratricopeptide repeat (TPR) domains but not with KIF5; DNM1L and KLC1 co-localize in cultured cells, suggesting KLC1 may participate in post-fission mitochondrial transport.","method":"Yeast two-hybrid screening, co-localization by fluorescence microscopy in cultured cells","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus co-localization only, no functional validation of transport role","pmids":["25082190"],"is_preprint":false},{"year":2015,"finding":"Vps1 is phosphorylated at serine 599 by the cyclin-associated kinase Pho85 in vivo and in vitro; phosphomimetic (S599D) and non-phosphorylatable (S599V) mutations selectively impair endocytic scission without affecting other Vps1 functions; S599V inhibits the interaction with Rvs167, while both S599 mutations cause defects in vesicle scission visualized by live imaging and EM.","method":"In vitro kinase assay (Pho85), phosphoproteomics confirmation, site-directed mutagenesis, live-cell imaging, electron microscopy of endocytic invaginations, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus mutagenesis, EM, live imaging, and interaction studies; multiple orthogonal methods in one study","pmids":["26711254"],"is_preprint":false},{"year":2015,"finding":"In the absence of DNM1L/Drp1, PARK2/Parkin-dependent mitophagy becomes critical for maintaining mitochondrial function and structural integrity in the mouse heart and brain, establishing a synergistic relationship between mitochondrial fission and mitophagy.","method":"Mouse genetic knockout/epistasis (Dnm1l and Park2 double mutant), mitochondrial functional and structural analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model, single lab, defined cellular phenotype","pmids":["25715097"],"is_preprint":false},{"year":2016,"finding":"DNM1L R403C mutation in the middle/assembly domain acts by a dominant-negative mechanism, reducing DRP1 oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent than the A395D lethal variant; this establishes that milder DRP1 oligomerization impairment correlates with later-onset disease.","method":"Patient fibroblast studies, fluorescence microscopy of mitochondrial morphology, assessment of DRP1 oligomerization, mitochondrial fission assays","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived fibroblasts, multiple functional readouts (oligomerization, fission, recruitment), single lab","pmids":["27145208"],"is_preprint":false},{"year":2016,"finding":"De novo heterozygous DNM1L G362S mutation (in the assembly/middle domain) acts as a dominant-negative, causing markedly impaired mitochondrial fission, partial respiratory chain defect (complex IV), and normal peroxisomal morphology in patient fibroblasts; human fibroblasts overexpressing the mutant gene recapitulate aberrant mitochondrial morphology.","method":"Patient fibroblast fluorescence microscopy, respiratory chain activity assay, overexpression of mutant DNM1L","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblasts plus overexpression confirmation, multiple functional readouts, single lab","pmids":["26992161"],"is_preprint":false},{"year":2016,"finding":"Biallelic (compound heterozygous) DNM1L variants cause recessive disease with impaired fission of both mitochondria and peroxisomes (abnormally elongated mitochondria and aberrant peroxisomes in patient fibroblasts); pathogenicity validated in a yeast model.","method":"Fluorescence microscopy of patient fibroblasts, yeast functional complementation model","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-model validation (patient fibroblasts and yeast), single lab","pmids":["27328748"],"is_preprint":false},{"year":2017,"finding":"DNM1L knockout neural stem cells (Dnm1l-/- NSCs) show elongated mitochondria, reduced mitochondrial respiratory capacity, metabolic shift to glycolysis, impaired self-renewal, and accelerated cellular aging; PARK2/Parkin becomes critical when DNM1L is absent in mouse heart and brain.","method":"Dnm1l knockout ESC-derived NSCs, mitochondrial morphology assessment, metabolic flux analysis, self-renewal assays","journal":"International journal of molecular sciences (2023) / Autophagy (2015)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts, single lab","pmids":["34573276","25715097"],"is_preprint":false},{"year":2017,"finding":"Dominant mutations in DNM1L in patients with isolated optic atrophy lead to homo-polymerization of DNM1L and formation of cytoplasmic aggregates on highly tubulated mitochondrial networks; Dnm1l+/- mice show increased mitochondrial length in retinal ganglion cell soma and axons, establishing DNM1L as required for mitochondrial fission in the optic nerve.","method":"Patient fibroblast analysis, fluorescence microscopy of mitochondrial network, mouse retinal ganglion cell analysis (Dnm1l+/- mouse)","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblasts, mouse heterozygous model, fluorescence microscopy; single lab","pmids":["28969390"],"is_preprint":false},{"year":2017,"finding":"PRKAA (AMPKα) regulates DNM1L protein levels via autophagy-dependent degradation; loss of PRKAA causes defective autophagy, DNM1L accumulation, and aberrant mitochondrial fragmentation; the autophagy receptor SQSTM1/p62 binds DNM1L and mediates its delivery to autophagosomes for lysosomal degradation.","method":"Mouse aortic endothelium knockout models, siRNA knockdown, co-immunoprecipitation (SQSTM1-DNM1L), ATG7 overexpression, rapamycin/chloroquine treatment","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple genetic and pharmacological interventions, mouse KO model with vascular functional readout; multiple orthogonal methods","pmids":["28085543"],"is_preprint":false},{"year":2017,"finding":"Mtfp1 (mitochondrial fission protein 1) acts upstream of Dnm1l to promote its accumulation at mitochondria; knockdown of Mtfp1 prevents Dnm1l mitochondrial accumulation and reduces doxorubicin-induced mitochondrial fission and apoptosis in cardiac myocytes; Mtfp1 overexpression enhances fission.","method":"siRNA knockdown, overexpression, fluorescence microscopy of mitochondrial morphology, cell death assays in HL-1 cardiomyocytes","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation (KD and OE) with mitochondrial localization and functional readouts, single lab","pmids":["28643438"],"is_preprint":false},{"year":2017,"finding":"Vps1 associates with clathrin heavy chain (Chc1) via the C-terminal region of Chc1; Vps1 arrives at the Golgi after clathrin; loss of Vps1 shifts clathrin localization to late endosome/vacuole; double vps1Δ chc1Δ cells show more severe CPY sorting defects than either single mutant.","method":"Yeast two-hybrid, genetic epistasis (double mutant CPY sorting), fluorescence microscopy of clathrin localization","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus genetic epistasis and localization, single lab","pmids":["28256270"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of Vps1 GTPase-BSE fusion reveal GTP hydrolysis intermediates and conformational changes; cryo-EM structure of full-length GMPPCP-bound Vps1 shows a more open and flexible helical architecture than dynamin, due to BSE opening away from GTPase domains and formation of a novel inter-GTPase domain interface instead of BSE-stalk contacts; disruption of this novel interface abolishes Vps1 function in vivo.","method":"X-ray crystallography (GTPase-BSE fusion, multiple nucleotide states), cryo-EM (full-length Vps1), in vivo mutagenesis of novel interface","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures + cryo-EM + mutagenesis with in vivo functional validation; multiple orthogonal methods in one study","pmids":["30087125"],"is_preprint":false},{"year":2019,"finding":"In HCC cells under hypoxia, DNM1L translocates to mitochondria (without changing total DNM1L levels), inducing excessive mitochondrial fission; DNM1L interacts with hexokinase 2 (HK2) and is involved in HK2 phosphorylation, causing HK2 detachment from mitochondria and consequent mitochondrial permeability transition pore (mPTP) opening. [Note: this paper was subsequently retracted (PMID 33907822) due to use of wrong cell line; the finding should be treated with very low confidence.]","method":"Co-immunoprecipitation (DNM1L-HK2), immunofluorescence, mitochondrial membrane potential assay — NOTE: retracted","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP finding from a retracted paper; unreliable","pmids":["31322265","33907822"],"is_preprint":false},{"year":2019,"finding":"Inhibition of DNM1L in rheumatoid arthritis fibroblast-like synoviocytes impairs mitochondrial fission, reduces mitochondrial membrane potential, decreases AKT/IKK activation, inhibits NF-κB p65 nuclear translocation, and reduces IL-8 and COX-2 production, placing DNM1L upstream of AKT/IKK/NF-κB inflammatory signaling.","method":"DNM1L siRNA knockdown, mdivi-1 pharmacological inhibition, fluorescence microscopy, western blot for signaling pathway components, cytokine measurement, CIA mouse model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological inhibition, multiple signaling pathway readouts, in vivo mouse model corroboration","pmids":["31755231"],"is_preprint":false},{"year":2019,"finding":"Vps1 Insert B region binds directly to lipids, preferentially PI(4,5)P2; mutation of three lysine residues (KKK-AAA) in Insert B reduces lipid binding, selectively disrupts endocytic scission (increased lifetime of endocytic reporter Sla2, defective scission events) without affecting other Vps1 functions.","method":"In vitro lipid-binding assay, site-directed mutagenesis, live-cell imaging of endocytic reporters, fluorescence localization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro lipid binding plus mutagenesis plus live-cell imaging; single lab","pmids":["31009484"],"is_preprint":false},{"year":2020,"finding":"The P-loop K42A mutation in Vps1 abrogates GTPase activity by disrupting organization of the GTPase active site (not nucleotide binding affinity); in cells, Vps1-K42A and Dnm1-K42A become trapped in assembled oligomeric states at their typical sites of action, explaining the dominant-negative mechanism.","method":"Biophysical nucleotide-binding assays, GTPase activity assays, crystal structure of K42A mutant, in vivo fluorescence microscopy of trapped assemblies","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus in vivo assembly trapping; multiple orthogonal methods","pmids":["31981262"],"is_preprint":false},{"year":2020,"finding":"DNM1L knockdown in mouse embryonic fibroblasts slows mitochondrial clearance (measured by photoactivatable mito-PAmCherry flow cytometry); impaired DNM1L-Ser616 and MAPK/ERK phosphorylation in LRRK2R1441G mutant cells attenuates mitochondrial fission and downstream mitophagy, placing DNM1L-MAPK/ERK signaling upstream of mitophagy.","method":"DNM1L siRNA knockdown, flow cytometry of photoactivatable mito-PAmCherry, western blot for DNM1L-pSer616 and MAPK/ERK phosphorylation, FCCP-induced stress","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel flow cytometry mitophagy assay plus phosphorylation analysis, single lab","pmids":["33300446"],"is_preprint":false},{"year":2021,"finding":"Mvp1 (SNX8 homolog) mediates endosomal recycling by deforming endosomal membrane and sorting cargo with a specific motif into tubules, then recruiting Vps1 to catalyze membrane scission and release the recycling tubule; this constitutes a mechanistically distinct pathway from retromer and Snx4 pathways.","method":"In vivo Vps1 recruitment assay, cargo sorting assays in null mutants, membrane tubulation analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo recruitment and cargo sorting with null mutant analysis, single lab","pmids":["34524084"],"is_preprint":false},{"year":2022,"finding":"Four distinct de novo DNM1L variants in different domains impair DRP1 function by divergent mechanisms: stalk domain variants show greater impairments in oligomerization, peroxisomal recruitment, and hyperfusion than GTPase domain variants; a novel p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, revealing that assembly-state information is transmitted to the GTPase domain.","method":"In vitro recombinant human DRP1 mutant characterization (oligomerization assays, GTPase activity), patient fibroblast mitochondrial/peroxisomal morphology","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro recombinant protein assays (oligomerization + GTPase) plus patient fibroblast functional studies; multiple variants and orthogonal methods","pmids":["35914810"],"is_preprint":false},{"year":2023,"finding":"Vps1 interacts with Atg9 at Atg9 reservoirs; in the absence of Vps1 or its GTPase activity, Atg9 fails to reach the phagophore assembly site, severely impairing autophagic flux; Vps1 oligomerization activity is also required for this autophagy function.","method":"Co-immunoprecipitation (Vps1-Atg9), fluorescence microscopy of Atg9 localization in vps1Δ and GTPase-dead mutants, autophagic flux assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, GTPase and oligomerization mutant analysis, localization assay, flux assay; multiple orthogonal methods","pmids":["37060997"],"is_preprint":false},{"year":2023,"finding":"Pex27 specifically mediates Vps1-dependent peroxisome fission (but not Dnm1-dependent fission); Pex27 physically interacts with Vps1 in vivo, accumulates at constricted peroxisomal regions, and is required for accumulation of GTPase-dead Vps1-K42A on peroxisomes, indicating Pex27 is a Vps1-specific peroxisomal receptor.","method":"Co-immunoprecipitation (Pex27-Vps1), fluorescence microscopy of peroxisome morphology, genetic epistasis (pex27Δ vs dnm1Δ), GTPase-dead mutant recruitment assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus genetic epistasis plus GTPase mutant recruitment assay; multiple orthogonal methods establishing specificity","pmids":["36825558"],"is_preprint":false},{"year":2023,"finding":"BCL2L13 targets DNM1L at Ser616, promoting mitochondrial fission and elevated mitophagy flux in glioblastoma cells; this mechanism promotes GBM proliferation and invasion.","method":"Co-immunoprecipitation-like target identification, fluorescence microscopy of mitochondrial morphology, mitophagy flux assays, in vitro and in vivo proliferation/invasion assays","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single interaction study with functional assays, single lab, abstract does not detail the biochemical interaction method precisely","pmids":["37660127"],"is_preprint":false},{"year":2023,"finding":"DNM1L knockout in mouse embryonic stem cell-derived neural stem cells causes elongated mitochondria, reduced respiratory capacity, metabolic shift to glycolysis, impaired self-renewal, accelerated cellular aging, elevated inflammation markers, and increased cell death.","method":"Dnm1l knockout ESC-derived NSCs, mitochondrial morphology fluorescence microscopy, metabolic flux (Seahorse), self-renewal and proliferation assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple cellular phenotype readouts, single lab","pmids":["37762596"],"is_preprint":false},{"year":2025,"finding":"PPA2 interacts with MTFP1 (inner mitochondrial membrane protein) to activate DNM1L Ser616 phosphorylation and mitochondrial translocation; MTFP1 knockdown abolishes PPA2-induced DNM1L activation; in physiological conditions PPA2 directs midzone fission via MFF-DNM1L, while under mitochondrial stress PPA2 drives peripheral fission via FIS1-DNM1L for mitophagy.","method":"Co-immunoprecipitation (PPA2-MTFP1), siRNA knockdown of MTFP1, phospho-DNM1L western blot, fluorescence microscopy of mitochondrial morphology, CCCP stress assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic knockdown plus phosphorylation analysis and functional fission assays, single lab","pmids":["40873007"],"is_preprint":false},{"year":2025,"finding":"USP3, a deubiquitinating enzyme, directly interacts with DNM1L and specifically cleaves K48-linked polyubiquitin chains, deubiquitinating and stabilizing DNM1L protein; elevated USP3-mediated DNM1L stabilization promotes mitochondrial fission and GBC progression.","method":"Co-immunoprecipitation (USP3-DNM1L), ubiquitin chain linkage analysis, cell-derived xenograft assays","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitin-linkage specificity analysis, single lab","pmids":["40197257"],"is_preprint":false},{"year":2025,"finding":"DNM1L mutations impair mitochondrial fission in hiPSC-derived cardiomyocytes, causing elongated mitochondria, reduced mitochondrial membrane potential, decreased oxygen consumption and ATP production, prolonged Ca2+ decay time, and impaired contractile/diastolic function under isoproterenol stimulation.","method":"hiPSC-derived cardiomyocytes from DNM1L-mutant patients, mitochondrial morphology fluorescence microscopy, Seahorse metabolic flux, Ca2+ imaging, high-precision live contractility imaging","journal":"Pediatric research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC model with multiple functional readouts, single lab, no in vitro reconstitution","pmids":["40269254"],"is_preprint":false},{"year":2025,"finding":"DNM1L-isoforms lacking the A-insert (exon 3) robustly rescue mitochondrial fission in Drp1-knockout fibroblasts, while isoforms containing exon 3 show only partial rescue, indicating that the B-insert (exon 2/3) region negatively regulates DNM1L fission activity; isoform abundance does not predict enzymatic activity.","method":"Functional rescue in Drp1-knockout mouse embryonic fibroblasts, long-read targeted sequencing for isoform characterization, GTPase/fission activity assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — functional rescue in KO cells with isoform-specific constructs plus enzymatic activity assays; single lab","pmids":["42053410"],"is_preprint":false},{"year":2025,"finding":"Liver-specific Dnm1l knockout mice develop hepatic fibrosis, DNA damage, senescence, and spontaneous hepatocellular adenomas by 12–18 months; activated cGAS-STING-interferon pathway and increased pyrimidine synthesis were identified as downstream consequences; additional deletion of Mfn1/Mfn2 in Dnm1l-KO mice abolished liver injury, fibrosis, and tumorigenesis, showing that liver pathology requires mitochondrial fusion in the absence of fission.","method":"Liver-specific Dnm1l knockout mouse model, triple KO (Dnm1l/Mfn1/Mfn2), RNA sequencing, metabolomics, histology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse KO model with multi-omic analysis; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"A DNM1L splice variant lacking exon 16 of the variable domain decreases DRP1 association with mitochondrial fission sites, promotes fused mitochondrial networks and enhanced respiration, abrogates mitochondrial fission in response to pro-apoptotic stimuli, and reduces chemotherapy sensitivity; specific siRNA targeting this transcript reverses these pro-tumorigenic effects.","method":"siRNA-mediated selective knockdown of exon-16-lacking transcript, live-cell mitochondrial morphology imaging, Seahorse metabolic assays, in vitro and in vivo tumor models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective siRNA knockdown with multiple functional readouts; preprint, single lab","pmids":["37790404"],"is_preprint":true},{"year":2024,"finding":"Patient-derived iPSC cortical neurons with DRP1 mutations show mutation-specific changes in mitochondrial motility (axonal transport of hyperfused mitochondria), altered synaptic development gene expression, disrupted calcium dynamics, and deficits in pre/post-synaptic marker colocalization, indicating that DRP1 function is required for normal synaptic maturation.","method":"iPSC-derived cortical neurons, high-resolution time-lapse axonal transport imaging, transcriptional profiling, live calcium imaging, super-resolution microscopy of synaptic markers","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC model with multiple orthogonal readouts (imaging, transcriptomics, calcium, super-res); preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"DNM1L/DRP1 is a large self-assembling GTPase of the dynamin superfamily that oligomerizes into helical ring structures at mitochondrial and peroxisomal constriction sites, where GTP hydrolysis drives membrane fission; its activity is regulated by phosphorylation (e.g., Ser616 by MAPK/ERK, CDK1; Ser637 by PKA), by autophagy-dependent protein turnover (SQSTM1-mediated delivery to autophagosomes), and by deubiquitination (USP3 cleaves K48-linked chains to stabilize it); distinct protein domains (GTPase, middle/stalk, GED, and variable B-insert) mediate oligomerization, membrane recruitment via specific receptors (MFF, FIS1, MiD49/51, Pex27 in yeast), and assembly-stimulated GTPase activation, while alternative splicing of the variable domain confers tissue-specific differences in fission efficiency; loss of DNM1L causes mitochondrial and peroxisomal hyperfusion with downstream impairments in mitophagy, respiratory chain function, ATP production, Ca2+ handling, and synaptic development, particularly in neurons and cardiomyocytes."},"narrative":{"mechanistic_narrative":"DNM1L/DRP1 is a self-assembling dynamin-family GTPase that drives membrane fission across organelles, with its mammalian role centered on the division of mitochondria and peroxisomes [PMID:9422767, PMID:20585624, PMID:27328748]. The enzymatic logic was established in the yeast ortholog Vps1, where the N-terminal domain provides GTP binding and hydrolysis essential for membrane traffic while the C-terminal half mediates membrane association and oligomerization [PMID:1429836, PMID:8299420]. Self-assembly couples directly to catalysis: assembly stimulates GTPase activity, and crystal/cryo-EM structures show that GTP hydrolysis intermediates and a novel inter-GTPase-domain interface transmit assembly-state information to the active site, a mechanism whose disruption abolishes function in vivo [PMID:30087125, PMID:35914810]. The P-loop K42A mutation abrogates catalysis by disorganizing the active site and traps the protein in assembled oligomers, explaining the dominant-negative behavior of GTPase-dead alleles [PMID:31981262]. Mitochondrial and peroxisomal fission depend on recruitment of DNM1L to constriction sites via receptors and upstream factors including MTFP1, the PPA2-MTFP1 axis acting through MFF and FIS1, and the Vps1-specific peroxisomal receptor Pex27 in yeast [PMID:28643438, PMID:36825558, PMID:40873007]. Activity is tuned by Ser616 phosphorylation linked to MAPK/ERK and mitophagy signaling, by autophagy-dependent turnover through PRKAA/AMPK with SQSTM1/p62 delivering DNM1L to autophagosomes, and by USP3-mediated removal of K48-linked ubiquitin that stabilizes the protein [PMID:28085543, PMID:33300446, PMID:40197257]. Alternative splicing of the variable B-insert and A-insert region modulates fission efficiency, with insert-lacking isoforms conferring more robust activity [PMID:42053410]. Loss or dominant-negative mutation of DNM1L produces elongated, hyperfused mitochondria and aberrant peroxisomes with respiratory chain defects, reduced ATP, impaired mitophagy, disrupted Ca2+ handling, and defects in neuronal and cardiomyocyte function; in humans these mutations cause dominant and recessive disease including dilated cardiomyopathy, optic atrophy, and encephalopathy [PMID:20585624, PMID:27145208, PMID:27328748, PMID:28969390, PMID:40269254]. In yeast, Vps1 additionally executes fission in endocytosis, Golgi-to-vacuole and endosomal recycling traffic, and Atg9 delivery for autophagy, using PI(4,5)P2-binding inserts, Pho85 phosphorylation, and partners such as Rvs167, Mvp1, and clathrin [PMID:20841380, PMID:24567361, PMID:26711254, PMID:31009484, PMID:37060997].","teleology":[{"year":1992,"claim":"Established that the founding ortholog is a bona fide GTPase whose N-terminal catalytic domain and C-terminal sorting-association domain are functionally separable, defining the enzymatic and modular architecture of the family.","evidence":"In vitro GTP binding/hydrolysis assays with hydroxylamine mutagenesis and deletion analysis in yeast Vps1","pmids":["1429836"],"confidence":"High","gaps":["Did not resolve how GTP hydrolysis is mechanically coupled to membrane fission","No structural model of the active site"]},{"year":1995,"claim":"Showed the protein is required for vesicle formation in membrane traffic, linking GTPase activity to a specific transport step rather than a generic role.","evidence":"Genetic epistasis with temperature-sensitive mutants and protease-protection assays, plus a multicopy suppressor (Mvp1) screen in yeast","pmids":["7698993","7862158"],"confidence":"High","gaps":["Membrane scission step not directly visualized","Receptor for membrane recruitment unidentified"]},{"year":1998,"claim":"Cloned the human gene and revealed tissue-specific alternative splice forms, establishing the conserved dynamin-family identity and isoform diversity of mammalian DNM1L.","evidence":"cDNA cloning, overexpression localization microscopy, and Northern blot of splice variants","pmids":["9422767"],"confidence":"Medium","gaps":["Endogenous localization not determined (overexpression only)","Functional consequences of each splice form unknown"]},{"year":2010,"claim":"Established DNM1L as essential for mitochondrial and peroxisomal morphology in mammals and linked a stalk-domain mutation to dominant cardiomyopathy with bioenergetic failure.","evidence":"ENU mutagenesis C452F mouse, yeast two-hybrid, organelle morphology, respiratory chain enzyme and ATP assays","pmids":["20585624"],"confidence":"High","gaps":["Precise intramolecular interaction disrupted not structurally defined","Mechanism connecting fission loss to ATP depletion not isolated"]},{"year":2010,"claim":"Defined the yeast ortholog's role in endocytic membrane scission and showed domain-specific separation of fission functions, generalizing the protein's fission activity beyond Golgi traffic.","evidence":"Live-cell imaging, EM, particle tracking, and GTPase/GED/self-assembly domain mutants in vps1-null cells","pmids":["20841380","20189679"],"confidence":"High","gaps":["How distinct domains partition between functions not fully mapped","Recruitment to endocytic sites mechanistically unresolved at this stage"]},{"year":2011,"claim":"Identified the amphiphysin Rvs167 partner and demonstrated that self-assembly drives the scission step, mechanistically tying oligomerization to membrane pinching.","evidence":"Reciprocal Co-IP, SH3-motif mutagenesis, in vitro oligomer disassembly, and EM of elongated invaginations in self-assembly-defective I649K mutant","pmids":["22082017","21509199"],"confidence":"High","gaps":["Whether Rvs167-mediated disassembly applies to mitochondrial fission unknown","Quantitative coupling of assembly to GTPase rate not measured here"]},{"year":2013,"claim":"Extended the fission function to endosome-to-vacuole and endosome-to-Golgi recycling traffic, establishing the protein as a general membrane-trafficking fission factor in yeast.","evidence":"FM4-64 pulse-chase, GFP-marker localization, synthetic lethality with ESCRT genes, and GFP-Snc1 recycling assays with domain mutants","pmids":["23385815","24219288"],"confidence":"Medium","gaps":["Direct fission events at these compartments not visualized","Relationship to HOPS/GARP integrity correlative"]},{"year":2014,"claim":"Established a receptor-mediated recruitment paradigm in which SNX-BAR proteins (Mvp1) target the GTPase to endosomal tubules and retromer/Rab7 cooperate for cargo retrieval.","evidence":"In vitro membrane remodeling, in vivo recruitment, null-mutant cargo export assays, and in vitro vacuole recycling assays","pmids":["24567361","25512334"],"confidence":"High","gaps":["Whether analogous adaptor logic operates at mitochondria not addressed here","Stoichiometry of recruitment unresolved"]},{"year":2014,"claim":"Linked mammalian DNM1L to a motor-adaptor (KLC1) raising the possibility of coordination between fission and organelle transport.","evidence":"Yeast two-hybrid against KLC1 TPR domains and co-localization in cultured cells","pmids":["25082190"],"confidence":"Low","gaps":["No functional validation of a transport role (interaction only)","No reciprocal biochemical confirmation in mammalian cells","KIF5 not involved, leaving transport mechanism unclear"]},{"year":2015,"claim":"Identified phospho-regulation of scission (Pho85/Ser599 in yeast) and the synergy between fission and Parkin-dependent mitophagy, embedding the GTPase in mitochondrial quality-control circuits.","evidence":"In vitro kinase and phosphomimetic mutant analysis with EM/imaging (Vps1); Dnm1l/Park2 double-mutant mouse epistasis","pmids":["26711254","25715097"],"confidence":"High","gaps":["Whether yeast Ser599 corresponds to a mammalian regulatory site not established","Molecular trigger for mitophagy dependence on fission loss unresolved"]},{"year":2016,"claim":"Defined human disease alleles across domains and showed graded dominant-negative impairment of oligomerization and recruitment correlating with phenotype severity.","evidence":"Patient fibroblast morphology, oligomerization and fission assays, respiratory chain activity, and yeast complementation for R403C, G362S, and biallelic variants","pmids":["27145208","26992161","27328748"],"confidence":"Medium","gaps":["Structural basis of variant-specific assembly defects not resolved at this stage","Tissue selectivity of phenotypes unexplained"]},{"year":2017,"claim":"Established that DNM1L abundance is set by autophagy-dependent turnover via AMPK and the SQSTM1/p62 receptor, and that MTFP1 acts upstream to promote mitochondrial accumulation.","evidence":"Reciprocal SQSTM1-DNM1L Co-IP with AMPK KO, ATG7/rapamycin/chloroquine interventions; MTFP1 knockdown/overexpression in cardiomyocytes","pmids":["28085543","28643438"],"confidence":"High","gaps":["Ubiquitin-ligase generating the degron not identified here","How MTFP1 promotes accumulation mechanistically undefined"]},{"year":2017,"claim":"Demonstrated that fission loss impairs respiration, forces a glycolytic shift, and accelerates aging in neural stem cells and is required for mitochondrial integrity in optic nerve.","evidence":"Dnm1l knockout NSCs with metabolic flux and self-renewal assays; patient fibroblasts and Dnm1l+/- mouse retinal ganglion cell analysis","pmids":["34573276","28969390"],"confidence":"Medium","gaps":["Causal chain from fission loss to metabolic reprogramming not dissected","Neuron-specific vulnerability mechanism unknown"]},{"year":2019,"claim":"Placed DNM1L-driven fission upstream of inflammatory AKT/IKK/NF-kB signaling, linking organelle dynamics to immune/inflammatory output.","evidence":"siRNA and mdivi-1 inhibition with signaling western blots, cytokine measurement, and CIA mouse model in synoviocytes","pmids":["31755231"],"confidence":"Medium","gaps":["Mechanism connecting membrane potential change to NF-kB activation not defined","Off-target effects of mdivi-1 not excluded"]},{"year":2020,"claim":"Provided the structural and catalytic mechanism by which GTPase-dead alleles act dominant-negatively, showing the K42A mutation traps assembled oligomers without losing nucleotide binding.","evidence":"Crystal structure of K42A, nucleotide-binding and GTPase assays, and in vivo imaging of trapped assemblies for Vps1 and Dnm1","pmids":["31981262"],"confidence":"High","gaps":["How active-site disorganization arrests the assembly cycle in real time unresolved","Generalization to all P-loop disease variants not tested"]},{"year":2020,"claim":"Connected DNM1L-Ser616/MAPK-ERK phosphorylation to mitophagy execution, showing fission signaling acts upstream of mitochondrial clearance.","evidence":"siRNA knockdown, photoactivatable mito-PAmCherry flow cytometry mitophagy assay, and phospho-Ser616/ERK western blots in LRRK2 mutant cells","pmids":["33300446"],"confidence":"Medium","gaps":["Direct kinase responsible for Ser616 in this context not isolated","Whether fission per se or DNM1L signaling drives mitophagy not separated"]},{"year":2022,"claim":"Resolved how assembly-state information is transmitted to the GTPase domain and how domain-specific human variants impair distinct steps, with an Arg710Gly variant uncoupling assembly from assembly-stimulated hydrolysis.","evidence":"In vitro recombinant human DRP1 oligomerization and GTPase assays across four de novo variants plus patient fibroblast morphology","pmids":["35914810"],"confidence":"High","gaps":["Full structural path of the assembly-to-catalysis signal not mapped","Why stalk variants disproportionately affect peroxisomal recruitment unresolved"]},{"year":2023,"claim":"Defined organelle-specific and pathway-specific recruitment determinants: a dedicated peroxisomal receptor (Pex27) and a role in Atg9 delivery for autophagy in yeast.","evidence":"Co-IP, genetic epistasis (pex27 vs dnm1), GTPase-dead recruitment assays, Atg9 localization and autophagic flux in vps1 mutants","pmids":["36825558","37060997"],"confidence":"High","gaps":["Mammalian equivalent of Pex27 not identified here","How GTPase activity enables Atg9 trafficking mechanistically open"]},{"year":2023,"claim":"Extended phospho- and disease-context regulation to cancer, with BCL2L13 targeting Ser616 to promote fission-driven mitophagy and tumor progression.","evidence":"Target identification, mitochondrial morphology and mitophagy flux assays, and proliferation/invasion models in glioblastoma","pmids":["37660127"],"confidence":"Low","gaps":["Biochemical interaction method not precisely defined","Single lab without reciprocal validation"]},{"year":2025,"claim":"Established a regulatory hierarchy in which a PPA2-MTFP1 module activates Ser616 phosphorylation and translocation, directing midzone (MFF) versus peripheral (FIS1) fission depending on stress state, and identified USP3 as a deubiquitinase that stabilizes DNM1L.","evidence":"Co-IP, MTFP1 knockdown, phospho-DNM1L western blots, CCCP stress fission assays; USP3-DNM1L Co-IP with K48 ubiquitin-linkage analysis and xenografts","pmids":["40873007","40197257"],"confidence":"Medium","gaps":["Whether PPA2 acts as a phosphatase or scaffold here not clarified","E3 ligase opposing USP3 not identified"]},{"year":2025,"claim":"Clarified isoform-dependent regulation, showing the A-insert/B-insert region negatively tunes fission activity and that exon-skipping variants alter mitochondrial network state and tumor/apoptotic behavior.","evidence":"Functional rescue in Drp1-KO MEFs with isoform-specific constructs and long-read sequencing; selective siRNA against exon-16-lacking transcript with metabolic and tumor assays (preprint)","pmids":["42053410","37790404"],"confidence":"Medium","gaps":["Structural basis for insert-mediated inhibition not resolved","Tissue distribution of functional isoforms not mapped"]},{"year":2025,"claim":"Demonstrated tissue-level consequences of fission loss in disease-relevant human and mouse models: bioenergetic and contractile failure in cardiomyocytes, synaptic maturation defects in neurons, and fusion-dependent liver injury and tumorigenesis.","evidence":"hiPSC cardiomyocytes (Seahorse, Ca2+ and contractility imaging); iPSC cortical neurons (axonal transport, transcriptomics, calcium, super-resolution); liver-specific Dnm1l KO and Dnm1l/Mfn1/Mfn2 triple-KO mice (preprint)","pmids":["40269254","40873007"],"confidence":"Medium","gaps":["cGAS-STING activation mechanism downstream of fission loss not fully causal","How hyperfusion specifically drives synaptic and contractile deficits unresolved"]},{"year":null,"claim":"How DNM1L recruitment receptors, phosphorylation events, ubiquitin turnover, and isoform composition are integrated to set fission rate at specific organelles and tissues in mammals remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model linking assembly, GTP hydrolysis, and receptor occupancy to fission output","Mammalian counterpart of the Pex27 peroxisomal receptor not identified in this corpus","E3 ligase generating the degron antagonized by USP3 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,26,30,33]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[29]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[9,26,33]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,22,24,38]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[6,20,35]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,13,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6,20,35]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,23,31,34]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,18,20,22,40]}],"complexes":[],"partners":["MTFP1","PEX27","RVS167","MVP1","SQSTM1","USP3","CHC1","ATG9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00429","full_name":"Dynamin-1-like protein","aliases":["Dnm1p/Vps1p-like protein","DVLP","Dynamin family member proline-rich carboxyl-terminal domain less","Dymple","Dynamin-like protein","Dynamin-like protein 4","Dynamin-like protein IV","HdynIV","Dynamin-related protein 1"],"length_aa":736,"mass_kda":81.9,"function":"Functions in mitochondrial and peroxisomal division (PubMed:11514614, PubMed:12499366, PubMed:17301055, PubMed:17460227, PubMed:17553808, PubMed:18695047, PubMed:18838687, PubMed:19342591, PubMed:19411255, PubMed:19638400, PubMed:23283981, PubMed:23530241, PubMed:23921378, PubMed:26992161, PubMed:27145208, PubMed:27145933, PubMed:27301544, PubMed:27328748, PubMed:29478834, PubMed:32439975, PubMed:32484300, PubMed:9570752, PubMed:9786947). Mediates membrane fission through oligomerization into membrane-associated tubular structures that wrap around the scission site to constrict and sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism (PubMed:23530241, PubMed:23584531, PubMed:33850055). The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes (PubMed:23283981, PubMed:23921378, PubMed:29899447). While the recruitment by the membrane receptors is GTP-dependent, the following hydrolysis of GTP induces the dissociation from the receptors and allows DNM1L filaments to curl into closed rings that are probably sufficient to sever a double membrane (PubMed:29899447). Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner (PubMed:32484300). Plays an important role in mitochondrial fission during mitosis (PubMed:19411255, PubMed:26992161, PubMed:27301544, PubMed:27328748). Through its function in mitochondrial division, ensures the survival of at least some types of postmitotic neurons, including Purkinje cells, by suppressing oxidative damage (By similarity). Required for normal brain development, including that of cerebellum (PubMed:17460227, PubMed:26992161, PubMed:27145208, PubMed:27301544, PubMed:27328748). Facilitates developmentally regulated apoptosis during neural tube formation (By similarity). Required for a normal rate of cytochrome c release and caspase activation during apoptosis; this requirement may depend upon the cell type and the physiological apoptotic cues (By similarity). Required for formation of endocytic vesicles (PubMed:20688057, PubMed:23792689, PubMed:9570752). Proposed to regulate synaptic vesicle membrane dynamics through association with BCL2L1 isoform Bcl-X(L) which stimulates its GTPase activity in synaptic vesicles; the function may require its recruitment by MFF to clathrin-containing vesicles (PubMed:17015472, PubMed:23792689). Required for programmed necrosis execution (PubMed:22265414). Rhythmic control of its activity following phosphorylation at Ser-637 is essential for the circadian control of mitochondrial ATP production (PubMed:29478834) Inhibits peroxisomal division when overexpressed Inhibits peroxisomal division when overexpressed","subcellular_location":"Cytoplasm, cytosol; Golgi apparatus; Endomembrane system; Mitochondrion outer membrane; Peroxisome; Membrane, clathrin-coated pit; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/O00429/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DNM1L","classification":"Common Essential","n_dependent_lines":761,"n_total_lines":1208,"dependency_fraction":0.6299668874172185},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000087470","cell_line_id":"CID001545","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"NACA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001545","total_profiled":1310},"omim":[{"mim_id":"621553","title":"GTP-BINDING PROTEIN 8; GTPBP8","url":"https://www.omim.org/entry/621553"},{"mim_id":"617086","title":"ENCEPHALOPATHY DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL FISSION 2; EMPF2","url":"https://www.omim.org/entry/617086"},{"mim_id":"616636","title":"IMMUNODEFICIENCY 44; IMD44","url":"https://www.omim.org/entry/616636"},{"mim_id":"615498","title":"MITOCHONDRIAL ELONGATION FACTOR 2; MIEF2","url":"https://www.omim.org/entry/615498"},{"mim_id":"615497","title":"MITOCHONDRIAL ELONGATION FACTOR 1; MIEF1","url":"https://www.omim.org/entry/615497"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DNM1L"},"hgnc":{"alias_symbol":["DRP1","DVLP","HDYNIV","DYMPLE","VPS1"],"prev_symbol":[]},"alphafold":{"accession":"O00429","domains":[{"cath_id":"3.40.50.300","chopping":"27-76_84-311","consensus_level":"high","plddt":87.2568,"start":27,"end":311},{"cath_id":"1.20.120.1240","chopping":"328-508_636-702","consensus_level":"high","plddt":88.7918,"start":328,"end":702}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00429","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00429-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00429-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNM1L","jax_strain_url":"https://www.jax.org/strain/search?query=DNM1L"},"sequence":{"accession":"O00429","fasta_url":"https://rest.uniprot.org/uniprotkb/O00429.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00429/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00429"}},"corpus_meta":[{"pmid":"1429836","id":"PMC_1429836","title":"The VPS1 protein, a homolog of dynamin required for vacuolar protein sorting in Saccharomyces cerevisiae, is a GTPase with two functionally separable domains.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1429836","citation_count":188,"is_preprint":false},{"pmid":"7698993","id":"PMC_7698993","title":"Golgi and vacuolar membrane proteins reach the vacuole in vps1 mutant yeast cells via the plasma membrane.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7698993","citation_count":157,"is_preprint":false},{"pmid":"20585624","id":"PMC_20585624","title":"A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20585624","citation_count":119,"is_preprint":false},{"pmid":"27145208","id":"PMC_27145208","title":"A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy.","date":"2016","source":"American journal of medical genetics. 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half, and recessive mutations produced truncated/unstable proteins.\",\n      \"method\": \"In vitro GTP binding/hydrolysis assay, hydroxylamine mutagenesis, deletion analysis, subcellular fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay combined with domain-deletion mutagenesis and dominant-negative analysis; foundational mechanistic paper replicated conceptually across many subsequent studies\",\n      \"pmids\": [\"1429836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Vps1p associates with the membrane fraction in subcellular fractionation experiments; the C-terminal half of Vps1p is important for this membrane association.\",\n      \"method\": \"Subcellular fractionation\",\n      \"journal\": \"Ciba Foundation symposium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single fractionation experiment, single lab, corroborates 1992 paper but adds membrane-association detail\",\n      \"pmids\": [\"8299420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Vps1p (yeast DNM1L ortholog) is an 80-kDa GTPase associated with the Golgi apparatus and is required for retention of late Golgi membrane proteins; in vps1Δ cells, Golgi and vacuolar membrane proteins are re-routed to the plasma membrane via the secretory pathway rather than the prevacuolar compartment, demonstrating Vps1p is required for vesicle formation from the late Golgi toward the prevacuolar compartment.\",\n      \"method\": \"Genetic epistasis (vps1Δ sec4-ts and vps1Δ end4-ts double mutants), protease protection assay, temperature-sensitive mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with two independent temperature-sensitive mutations, protease-protection biochemical assay, consistent model across multiple markers\",\n      \"pmids\": [\"7698993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"MVP1 genetically interacts with VPS1; overproduction of Mvp1p suppresses multiple dominant vps1 alleles in a wild-type Vps1p-dependent manner, and Mvp1p co-localizes with Vps1p at late Golgi/prevacuolar compartments, indicating they act in concert to promote membrane traffic to the vacuole.\",\n      \"method\": \"Multicopy suppressor screen, genetic epistasis, fluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — suppressor screen plus co-localization, single lab, two complementary methods\",\n      \"pmids\": [\"7862158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A dominant-negative Vps1p A293D point mutation (downstream of the GTP-binding motif) causes missorting of carboxypeptidase Y; expression of wild-type Vps1p partially suppresses this, consistent with competition for a shared sorting factor binding site.\",\n      \"method\": \"Point mutagenesis, CPY sorting assay, dominant-negative complementation\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single mutagenesis study, single lab, functional sorting assay\",\n      \"pmids\": [\"9372190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human DYMPLE (DNM1L/DRP1) was cloned; it encodes an 80-kDa dynamin-family GTPase lacking a proline-rich C-terminal domain; overexpressed wild-type protein shows a punctate perinuclear cytoplasmic pattern, while an N-terminal deletion mutant forms large aggregates bounded by a trans-Golgi network marker; three tissue-specific alternative splice forms produce in-frame deletions.\",\n      \"method\": \"cDNA cloning, overexpression with subcellular localization by fluorescence microscopy, Northern blot for splice variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by overexpression microscopy plus splice-variant characterization; single lab\",\n      \"pmids\": [\"9422767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A C452F missense mutation in the M (middle/stalk) domain of mouse Dnm1l causes dominant dilated cardiomyopathy; heterozygous mutant fibroblasts show abnormal mitochondrial and peroxisomal morphology; hearts show reduced mitochondrial enzyme complexes and ATP depletion; homozygosity is embryonic lethal; the mutation alters protein–protein interactions in a yeast two-hybrid assay, suggesting disrupted intramolecular interactions within the Dnm1l monomer.\",\n      \"method\": \"ENU mutagenesis screen, yeast two-hybrid protein interaction assay, mitochondrial morphology (fluorescence microscopy), enzymatic activity assays for respiratory chain complexes, ATP measurement\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, organelle morphology, biochemical enzyme/ATP assays) in a single rigorous study with defined dominant phenotype\",\n      \"pmids\": [\"20585624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Vps1 transiently localizes to endocytic sites and facilitates endocytic membrane invagination; the C-terminal self-assembly domain is required for endocytic function but not for other membrane fission events (e.g., Golgi-to-vacuole sorting).\",\n      \"method\": \"Live-cell imaging of endocytic reporters, electron microscopy, biochemical approaches, domain-mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging, EM, and biochemical approaches in one study; localization tied to functional consequence via domain mutants\",\n      \"pmids\": [\"20841380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Vps1 disrupts assembly and maturation of endocytic vesicles at the plasma membrane (increased lifespan of cortical endocytic complexes), impairs directed post-internalization vesicle motility toward the vacuole, and causes severe disruption of actin cables; both the GTPase and GED domains are required for endocytic function.\",\n      \"method\": \"Time-lapse fluorescence live-cell imaging with particle tracking, GFP-tagged endocytic markers in vps1 null cells\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with particle tracking plus domain mutants, single lab\",\n      \"pmids\": [\"20189679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Vps1 and the amphiphysin Rvs167 interact via Vps1's single type I SH3-binding motif and the Rvs167 SH3 domain; this interaction is specifically required for endocytic scission but not for other Vps1 membrane functions; in vitro, the Rvs161/Rvs167 heterodimer can disassemble Vps1 oligomers.\",\n      \"method\": \"Co-immunoprecipitation, in vitro oligomer disassembly assay, site-directed mutagenesis of SH3-binding motif, live-cell imaging, electron microscopy\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal interaction confirmed biochemically, in vitro disassembly assay, mutagenesis showing specificity, EM of endocytic invaginations\",\n      \"pmids\": [\"22082017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The self-assembly-defective Vps1 I649K mutation causes formation of elongated endocytic invaginations (equivalent to I690K in human Dyn1), demonstrating that Vps1 self-assembly and consequent GTPase stimulation are critical for the vesicle scission/pinching-off step of endocytosis.\",\n      \"method\": \"Electron microscopy of endocytic invaginations in cells expressing Vps1-I649K\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EM provides direct structural evidence, single lab, single method\",\n      \"pmids\": [\"21509199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vps1 localizes to late endosomes and is required for efficient late endosome-to-vacuole transport; loss of Vps1 disrupts HOPS tethering complex integrity by mislocalizing Vps39 to the cytoplasm; double mutants of VPS1 with individual ESCRT I, II, or III genes show synthetic lethality.\",\n      \"method\": \"Fluorescence microscopy (FM4-64 pulse-chase, GFP-tagged markers), subcellular localization analysis, genetic epistasis (synthetic lethality)\",\n      \"journal\": \"Journal of biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple fluorescence markers plus genetic epistasis, single lab\",\n      \"pmids\": [\"23385815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vps1 functions in early endosome-to-late Golgi recycling of GFP-Snc1; the GTPase and GED domains of Vps1 are essential for this recycling function; loss of Vps1 also causes Vps51 (GARP component) mislocalization from the late Golgi and severe disruption of actin cables.\",\n      \"method\": \"Fluorescence microscopy of GFP-Snc1, genetic interaction analysis, domain mutant analysis\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — fluorescence microscopy plus domain mutants, single lab\",\n      \"pmids\": [\"24219288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Vps1 promotes fission of retromer SNX-BAR-coated tubules from yeast endosomes; Mvp1 (SNX8 homolog) recruits Vps1 to the endosome in vivo and has potent membrane-remodeling activity in vitro; cargo export completely fails in vps1-null cells but is only delayed in mvp1-null cells.\",\n      \"method\": \"In vitro membrane remodeling assay (Mvp1), in vivo Vps1 endosomal localization, cargo export assays in null mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro membrane remodeling, in vivo recruitment assay, null mutant cargo export with distinct phenotypic endpoints\",\n      \"pmids\": [\"24567361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Retromer, Vps1, and the Rab7 GTPase Ypt7 cooperate to retrieve transmembrane receptor Vps10 from vacuoles; retromer and Vps1 leave the vacuole with the cargo while Ypt7 remains, indicating Ypt7 has a regulatory role; both retromer and Vps1 are essential for vacuole membrane organization.\",\n      \"method\": \"In vitro vacuole recycling assay, cargo co-fractionation, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay with co-fractionation and microscopy, single lab\",\n      \"pmids\": [\"25512334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DNM1L (DRP1) interacts with kinesin light chain 1 (KLC1) through KLC1's tetratricopeptide repeat (TPR) domains but not with KIF5; DNM1L and KLC1 co-localize in cultured cells, suggesting KLC1 may participate in post-fission mitochondrial transport.\",\n      \"method\": \"Yeast two-hybrid screening, co-localization by fluorescence microscopy in cultured cells\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus co-localization only, no functional validation of transport role\",\n      \"pmids\": [\"25082190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vps1 is phosphorylated at serine 599 by the cyclin-associated kinase Pho85 in vivo and in vitro; phosphomimetic (S599D) and non-phosphorylatable (S599V) mutations selectively impair endocytic scission without affecting other Vps1 functions; S599V inhibits the interaction with Rvs167, while both S599 mutations cause defects in vesicle scission visualized by live imaging and EM.\",\n      \"method\": \"In vitro kinase assay (Pho85), phosphoproteomics confirmation, site-directed mutagenesis, live-cell imaging, electron microscopy of endocytic invaginations, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus mutagenesis, EM, live imaging, and interaction studies; multiple orthogonal methods in one study\",\n      \"pmids\": [\"26711254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the absence of DNM1L/Drp1, PARK2/Parkin-dependent mitophagy becomes critical for maintaining mitochondrial function and structural integrity in the mouse heart and brain, establishing a synergistic relationship between mitochondrial fission and mitophagy.\",\n      \"method\": \"Mouse genetic knockout/epistasis (Dnm1l and Park2 double mutant), mitochondrial functional and structural analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model, single lab, defined cellular phenotype\",\n      \"pmids\": [\"25715097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNM1L R403C mutation in the middle/assembly domain acts by a dominant-negative mechanism, reducing DRP1 oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent than the A395D lethal variant; this establishes that milder DRP1 oligomerization impairment correlates with later-onset disease.\",\n      \"method\": \"Patient fibroblast studies, fluorescence microscopy of mitochondrial morphology, assessment of DRP1 oligomerization, mitochondrial fission assays\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived fibroblasts, multiple functional readouts (oligomerization, fission, recruitment), single lab\",\n      \"pmids\": [\"27145208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo heterozygous DNM1L G362S mutation (in the assembly/middle domain) acts as a dominant-negative, causing markedly impaired mitochondrial fission, partial respiratory chain defect (complex IV), and normal peroxisomal morphology in patient fibroblasts; human fibroblasts overexpressing the mutant gene recapitulate aberrant mitochondrial morphology.\",\n      \"method\": \"Patient fibroblast fluorescence microscopy, respiratory chain activity assay, overexpression of mutant DNM1L\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblasts plus overexpression confirmation, multiple functional readouts, single lab\",\n      \"pmids\": [\"26992161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic (compound heterozygous) DNM1L variants cause recessive disease with impaired fission of both mitochondria and peroxisomes (abnormally elongated mitochondria and aberrant peroxisomes in patient fibroblasts); pathogenicity validated in a yeast model.\",\n      \"method\": \"Fluorescence microscopy of patient fibroblasts, yeast functional complementation model\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-model validation (patient fibroblasts and yeast), single lab\",\n      \"pmids\": [\"27328748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNM1L knockout neural stem cells (Dnm1l-/- NSCs) show elongated mitochondria, reduced mitochondrial respiratory capacity, metabolic shift to glycolysis, impaired self-renewal, and accelerated cellular aging; PARK2/Parkin becomes critical when DNM1L is absent in mouse heart and brain.\",\n      \"method\": \"Dnm1l knockout ESC-derived NSCs, mitochondrial morphology assessment, metabolic flux analysis, self-renewal assays\",\n      \"journal\": \"International journal of molecular sciences (2023) / Autophagy (2015)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"34573276\", \"25715097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Dominant mutations in DNM1L in patients with isolated optic atrophy lead to homo-polymerization of DNM1L and formation of cytoplasmic aggregates on highly tubulated mitochondrial networks; Dnm1l+/- mice show increased mitochondrial length in retinal ganglion cell soma and axons, establishing DNM1L as required for mitochondrial fission in the optic nerve.\",\n      \"method\": \"Patient fibroblast analysis, fluorescence microscopy of mitochondrial network, mouse retinal ganglion cell analysis (Dnm1l+/- mouse)\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblasts, mouse heterozygous model, fluorescence microscopy; single lab\",\n      \"pmids\": [\"28969390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRKAA (AMPKα) regulates DNM1L protein levels via autophagy-dependent degradation; loss of PRKAA causes defective autophagy, DNM1L accumulation, and aberrant mitochondrial fragmentation; the autophagy receptor SQSTM1/p62 binds DNM1L and mediates its delivery to autophagosomes for lysosomal degradation.\",\n      \"method\": \"Mouse aortic endothelium knockout models, siRNA knockdown, co-immunoprecipitation (SQSTM1-DNM1L), ATG7 overexpression, rapamycin/chloroquine treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple genetic and pharmacological interventions, mouse KO model with vascular functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"28085543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mtfp1 (mitochondrial fission protein 1) acts upstream of Dnm1l to promote its accumulation at mitochondria; knockdown of Mtfp1 prevents Dnm1l mitochondrial accumulation and reduces doxorubicin-induced mitochondrial fission and apoptosis in cardiac myocytes; Mtfp1 overexpression enhances fission.\",\n      \"method\": \"siRNA knockdown, overexpression, fluorescence microscopy of mitochondrial morphology, cell death assays in HL-1 cardiomyocytes\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation (KD and OE) with mitochondrial localization and functional readouts, single lab\",\n      \"pmids\": [\"28643438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vps1 associates with clathrin heavy chain (Chc1) via the C-terminal region of Chc1; Vps1 arrives at the Golgi after clathrin; loss of Vps1 shifts clathrin localization to late endosome/vacuole; double vps1Δ chc1Δ cells show more severe CPY sorting defects than either single mutant.\",\n      \"method\": \"Yeast two-hybrid, genetic epistasis (double mutant CPY sorting), fluorescence microscopy of clathrin localization\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus genetic epistasis and localization, single lab\",\n      \"pmids\": [\"28256270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of Vps1 GTPase-BSE fusion reveal GTP hydrolysis intermediates and conformational changes; cryo-EM structure of full-length GMPPCP-bound Vps1 shows a more open and flexible helical architecture than dynamin, due to BSE opening away from GTPase domains and formation of a novel inter-GTPase domain interface instead of BSE-stalk contacts; disruption of this novel interface abolishes Vps1 function in vivo.\",\n      \"method\": \"X-ray crystallography (GTPase-BSE fusion, multiple nucleotide states), cryo-EM (full-length Vps1), in vivo mutagenesis of novel interface\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures + cryo-EM + mutagenesis with in vivo functional validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"30087125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In HCC cells under hypoxia, DNM1L translocates to mitochondria (without changing total DNM1L levels), inducing excessive mitochondrial fission; DNM1L interacts with hexokinase 2 (HK2) and is involved in HK2 phosphorylation, causing HK2 detachment from mitochondria and consequent mitochondrial permeability transition pore (mPTP) opening. [Note: this paper was subsequently retracted (PMID 33907822) due to use of wrong cell line; the finding should be treated with very low confidence.]\",\n      \"method\": \"Co-immunoprecipitation (DNM1L-HK2), immunofluorescence, mitochondrial membrane potential assay — NOTE: retracted\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP finding from a retracted paper; unreliable\",\n      \"pmids\": [\"31322265\", \"33907822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inhibition of DNM1L in rheumatoid arthritis fibroblast-like synoviocytes impairs mitochondrial fission, reduces mitochondrial membrane potential, decreases AKT/IKK activation, inhibits NF-κB p65 nuclear translocation, and reduces IL-8 and COX-2 production, placing DNM1L upstream of AKT/IKK/NF-κB inflammatory signaling.\",\n      \"method\": \"DNM1L siRNA knockdown, mdivi-1 pharmacological inhibition, fluorescence microscopy, western blot for signaling pathway components, cytokine measurement, CIA mouse model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological inhibition, multiple signaling pathway readouts, in vivo mouse model corroboration\",\n      \"pmids\": [\"31755231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Vps1 Insert B region binds directly to lipids, preferentially PI(4,5)P2; mutation of three lysine residues (KKK-AAA) in Insert B reduces lipid binding, selectively disrupts endocytic scission (increased lifetime of endocytic reporter Sla2, defective scission events) without affecting other Vps1 functions.\",\n      \"method\": \"In vitro lipid-binding assay, site-directed mutagenesis, live-cell imaging of endocytic reporters, fluorescence localization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro lipid binding plus mutagenesis plus live-cell imaging; single lab\",\n      \"pmids\": [\"31009484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The P-loop K42A mutation in Vps1 abrogates GTPase activity by disrupting organization of the GTPase active site (not nucleotide binding affinity); in cells, Vps1-K42A and Dnm1-K42A become trapped in assembled oligomeric states at their typical sites of action, explaining the dominant-negative mechanism.\",\n      \"method\": \"Biophysical nucleotide-binding assays, GTPase activity assays, crystal structure of K42A mutant, in vivo fluorescence microscopy of trapped assemblies\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus in vivo assembly trapping; multiple orthogonal methods\",\n      \"pmids\": [\"31981262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DNM1L knockdown in mouse embryonic fibroblasts slows mitochondrial clearance (measured by photoactivatable mito-PAmCherry flow cytometry); impaired DNM1L-Ser616 and MAPK/ERK phosphorylation in LRRK2R1441G mutant cells attenuates mitochondrial fission and downstream mitophagy, placing DNM1L-MAPK/ERK signaling upstream of mitophagy.\",\n      \"method\": \"DNM1L siRNA knockdown, flow cytometry of photoactivatable mito-PAmCherry, western blot for DNM1L-pSer616 and MAPK/ERK phosphorylation, FCCP-induced stress\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel flow cytometry mitophagy assay plus phosphorylation analysis, single lab\",\n      \"pmids\": [\"33300446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mvp1 (SNX8 homolog) mediates endosomal recycling by deforming endosomal membrane and sorting cargo with a specific motif into tubules, then recruiting Vps1 to catalyze membrane scission and release the recycling tubule; this constitutes a mechanistically distinct pathway from retromer and Snx4 pathways.\",\n      \"method\": \"In vivo Vps1 recruitment assay, cargo sorting assays in null mutants, membrane tubulation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo recruitment and cargo sorting with null mutant analysis, single lab\",\n      \"pmids\": [\"34524084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Four distinct de novo DNM1L variants in different domains impair DRP1 function by divergent mechanisms: stalk domain variants show greater impairments in oligomerization, peroxisomal recruitment, and hyperfusion than GTPase domain variants; a novel p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, revealing that assembly-state information is transmitted to the GTPase domain.\",\n      \"method\": \"In vitro recombinant human DRP1 mutant characterization (oligomerization assays, GTPase activity), patient fibroblast mitochondrial/peroxisomal morphology\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro recombinant protein assays (oligomerization + GTPase) plus patient fibroblast functional studies; multiple variants and orthogonal methods\",\n      \"pmids\": [\"35914810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vps1 interacts with Atg9 at Atg9 reservoirs; in the absence of Vps1 or its GTPase activity, Atg9 fails to reach the phagophore assembly site, severely impairing autophagic flux; Vps1 oligomerization activity is also required for this autophagy function.\",\n      \"method\": \"Co-immunoprecipitation (Vps1-Atg9), fluorescence microscopy of Atg9 localization in vps1Δ and GTPase-dead mutants, autophagic flux assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, GTPase and oligomerization mutant analysis, localization assay, flux assay; multiple orthogonal methods\",\n      \"pmids\": [\"37060997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pex27 specifically mediates Vps1-dependent peroxisome fission (but not Dnm1-dependent fission); Pex27 physically interacts with Vps1 in vivo, accumulates at constricted peroxisomal regions, and is required for accumulation of GTPase-dead Vps1-K42A on peroxisomes, indicating Pex27 is a Vps1-specific peroxisomal receptor.\",\n      \"method\": \"Co-immunoprecipitation (Pex27-Vps1), fluorescence microscopy of peroxisome morphology, genetic epistasis (pex27Δ vs dnm1Δ), GTPase-dead mutant recruitment assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus genetic epistasis plus GTPase mutant recruitment assay; multiple orthogonal methods establishing specificity\",\n      \"pmids\": [\"36825558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BCL2L13 targets DNM1L at Ser616, promoting mitochondrial fission and elevated mitophagy flux in glioblastoma cells; this mechanism promotes GBM proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation-like target identification, fluorescence microscopy of mitochondrial morphology, mitophagy flux assays, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single interaction study with functional assays, single lab, abstract does not detail the biochemical interaction method precisely\",\n      \"pmids\": [\"37660127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNM1L knockout in mouse embryonic stem cell-derived neural stem cells causes elongated mitochondria, reduced respiratory capacity, metabolic shift to glycolysis, impaired self-renewal, accelerated cellular aging, elevated inflammation markers, and increased cell death.\",\n      \"method\": \"Dnm1l knockout ESC-derived NSCs, mitochondrial morphology fluorescence microscopy, metabolic flux (Seahorse), self-renewal and proliferation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"37762596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PPA2 interacts with MTFP1 (inner mitochondrial membrane protein) to activate DNM1L Ser616 phosphorylation and mitochondrial translocation; MTFP1 knockdown abolishes PPA2-induced DNM1L activation; in physiological conditions PPA2 directs midzone fission via MFF-DNM1L, while under mitochondrial stress PPA2 drives peripheral fission via FIS1-DNM1L for mitophagy.\",\n      \"method\": \"Co-immunoprecipitation (PPA2-MTFP1), siRNA knockdown of MTFP1, phospho-DNM1L western blot, fluorescence microscopy of mitochondrial morphology, CCCP stress assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic knockdown plus phosphorylation analysis and functional fission assays, single lab\",\n      \"pmids\": [\"40873007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP3, a deubiquitinating enzyme, directly interacts with DNM1L and specifically cleaves K48-linked polyubiquitin chains, deubiquitinating and stabilizing DNM1L protein; elevated USP3-mediated DNM1L stabilization promotes mitochondrial fission and GBC progression.\",\n      \"method\": \"Co-immunoprecipitation (USP3-DNM1L), ubiquitin chain linkage analysis, cell-derived xenograft assays\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitin-linkage specificity analysis, single lab\",\n      \"pmids\": [\"40197257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNM1L mutations impair mitochondrial fission in hiPSC-derived cardiomyocytes, causing elongated mitochondria, reduced mitochondrial membrane potential, decreased oxygen consumption and ATP production, prolonged Ca2+ decay time, and impaired contractile/diastolic function under isoproterenol stimulation.\",\n      \"method\": \"hiPSC-derived cardiomyocytes from DNM1L-mutant patients, mitochondrial morphology fluorescence microscopy, Seahorse metabolic flux, Ca2+ imaging, high-precision live contractility imaging\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC model with multiple functional readouts, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"40269254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNM1L-isoforms lacking the A-insert (exon 3) robustly rescue mitochondrial fission in Drp1-knockout fibroblasts, while isoforms containing exon 3 show only partial rescue, indicating that the B-insert (exon 2/3) region negatively regulates DNM1L fission activity; isoform abundance does not predict enzymatic activity.\",\n      \"method\": \"Functional rescue in Drp1-knockout mouse embryonic fibroblasts, long-read targeted sequencing for isoform characterization, GTPase/fission activity assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — functional rescue in KO cells with isoform-specific constructs plus enzymatic activity assays; single lab\",\n      \"pmids\": [\"42053410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Liver-specific Dnm1l knockout mice develop hepatic fibrosis, DNA damage, senescence, and spontaneous hepatocellular adenomas by 12–18 months; activated cGAS-STING-interferon pathway and increased pyrimidine synthesis were identified as downstream consequences; additional deletion of Mfn1/Mfn2 in Dnm1l-KO mice abolished liver injury, fibrosis, and tumorigenesis, showing that liver pathology requires mitochondrial fusion in the absence of fission.\",\n      \"method\": \"Liver-specific Dnm1l knockout mouse model, triple KO (Dnm1l/Mfn1/Mfn2), RNA sequencing, metabolomics, histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse KO model with multi-omic analysis; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A DNM1L splice variant lacking exon 16 of the variable domain decreases DRP1 association with mitochondrial fission sites, promotes fused mitochondrial networks and enhanced respiration, abrogates mitochondrial fission in response to pro-apoptotic stimuli, and reduces chemotherapy sensitivity; specific siRNA targeting this transcript reverses these pro-tumorigenic effects.\",\n      \"method\": \"siRNA-mediated selective knockdown of exon-16-lacking transcript, live-cell mitochondrial morphology imaging, Seahorse metabolic assays, in vitro and in vivo tumor models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective siRNA knockdown with multiple functional readouts; preprint, single lab\",\n      \"pmids\": [\"37790404\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Patient-derived iPSC cortical neurons with DRP1 mutations show mutation-specific changes in mitochondrial motility (axonal transport of hyperfused mitochondria), altered synaptic development gene expression, disrupted calcium dynamics, and deficits in pre/post-synaptic marker colocalization, indicating that DRP1 function is required for normal synaptic maturation.\",\n      \"method\": \"iPSC-derived cortical neurons, high-resolution time-lapse axonal transport imaging, transcriptional profiling, live calcium imaging, super-resolution microscopy of synaptic markers\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC model with multiple orthogonal readouts (imaging, transcriptomics, calcium, super-res); preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DNM1L/DRP1 is a large self-assembling GTPase of the dynamin superfamily that oligomerizes into helical ring structures at mitochondrial and peroxisomal constriction sites, where GTP hydrolysis drives membrane fission; its activity is regulated by phosphorylation (e.g., Ser616 by MAPK/ERK, CDK1; Ser637 by PKA), by autophagy-dependent protein turnover (SQSTM1-mediated delivery to autophagosomes), and by deubiquitination (USP3 cleaves K48-linked chains to stabilize it); distinct protein domains (GTPase, middle/stalk, GED, and variable B-insert) mediate oligomerization, membrane recruitment via specific receptors (MFF, FIS1, MiD49/51, Pex27 in yeast), and assembly-stimulated GTPase activation, while alternative splicing of the variable domain confers tissue-specific differences in fission efficiency; loss of DNM1L causes mitochondrial and peroxisomal hyperfusion with downstream impairments in mitophagy, respiratory chain function, ATP production, Ca2+ handling, and synaptic development, particularly in neurons and cardiomyocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNM1L/DRP1 is a self-assembling dynamin-family GTPase that drives membrane fission across organelles, with its mammalian role centered on the division of mitochondria and peroxisomes [#5, #6, #20]. The enzymatic logic was established in the yeast ortholog Vps1, where the N-terminal domain provides GTP binding and hydrolysis essential for membrane traffic while the C-terminal half mediates membrane association and oligomerization [#0, #1]. Self-assembly couples directly to catalysis: assembly stimulates GTPase activity, and crystal/cryo-EM structures show that GTP hydrolysis intermediates and a novel inter-GTPase-domain interface transmit assembly-state information to the active site, a mechanism whose disruption abolishes function in vivo [#26, #33]. The P-loop K42A mutation abrogates catalysis by disorganizing the active site and traps the protein in assembled oligomers, explaining the dominant-negative behavior of GTPase-dead alleles [#30]. Mitochondrial and peroxisomal fission depend on recruitment of DNM1L to constriction sites via receptors and upstream factors including MTFP1, the PPA2-MTFP1 axis acting through MFF and FIS1, and the Vps1-specific peroxisomal receptor Pex27 in yeast [#24, #35, #38]. Activity is tuned by Ser616 phosphorylation linked to MAPK/ERK and mitophagy signaling, by autophagy-dependent turnover through PRKAA/AMPK with SQSTM1/p62 delivering DNM1L to autophagosomes, and by USP3-mediated removal of K48-linked ubiquitin that stabilizes the protein [#23, #31, #39]. Alternative splicing of the variable B-insert and A-insert region modulates fission efficiency, with insert-lacking isoforms conferring more robust activity [#41]. Loss or dominant-negative mutation of DNM1L produces elongated, hyperfused mitochondria and aberrant peroxisomes with respiratory chain defects, reduced ATP, impaired mitophagy, disrupted Ca2+ handling, and defects in neuronal and cardiomyocyte function; in humans these mutations cause dominant and recessive disease including dilated cardiomyopathy, optic atrophy, and encephalopathy [#6, #18, #20, #22, #40]. In yeast, Vps1 additionally executes fission in endocytosis, Golgi-to-vacuole and endosomal recycling traffic, and Atg9 delivery for autophagy, using PI(4,5)P2-binding inserts, Pho85 phosphorylation, and partners such as Rvs167, Mvp1, and clathrin [#7, #13, #16, #29, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that the founding ortholog is a bona fide GTPase whose N-terminal catalytic domain and C-terminal sorting-association domain are functionally separable, defining the enzymatic and modular architecture of the family.\",\n      \"evidence\": \"In vitro GTP binding/hydrolysis assays with hydroxylamine mutagenesis and deletion analysis in yeast Vps1\",\n      \"pmids\": [\"1429836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how GTP hydrolysis is mechanically coupled to membrane fission\", \"No structural model of the active site\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed the protein is required for vesicle formation in membrane traffic, linking GTPase activity to a specific transport step rather than a generic role.\",\n      \"evidence\": \"Genetic epistasis with temperature-sensitive mutants and protease-protection assays, plus a multicopy suppressor (Mvp1) screen in yeast\",\n      \"pmids\": [\"7698993\", \"7862158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane scission step not directly visualized\", \"Receptor for membrane recruitment unidentified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloned the human gene and revealed tissue-specific alternative splice forms, establishing the conserved dynamin-family identity and isoform diversity of mammalian DNM1L.\",\n      \"evidence\": \"cDNA cloning, overexpression localization microscopy, and Northern blot of splice variants\",\n      \"pmids\": [\"9422767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous localization not determined (overexpression only)\", \"Functional consequences of each splice form unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established DNM1L as essential for mitochondrial and peroxisomal morphology in mammals and linked a stalk-domain mutation to dominant cardiomyopathy with bioenergetic failure.\",\n      \"evidence\": \"ENU mutagenesis C452F mouse, yeast two-hybrid, organelle morphology, respiratory chain enzyme and ATP assays\",\n      \"pmids\": [\"20585624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise intramolecular interaction disrupted not structurally defined\", \"Mechanism connecting fission loss to ATP depletion not isolated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the yeast ortholog's role in endocytic membrane scission and showed domain-specific separation of fission functions, generalizing the protein's fission activity beyond Golgi traffic.\",\n      \"evidence\": \"Live-cell imaging, EM, particle tracking, and GTPase/GED/self-assembly domain mutants in vps1-null cells\",\n      \"pmids\": [\"20841380\", \"20189679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct domains partition between functions not fully mapped\", \"Recruitment to endocytic sites mechanistically unresolved at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the amphiphysin Rvs167 partner and demonstrated that self-assembly drives the scission step, mechanistically tying oligomerization to membrane pinching.\",\n      \"evidence\": \"Reciprocal Co-IP, SH3-motif mutagenesis, in vitro oligomer disassembly, and EM of elongated invaginations in self-assembly-defective I649K mutant\",\n      \"pmids\": [\"22082017\", \"21509199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rvs167-mediated disassembly applies to mitochondrial fission unknown\", \"Quantitative coupling of assembly to GTPase rate not measured here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the fission function to endosome-to-vacuole and endosome-to-Golgi recycling traffic, establishing the protein as a general membrane-trafficking fission factor in yeast.\",\n      \"evidence\": \"FM4-64 pulse-chase, GFP-marker localization, synthetic lethality with ESCRT genes, and GFP-Snc1 recycling assays with domain mutants\",\n      \"pmids\": [\"23385815\", \"24219288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct fission events at these compartments not visualized\", \"Relationship to HOPS/GARP integrity correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a receptor-mediated recruitment paradigm in which SNX-BAR proteins (Mvp1) target the GTPase to endosomal tubules and retromer/Rab7 cooperate for cargo retrieval.\",\n      \"evidence\": \"In vitro membrane remodeling, in vivo recruitment, null-mutant cargo export assays, and in vitro vacuole recycling assays\",\n      \"pmids\": [\"24567361\", \"25512334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether analogous adaptor logic operates at mitochondria not addressed here\", \"Stoichiometry of recruitment unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked mammalian DNM1L to a motor-adaptor (KLC1) raising the possibility of coordination between fission and organelle transport.\",\n      \"evidence\": \"Yeast two-hybrid against KLC1 TPR domains and co-localization in cultured cells\",\n      \"pmids\": [\"25082190\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation of a transport role (interaction only)\", \"No reciprocal biochemical confirmation in mammalian cells\", \"KIF5 not involved, leaving transport mechanism unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified phospho-regulation of scission (Pho85/Ser599 in yeast) and the synergy between fission and Parkin-dependent mitophagy, embedding the GTPase in mitochondrial quality-control circuits.\",\n      \"evidence\": \"In vitro kinase and phosphomimetic mutant analysis with EM/imaging (Vps1); Dnm1l/Park2 double-mutant mouse epistasis\",\n      \"pmids\": [\"26711254\", \"25715097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether yeast Ser599 corresponds to a mammalian regulatory site not established\", \"Molecular trigger for mitophagy dependence on fission loss unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined human disease alleles across domains and showed graded dominant-negative impairment of oligomerization and recruitment correlating with phenotype severity.\",\n      \"evidence\": \"Patient fibroblast morphology, oligomerization and fission assays, respiratory chain activity, and yeast complementation for R403C, G362S, and biallelic variants\",\n      \"pmids\": [\"27145208\", \"26992161\", \"27328748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of variant-specific assembly defects not resolved at this stage\", \"Tissue selectivity of phenotypes unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that DNM1L abundance is set by autophagy-dependent turnover via AMPK and the SQSTM1/p62 receptor, and that MTFP1 acts upstream to promote mitochondrial accumulation.\",\n      \"evidence\": \"Reciprocal SQSTM1-DNM1L Co-IP with AMPK KO, ATG7/rapamycin/chloroquine interventions; MTFP1 knockdown/overexpression in cardiomyocytes\",\n      \"pmids\": [\"28085543\", \"28643438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin-ligase generating the degron not identified here\", \"How MTFP1 promotes accumulation mechanistically undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that fission loss impairs respiration, forces a glycolytic shift, and accelerates aging in neural stem cells and is required for mitochondrial integrity in optic nerve.\",\n      \"evidence\": \"Dnm1l knockout NSCs with metabolic flux and self-renewal assays; patient fibroblasts and Dnm1l+/- mouse retinal ganglion cell analysis\",\n      \"pmids\": [\"34573276\", \"28969390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from fission loss to metabolic reprogramming not dissected\", \"Neuron-specific vulnerability mechanism unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed DNM1L-driven fission upstream of inflammatory AKT/IKK/NF-kB signaling, linking organelle dynamics to immune/inflammatory output.\",\n      \"evidence\": \"siRNA and mdivi-1 inhibition with signaling western blots, cytokine measurement, and CIA mouse model in synoviocytes\",\n      \"pmids\": [\"31755231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting membrane potential change to NF-kB activation not defined\", \"Off-target effects of mdivi-1 not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural and catalytic mechanism by which GTPase-dead alleles act dominant-negatively, showing the K42A mutation traps assembled oligomers without losing nucleotide binding.\",\n      \"evidence\": \"Crystal structure of K42A, nucleotide-binding and GTPase assays, and in vivo imaging of trapped assemblies for Vps1 and Dnm1\",\n      \"pmids\": [\"31981262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How active-site disorganization arrests the assembly cycle in real time unresolved\", \"Generalization to all P-loop disease variants not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected DNM1L-Ser616/MAPK-ERK phosphorylation to mitophagy execution, showing fission signaling acts upstream of mitochondrial clearance.\",\n      \"evidence\": \"siRNA knockdown, photoactivatable mito-PAmCherry flow cytometry mitophagy assay, and phospho-Ser616/ERK western blots in LRRK2 mutant cells\",\n      \"pmids\": [\"33300446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase responsible for Ser616 in this context not isolated\", \"Whether fission per se or DNM1L signaling drives mitophagy not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how assembly-state information is transmitted to the GTPase domain and how domain-specific human variants impair distinct steps, with an Arg710Gly variant uncoupling assembly from assembly-stimulated hydrolysis.\",\n      \"evidence\": \"In vitro recombinant human DRP1 oligomerization and GTPase assays across four de novo variants plus patient fibroblast morphology\",\n      \"pmids\": [\"35914810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural path of the assembly-to-catalysis signal not mapped\", \"Why stalk variants disproportionately affect peroxisomal recruitment unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined organelle-specific and pathway-specific recruitment determinants: a dedicated peroxisomal receptor (Pex27) and a role in Atg9 delivery for autophagy in yeast.\",\n      \"evidence\": \"Co-IP, genetic epistasis (pex27 vs dnm1), GTPase-dead recruitment assays, Atg9 localization and autophagic flux in vps1 mutants\",\n      \"pmids\": [\"36825558\", \"37060997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian equivalent of Pex27 not identified here\", \"How GTPase activity enables Atg9 trafficking mechanistically open\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended phospho- and disease-context regulation to cancer, with BCL2L13 targeting Ser616 to promote fission-driven mitophagy and tumor progression.\",\n      \"evidence\": \"Target identification, mitochondrial morphology and mitophagy flux assays, and proliferation/invasion models in glioblastoma\",\n      \"pmids\": [\"37660127\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Biochemical interaction method not precisely defined\", \"Single lab without reciprocal validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a regulatory hierarchy in which a PPA2-MTFP1 module activates Ser616 phosphorylation and translocation, directing midzone (MFF) versus peripheral (FIS1) fission depending on stress state, and identified USP3 as a deubiquitinase that stabilizes DNM1L.\",\n      \"evidence\": \"Co-IP, MTFP1 knockdown, phospho-DNM1L western blots, CCCP stress fission assays; USP3-DNM1L Co-IP with K48 ubiquitin-linkage analysis and xenografts\",\n      \"pmids\": [\"40873007\", \"40197257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PPA2 acts as a phosphatase or scaffold here not clarified\", \"E3 ligase opposing USP3 not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified isoform-dependent regulation, showing the A-insert/B-insert region negatively tunes fission activity and that exon-skipping variants alter mitochondrial network state and tumor/apoptotic behavior.\",\n      \"evidence\": \"Functional rescue in Drp1-KO MEFs with isoform-specific constructs and long-read sequencing; selective siRNA against exon-16-lacking transcript with metabolic and tumor assays (preprint)\",\n      \"pmids\": [\"42053410\", \"37790404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for insert-mediated inhibition not resolved\", \"Tissue distribution of functional isoforms not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated tissue-level consequences of fission loss in disease-relevant human and mouse models: bioenergetic and contractile failure in cardiomyocytes, synaptic maturation defects in neurons, and fusion-dependent liver injury and tumorigenesis.\",\n      \"evidence\": \"hiPSC cardiomyocytes (Seahorse, Ca2+ and contractility imaging); iPSC cortical neurons (axonal transport, transcriptomics, calcium, super-resolution); liver-specific Dnm1l KO and Dnm1l/Mfn1/Mfn2 triple-KO mice (preprint)\",\n      \"pmids\": [\"40269254\", \"40873007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cGAS-STING activation mechanism downstream of fission loss not fully causal\", \"How hyperfusion specifically drives synaptic and contractile deficits unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNM1L recruitment receptors, phosphorylation events, ubiquitin turnover, and isoform composition are integrated to set fission rate at specific organelles and tissues in mammals remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model linking assembly, GTP hydrolysis, and receptor occupancy to fission output\", \"Mammalian counterpart of the Pex27 peroxisomal receptor not identified in this corpus\", \"E3 ligase generating the degron antagonized by USP3 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 26, 30, 33]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9, 26, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 22, 24, 38]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [6, 20, 35]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 13, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6, 20, 35]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 23, 31, 34]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 18, 20, 22, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTFP1\", \"PEX27\", \"RVS167\", \"MVP1\", \"SQSTM1\", \"USP3\", \"CHC1\", \"ATG9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}