{"gene":"MYO19","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2009,"finding":"MYO19 is a novel myosin whose tail domain (C-terminal) is necessary and sufficient for mitochondrial localization. Full-length GFP-MYO19 drives actin-dependent continuous mitochondrial movement, and expressing the tail alone in CAD cells decreases mitochondrial run lengths in neurites.","method":"GFP-fusion deletion analysis, live fluorescence imaging, latrunculin B treatment, antibody detection of endogenous protein","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — deletion mapping with functional readout replicated across cell lines, actin-dependence confirmed by pharmacological inhibition, founding mechanistic characterization","pmids":["19932026"],"is_preprint":false},{"year":2014,"finding":"MYO19 localizes to mitochondria during cell division, and its depletion causes asymmetric partitioning of mitochondria to daughter cells, inappropriate movement of mitochondria to spindle poles in anaphase, and stochastic cytokinesis failure that can be rescued by reducing mitochondrial fusion.","method":"siRNA knockdown, high-content live-imaging screen, RNAi epistasis with mitochondrial fission/fusion modulators","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with live imaging, genetic epistasis via fusion/fission modulation rescuing the cytokinesis phenotype, replicated observations","pmids":["25447992"],"is_preprint":false},{"year":2015,"finding":"MYO19 is stably anchored to the outer mitochondrial membrane (OMM) via a 30–45-residue motif within its tail, and this OMM-anchored motor drives mitochondrial localization to the tips of starvation-induced filopodia.","method":"RNAi knockdown, ectopic expression of GFP-tagged truncations, subcellular fractionation/localization assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping by truncation series, RNAi loss-of-function with specific filopodia phenotype, two orthogonal methods in one study","pmids":["26659663"],"is_preprint":false},{"year":2016,"finding":"Positively charged residues R882 and K883 within an 83-amino-acid minimal binding region of the MyMOMA domain are essential for MYO19 localization to the mitochondrial outer membrane; mutating these residues redirects MYO19 to the endoplasmic reticulum. Membrane-bound MYO19 shows slow dissociation kinetics from both membranes as assessed by PARF.","method":"Alanine-scanning mutagenesis of GFP-MyMOMA truncations, FRAP, permeabilization-activated reduction in fluorescence (PARF)","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of specific residues combined with FRAP and PARF kinetic assays, multiple orthogonal methods","pmids":["27126804"],"is_preprint":false},{"year":2017,"finding":"Reactive oxygen species (ROS) mimic and mediate glucose-starvation-induced localization of MYO19-positive mitochondria to filopodia tips. A class-specific tryptophan in the MYO19 motor domain is required for this function; back-to-consensus mutation of this residue severely reduces the duty ratio of the purified motor domain, demonstrating that MYO19's unique motor kinetics are necessary for mitochondrial transport to filopodia.","method":"Live fluorescence time-lapse microscopy, ROS treatment, site-directed mutagenesis, in vitro ATPase kinetics of purified motor domain","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with in vitro kinetic characterization of purified motor and cell-based phenotypic rescue, two orthogonal methods","pmids":["28912530"],"is_preprint":false},{"year":2017,"finding":"Purified MYO19 motor domain (Myo19-3IQ) has a high duty ratio driven by slow ADP isomerization and ADP release as rate-limiting steps of its ATPase cycle, and its motility may be regulated by the local ATP/ADP ratio; the predicted duty ratio suggests multiple MYO19 motors are needed for processive transport.","method":"Transient kinetics (stopped-flow), in vitro ATPase assays on purified Myo19-3IQ expressed in human cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with transient kinetics and multiple ATPase measurements on purified protein","pmids":["28912602"],"is_preprint":false},{"year":2019,"finding":"The MYO19 MyMOMA domain mediates two distinct mitochondrial-targeting mechanisms: (1) membrane insertion via a conserved motif with slow exchange kinetics, and (2) interaction with the mitochondrial GTPase Miro2 that enhances localization in a nucleotide-state-dependent manner. Conserved charged residues in MYO19 and in the switch I/II regions of Miro2 are required for this interaction.","method":"Promiscuous biotinylation (BioID), GFP-fragment co-expression recruitment assay, site-directed mutagenesis of MYO19 and Miro2, FRAP, PARF","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (BioID, mutagenesis, FRAP/PARF) in one study identifying two mechanistically distinct targeting modes","pmids":["31479585"],"is_preprint":false},{"year":2021,"finding":"MYO19 competes with microtubule-motor adaptors for binding to outer mitochondrial membrane GTPases Miro1 and Miro2. In MYO19-deficient HEK293T cells, mitochondria fail to fragment at mitosis, are partitioned asymmetrically, show impaired respiratory function and elevated ROS, and cells display defects in cytokinesis and focal adhesion regulation. MYO19 also regulates mitochondrially associated levels of Drp1, dynactin, and TRAK1 at prometaphase.","method":"CRISPR/Cas9 knockout of MYO19 in HEK293T cells, live imaging, Western blot, ROS and respiratory assays, focal adhesion analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple orthogonal functional readouts (respiration, ROS, cell division, adhesion) and molecular-level analysis of Miro/Drp1/TRAK1","pmids":["34013964"],"is_preprint":false},{"year":2023,"finding":"MYO19 promotes mitochondrial fission by tethering mitochondria to ER-associated actin at mitochondria-ER contact sites. This function requires ATPase activity and strong actin binding (but not the working stroke per se), depends on the ER formin INF2 (CAAX isoform) and Spire1C for local actin polymerization, and is mediated through metaxins that control MYO19 dispersal on mitochondria. MYO19 depletion reduces mitochondria-ER contact site frequency as measured by split-luciferase complementation.","method":"MYO19 knockdown/overexpression, ATPase-dead and working-stroke mutants, super-resolution imaging, split-luciferase ER-mitochondria contact assay, siRNA depletion of INF2/Spire1C/metaxins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of catalytic residues, super-resolution imaging, split-luciferase contact-site assay, epistasis with actin nucleators, multiple orthogonal methods","pmids":["36744380"],"is_preprint":false},{"year":2024,"finding":"MYL9 (myosin light chain 9) physically binds to MYO19 as demonstrated by co-immunoprecipitation and GST pull-down assay, and this interaction suppresses MYO19-driven cell migration and EMT marker expression in NSCLC cells.","method":"Co-immunoprecipitation, GST pull-down, scratch wound healing assay, Western blot for EMT markers, rescue overexpression experiments","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and GST pull-down confirming direct binding, functional rescue experiment, single lab","pmids":["39437553"],"is_preprint":false},{"year":2024,"finding":"MYO19 knockdown elevates ACSL4 and reduces SLC7A11, sensitizing lung squamous cell carcinoma cells to RSL3-induced ferroptosis; re-expression of MYO19 partially reverses these changes, placing MYO19 upstream of ferroptosis regulators.","method":"MYO19 knockdown/overexpression, RSL3 ferroptosis induction, Western blot for ACSL4/SLC7A11, MDA/GSH measurement","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown/overexpression approach with Western blot readout, no direct mechanistic link established","pmids":["41568382"],"is_preprint":false},{"year":2026,"finding":"Proximity-labeling (TurboID) mass spectrometry reveals that MYO19 associates differentially with functional protein clusters during interphase vs. prometaphase, including mitochondrial trafficking, ER-mitochondria contact site, and MINOS/CIOS complexes. Miro2 stabilizes MYO19 at the OMM in a manner dependent on the nucleotide state of Miro2's N-terminal GTPase domain.","method":"TurboID proximity biotinylation followed by mass spectrometry, Miro2 GTPase-dead mutant (T18N) analysis","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics with GTPase mutant validation, single lab, mass spectrometry-based interactome","pmids":["42102968"],"is_preprint":false},{"year":2025,"finding":"EGF stimulation increases cytosolic calcium, which weakens Kif5B-mediated mitochondrial transport and makes MYO19 the primary transporter driving mitochondria to filopodia tips. Mitochondrial calcium uptake through the MCU channel is required for MYO19-dependent mitochondrial redistribution and filopodia extension.","method":"Live fluorescence imaging, calcium chelation, MCU inhibition, Kif5B and MYO19 knockdown, EGF stimulation of A431 cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, loss-of-function with imaging readout but no in vitro mechanistic validation of calcium effect on MYO19 directly","pmids":[],"is_preprint":true},{"year":2024,"finding":"A specialized subset of mitochondria in the cell periphery (termed METEORs) is enriched for MYO19, which promotes their trafficking to a subset of filopodia. Eliminating mitochondria from filopodia impairs cellular motility.","method":"Fluorescence imaging of mitochondrial markers (MICOS, MCU, MYO19-GFP), filopodia length correlation analysis, mitochondria depletion from filopodia with motility assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, imaging-based localization with functional motility readout, single lab, no mechanistic dissection of MYO19 specifically","pmids":[],"is_preprint":true}],"current_model":"MYO19 is a high-duty-ratio, actin-based myosin motor that is stably anchored to the outer mitochondrial membrane (OMM) via positively charged residues (R882/K883) in its MyMOMA tail domain, with additional OMM targeting mediated through nucleotide-state-dependent binding to the GTPase Miro2 (facilitated by metaxins); as a motor, MYO19 drives actin-dependent mitochondrial motility—transporting mitochondria to filopodia tips in response to ROS/starvation/EGF signals and tethering mitochondria to ER-associated actin (polymerized by INF2-CAAX and Spire1C) at ER-mitochondria contact sites to promote Drp1-mediated fission—and coordinates with microtubule-based motors (competing via Miro) to ensure symmetric mitochondrial partitioning during cytokinesis, with its unique motor kinetics (slow ADP release, high duty ratio) being essential for these transport functions."},"narrative":{"mechanistic_narrative":"MYO19 is an actin-based myosin motor that is stably anchored to the outer mitochondrial membrane and drives actin-dependent mitochondrial motility and positioning [PMID:19932026, PMID:26659663]. Membrane targeting is mediated by its C-terminal MyMOMA tail through two distinct mechanisms: direct insertion into the outer mitochondrial membrane via positively charged residues R882/K883 (whose mutation redirects the protein to the ER), and a nucleotide-state-dependent interaction with the mitochondrial GTPase Miro2 that stabilizes MYO19 at the membrane [PMID:27126804, PMID:31479585, PMID:42102968]. Both anchoring modes display slow membrane dissociation kinetics, and the motor itself is a high-duty-ratio enzyme limited by slow ADP isomerization and ADP release; these kinetics, including a class-specific motor-domain tryptophan, are required for transporting mitochondria to the tips of filopodia in response to ROS and glucose-starvation signals [PMID:27126804, PMID:28912530, PMID:28912602]. At ER–mitochondria contact sites, MYO19 tethers mitochondria to ER-associated actin polymerized by the formin INF2-CAAX and Spire1C—a function requiring ATPase activity and strong actin binding and controlled by metaxins—thereby promoting Drp1-mediated mitochondrial fission [PMID:36744380]. During cell division MYO19 ensures symmetric mitochondrial partitioning to daughter cells; it competes with microtubule-motor adaptors for binding to Miro1/Miro2 and regulates mitochondrial levels of Drp1, dynactin, and TRAK1, with its loss causing mitotic fission failure, asymmetric partitioning, impaired respiration, elevated ROS, and cytokinesis defects [PMID:25447992, PMID:34013964]. MYO19 also physically binds the myosin light chain MYL9 [PMID:39437553].","teleology":[{"year":2009,"claim":"Establishing whether a dedicated motor links mitochondria to actin, this work identified MYO19 as a myosin whose tail is necessary and sufficient for mitochondrial localization and drives actin-dependent organelle movement.","evidence":"GFP-fusion deletion analysis with live imaging and latrunculin B treatment in CAD cells","pmids":["19932026"],"confidence":"High","gaps":["Did not define the molecular anchor on the membrane","Motor kinetics uncharacterized"]},{"year":2014,"claim":"Addressing how mitochondria are inherited during division, depletion showed MYO19 is required for symmetric mitochondrial partitioning and cytokinesis completion, linking the motor to mitotic organelle distribution.","evidence":"siRNA knockdown with high-content live imaging and epistasis with fission/fusion modulators","pmids":["25447992"],"confidence":"High","gaps":["Molecular receptor for MYO19 at the OMM still unknown","Mechanism of competition with spindle-directed transport not defined"]},{"year":2015,"claim":"To localize the anchoring activity, a 30–45 residue tail motif was shown to stably attach MYO19 to the OMM and to direct mitochondria to starvation-induced filopodia tips.","evidence":"RNAi, GFP-truncation expression, and subcellular fractionation","pmids":["26659663"],"confidence":"High","gaps":["Specific anchoring residues not yet identified","Whether anchoring is via lipid or protein partner unresolved"]},{"year":2016,"claim":"Pinpointing the membrane-insertion determinant, alanine scanning identified R882/K883 as essential charged residues whose mutation redirects MYO19 to the ER, and kinetic assays showed slow membrane dissociation.","evidence":"Alanine-scanning mutagenesis of GFP-MyMOMA truncations with FRAP and PARF","pmids":["27126804"],"confidence":"High","gaps":["Did not establish whether a protein receptor also contributes","Lipid specificity of the insertion motif not defined"]},{"year":2017,"claim":"Connecting motor enzymology to function, purified-motor kinetics and mutagenesis showed MYO19's high duty ratio (slow ADP isomerization/release) and a class-specific tryptophan are required for ROS- and starvation-driven mitochondrial transport to filopodia.","evidence":"Stopped-flow transient kinetics and ATPase assays on purified Myo19-3IQ plus site-directed mutagenesis and live imaging","pmids":["28912530","28912602"],"confidence":"High","gaps":["Number of motors needed for processive transport inferred, not directly measured","How ROS signaling engages the motor mechanistically unresolved"]},{"year":2019,"claim":"Resolving the dual nature of OMM targeting, the MyMOMA domain was shown to use both membrane insertion and a nucleotide-state-dependent interaction with the GTPase Miro2 requiring conserved charged residues in both proteins.","evidence":"BioID, GFP-fragment recruitment assay, mutagenesis of MYO19 and Miro2, FRAP and PARF","pmids":["31479585"],"confidence":"High","gaps":["Relative contribution of the two targeting modes in vivo not quantified","Role of metaxins not yet implicated"]},{"year":2021,"claim":"Defining MYO19's role in mitotic mitochondrial dynamics, knockout showed it competes with microtubule-motor adaptors for Miro1/Miro2 and regulates Drp1/dynactin/TRAK1 levels, with loss causing fission failure, asymmetric partitioning, impaired respiration, and elevated ROS.","evidence":"CRISPR/Cas9 knockout in HEK293T with live imaging, Western blot, respiratory/ROS assays, and focal adhesion analysis","pmids":["34013964"],"confidence":"High","gaps":["Direct biochemical competition with TRAK adaptors not reconstituted","Mechanism linking MYO19 loss to focal adhesion defects unclear"]},{"year":2023,"claim":"Establishing how MYO19 promotes fission, it was shown to tether mitochondria to ER-associated actin at contact sites in an ATPase- and actin-binding-dependent manner requiring INF2-CAAX, Spire1C, and metaxins.","evidence":"ATPase-dead and working-stroke mutants, super-resolution imaging, split-luciferase ER-mitochondria contact assay, and siRNA of actin nucleators/metaxins","pmids":["36744380"],"confidence":"High","gaps":["How metaxins control MYO19 dispersal mechanistically not detailed","Direct interaction between MYO19 and INF2/Spire1C not established"]},{"year":2024,"claim":"Identifying a regulatory binding partner, MYL9 was shown to bind MYO19 directly and suppress MYO19-driven migration and EMT in NSCLC cells.","evidence":"Reciprocal Co-IP, GST pull-down, scratch wound healing, and rescue overexpression","pmids":["39437553"],"confidence":"Medium","gaps":["Single lab without independent replication","Whether MYL9 acts as a regulatory light chain on the motor not biochemically resolved"]},{"year":2024,"claim":"Probing a possible link to cell-death regulation, knockdown placed MYO19 upstream of ferroptosis regulators ACSL4 and SLC7A11 in lung squamous carcinoma cells.","evidence":"Knockdown/overexpression with RSL3 induction, Western blot, and MDA/GSH measurement","pmids":["41568382"],"confidence":"Low","gaps":["No direct mechanistic link between MYO19 and ferroptosis machinery established","Single-lab knockdown/overexpression with indirect readouts"]},{"year":2026,"claim":"Mapping context-dependent interactomes, proximity proteomics revealed MYO19 associates with distinct mitochondrial trafficking, ER-contact, and MICOS/CIOS clusters between interphase and prometaphase, with Miro2 stabilizing MYO19 in a GTPase-state-dependent manner.","evidence":"TurboID proximity biotinylation/mass spectrometry with a Miro2 T18N GTPase-dead mutant","pmids":["42102968"],"confidence":"Medium","gaps":["Proximity associations not validated as direct interactions","Functional consequence of cell-cycle-dependent partner switching not tested"]},{"year":null,"claim":"How upstream signals (ROS, EGF/calcium) are transduced to switch MYO19 between resting and transport-competent states, and how the motor's activity is regulated by light chains and Miro nucleotide cycling in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the autoinhibited or active motor","Direct effect of calcium on MYO19 not demonstrated in vitro","Light-chain regulation of duty ratio uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,4,5,8]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,8]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,7,8]}],"complexes":[],"partners":["MIRO2","MIRO1","INF2","SPIRE1","MYL9","DRP1","TRAK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96H55","full_name":"Unconventional myosin-XIX","aliases":["Myosin head domain-containing protein 1"],"length_aa":970,"mass_kda":109.1,"function":"Actin-based motor molecule with ATPase activity that localizes to the mitochondrion outer membrane (PubMed:19932026, PubMed:23568824, PubMed:25447992). Motor protein that moves towards the plus-end of actin filaments (By similarity). Required for mitochondrial inheritance during mitosis (PubMed:25447992). May be involved in mitochondrial transport or positioning (PubMed:23568824)","subcellular_location":"Mitochondrion outer membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q96H55/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO19","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000278259","cell_line_id":"CID001439","localizations":[{"compartment":"mitochondria","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001439","total_profiled":1310},"omim":[{"mim_id":"617379","title":"MYOSIN XIX; MYO19","url":"https://www.omim.org/entry/617379"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYO19"},"hgnc":{"alias_symbol":["FLJ22865"],"prev_symbol":["MYOHD1"]},"alphafold":{"accession":"Q96H55","domains":[{"cath_id":"1.20.120.720","chopping":"190-416_549-574","consensus_level":"medium","plddt":89.8785,"start":190,"end":574},{"cath_id":"1.20.58.530","chopping":"427-542","consensus_level":"medium","plddt":86.0093,"start":427,"end":542},{"cath_id":"1.20.58","chopping":"661-676_734-804","consensus_level":"medium","plddt":86.63,"start":661,"end":804}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96H55","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96H55-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96H55-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO19","jax_strain_url":"https://www.jax.org/strain/search?query=MYO19"},"sequence":{"accession":"Q96H55","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96H55.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96H55/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96H55"}},"corpus_meta":[{"pmid":"19932026","id":"PMC_19932026","title":"Human Myo19 is a novel myosin that associates with mitochondria.","date":"2009","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/19932026","citation_count":163,"is_preprint":false},{"pmid":"25447992","id":"PMC_25447992","title":"Myo19 ensures symmetric partitioning of mitochondria and coupling of mitochondrial segregation to cell division.","date":"2014","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/25447992","citation_count":74,"is_preprint":false},{"pmid":"26659663","id":"PMC_26659663","title":"Myo19 is an outer mitochondrial membrane motor and effector of starvation-induced filopodia.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/26659663","citation_count":53,"is_preprint":false},{"pmid":"36744380","id":"PMC_36744380","title":"Myo19 tethers mitochondria to endoplasmic reticulum-associated actin to promote mitochondrial fission.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36744380","citation_count":40,"is_preprint":false},{"pmid":"34013964","id":"PMC_34013964","title":"Coordination of mitochondrial and cellular dynamics by the actin-based motor Myo19.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34013964","citation_count":33,"is_preprint":false},{"pmid":"28912530","id":"PMC_28912530","title":"ROS induced distribution of mitochondria to filopodia by Myo19 depends on a class specific tryptophan in the motor domain.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28912530","citation_count":31,"is_preprint":false},{"pmid":"31479585","id":"PMC_31479585","title":"The MyMOMA domain of MYO19 encodes for distinct Miro-dependent and Miro-independent mechanisms of interaction with mitochondrial membranes.","date":"2019","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/31479585","citation_count":30,"is_preprint":false},{"pmid":"28912602","id":"PMC_28912602","title":"Kinetic adaptation of human Myo19 for active mitochondrial transport to growing filopodia tips.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28912602","citation_count":20,"is_preprint":false},{"pmid":"27126804","id":"PMC_27126804","title":"Positively charged residues within the MYO19 MyMOMA domain are essential for proper localization of MYO19 to the mitochondrial outer membrane.","date":"2016","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27126804","citation_count":19,"is_preprint":false},{"pmid":"38615544","id":"PMC_38615544","title":"Bisphenol S impairs mitochondrial function by targeting Myo19/oxidative phosphorylation pathway contributing to axonal and dendritic injury.","date":"2024","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/38615544","citation_count":19,"is_preprint":false},{"pmid":"38279020","id":"PMC_38279020","title":"Loss of Myo19 increases metastasis by enhancing microenvironmental ROS gradient and chemotaxis.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38279020","citation_count":13,"is_preprint":false},{"pmid":"39437553","id":"PMC_39437553","title":"MYL9 binding with MYO19 suppresses epithelial-mesenchymal transition in non-small-cell lung cancer.","date":"2024","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39437553","citation_count":3,"is_preprint":false},{"pmid":"40177064","id":"PMC_40177064","title":"Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway.","date":"2024","source":"Journal of pharmaceutical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/40177064","citation_count":2,"is_preprint":false},{"pmid":"40634996","id":"PMC_40634996","title":"Identification of novel MYO19 variants in neonatal hypertrophic cardiomyopathy: a familial analysis revealing oligogenic contributors to disease severity.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40634996","citation_count":0,"is_preprint":false},{"pmid":"41568382","id":"PMC_41568382","title":"MYO19 is associated with tumor progression, immune evasion, ferroptosis-related signatures in lung squamous cell carcinoma.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41568382","citation_count":0,"is_preprint":false},{"pmid":"42102968","id":"PMC_42102968","title":"Dynamic Proximity Networks of Myosin-19 (Myo19) and its Mitochondrial Receptors Miro2 and Metaxin-3.","date":"2026","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/42102968","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.04.680418","title":"Calcium-Regulated Mitochondria Remodeling by Myo19 is Required for Filopodia Tip-Extension","date":"2025-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.04.680418","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.21.600105","title":"Compositionally unique mitochondria in filopodia support cellular migration","date":"2024-06-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.21.600105","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11508,"output_tokens":3743,"usd":0.045334,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11331,"output_tokens":3915,"usd":0.077265,"stage2_stop_reason":"end_turn"},"total_usd":0.122599,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"MYO19 is a novel myosin whose tail domain (C-terminal) is necessary and sufficient for mitochondrial localization. Full-length GFP-MYO19 drives actin-dependent continuous mitochondrial movement, and expressing the tail alone in CAD cells decreases mitochondrial run lengths in neurites.\",\n      \"method\": \"GFP-fusion deletion analysis, live fluorescence imaging, latrunculin B treatment, antibody detection of endogenous protein\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — deletion mapping with functional readout replicated across cell lines, actin-dependence confirmed by pharmacological inhibition, founding mechanistic characterization\",\n      \"pmids\": [\"19932026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYO19 localizes to mitochondria during cell division, and its depletion causes asymmetric partitioning of mitochondria to daughter cells, inappropriate movement of mitochondria to spindle poles in anaphase, and stochastic cytokinesis failure that can be rescued by reducing mitochondrial fusion.\",\n      \"method\": \"siRNA knockdown, high-content live-imaging screen, RNAi epistasis with mitochondrial fission/fusion modulators\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with live imaging, genetic epistasis via fusion/fission modulation rescuing the cytokinesis phenotype, replicated observations\",\n      \"pmids\": [\"25447992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYO19 is stably anchored to the outer mitochondrial membrane (OMM) via a 30–45-residue motif within its tail, and this OMM-anchored motor drives mitochondrial localization to the tips of starvation-induced filopodia.\",\n      \"method\": \"RNAi knockdown, ectopic expression of GFP-tagged truncations, subcellular fractionation/localization assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by truncation series, RNAi loss-of-function with specific filopodia phenotype, two orthogonal methods in one study\",\n      \"pmids\": [\"26659663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Positively charged residues R882 and K883 within an 83-amino-acid minimal binding region of the MyMOMA domain are essential for MYO19 localization to the mitochondrial outer membrane; mutating these residues redirects MYO19 to the endoplasmic reticulum. Membrane-bound MYO19 shows slow dissociation kinetics from both membranes as assessed by PARF.\",\n      \"method\": \"Alanine-scanning mutagenesis of GFP-MyMOMA truncations, FRAP, permeabilization-activated reduction in fluorescence (PARF)\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of specific residues combined with FRAP and PARF kinetic assays, multiple orthogonal methods\",\n      \"pmids\": [\"27126804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Reactive oxygen species (ROS) mimic and mediate glucose-starvation-induced localization of MYO19-positive mitochondria to filopodia tips. A class-specific tryptophan in the MYO19 motor domain is required for this function; back-to-consensus mutation of this residue severely reduces the duty ratio of the purified motor domain, demonstrating that MYO19's unique motor kinetics are necessary for mitochondrial transport to filopodia.\",\n      \"method\": \"Live fluorescence time-lapse microscopy, ROS treatment, site-directed mutagenesis, in vitro ATPase kinetics of purified motor domain\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with in vitro kinetic characterization of purified motor and cell-based phenotypic rescue, two orthogonal methods\",\n      \"pmids\": [\"28912530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Purified MYO19 motor domain (Myo19-3IQ) has a high duty ratio driven by slow ADP isomerization and ADP release as rate-limiting steps of its ATPase cycle, and its motility may be regulated by the local ATP/ADP ratio; the predicted duty ratio suggests multiple MYO19 motors are needed for processive transport.\",\n      \"method\": \"Transient kinetics (stopped-flow), in vitro ATPase assays on purified Myo19-3IQ expressed in human cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with transient kinetics and multiple ATPase measurements on purified protein\",\n      \"pmids\": [\"28912602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The MYO19 MyMOMA domain mediates two distinct mitochondrial-targeting mechanisms: (1) membrane insertion via a conserved motif with slow exchange kinetics, and (2) interaction with the mitochondrial GTPase Miro2 that enhances localization in a nucleotide-state-dependent manner. Conserved charged residues in MYO19 and in the switch I/II regions of Miro2 are required for this interaction.\",\n      \"method\": \"Promiscuous biotinylation (BioID), GFP-fragment co-expression recruitment assay, site-directed mutagenesis of MYO19 and Miro2, FRAP, PARF\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (BioID, mutagenesis, FRAP/PARF) in one study identifying two mechanistically distinct targeting modes\",\n      \"pmids\": [\"31479585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO19 competes with microtubule-motor adaptors for binding to outer mitochondrial membrane GTPases Miro1 and Miro2. In MYO19-deficient HEK293T cells, mitochondria fail to fragment at mitosis, are partitioned asymmetrically, show impaired respiratory function and elevated ROS, and cells display defects in cytokinesis and focal adhesion regulation. MYO19 also regulates mitochondrially associated levels of Drp1, dynactin, and TRAK1 at prometaphase.\",\n      \"method\": \"CRISPR/Cas9 knockout of MYO19 in HEK293T cells, live imaging, Western blot, ROS and respiratory assays, focal adhesion analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple orthogonal functional readouts (respiration, ROS, cell division, adhesion) and molecular-level analysis of Miro/Drp1/TRAK1\",\n      \"pmids\": [\"34013964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYO19 promotes mitochondrial fission by tethering mitochondria to ER-associated actin at mitochondria-ER contact sites. This function requires ATPase activity and strong actin binding (but not the working stroke per se), depends on the ER formin INF2 (CAAX isoform) and Spire1C for local actin polymerization, and is mediated through metaxins that control MYO19 dispersal on mitochondria. MYO19 depletion reduces mitochondria-ER contact site frequency as measured by split-luciferase complementation.\",\n      \"method\": \"MYO19 knockdown/overexpression, ATPase-dead and working-stroke mutants, super-resolution imaging, split-luciferase ER-mitochondria contact assay, siRNA depletion of INF2/Spire1C/metaxins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of catalytic residues, super-resolution imaging, split-luciferase contact-site assay, epistasis with actin nucleators, multiple orthogonal methods\",\n      \"pmids\": [\"36744380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYL9 (myosin light chain 9) physically binds to MYO19 as demonstrated by co-immunoprecipitation and GST pull-down assay, and this interaction suppresses MYO19-driven cell migration and EMT marker expression in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, scratch wound healing assay, Western blot for EMT markers, rescue overexpression experiments\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and GST pull-down confirming direct binding, functional rescue experiment, single lab\",\n      \"pmids\": [\"39437553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO19 knockdown elevates ACSL4 and reduces SLC7A11, sensitizing lung squamous cell carcinoma cells to RSL3-induced ferroptosis; re-expression of MYO19 partially reverses these changes, placing MYO19 upstream of ferroptosis regulators.\",\n      \"method\": \"MYO19 knockdown/overexpression, RSL3 ferroptosis induction, Western blot for ACSL4/SLC7A11, MDA/GSH measurement\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown/overexpression approach with Western blot readout, no direct mechanistic link established\",\n      \"pmids\": [\"41568382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Proximity-labeling (TurboID) mass spectrometry reveals that MYO19 associates differentially with functional protein clusters during interphase vs. prometaphase, including mitochondrial trafficking, ER-mitochondria contact site, and MINOS/CIOS complexes. Miro2 stabilizes MYO19 at the OMM in a manner dependent on the nucleotide state of Miro2's N-terminal GTPase domain.\",\n      \"method\": \"TurboID proximity biotinylation followed by mass spectrometry, Miro2 GTPase-dead mutant (T18N) analysis\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics with GTPase mutant validation, single lab, mass spectrometry-based interactome\",\n      \"pmids\": [\"42102968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EGF stimulation increases cytosolic calcium, which weakens Kif5B-mediated mitochondrial transport and makes MYO19 the primary transporter driving mitochondria to filopodia tips. Mitochondrial calcium uptake through the MCU channel is required for MYO19-dependent mitochondrial redistribution and filopodia extension.\",\n      \"method\": \"Live fluorescence imaging, calcium chelation, MCU inhibition, Kif5B and MYO19 knockdown, EGF stimulation of A431 cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, loss-of-function with imaging readout but no in vitro mechanistic validation of calcium effect on MYO19 directly\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A specialized subset of mitochondria in the cell periphery (termed METEORs) is enriched for MYO19, which promotes their trafficking to a subset of filopodia. Eliminating mitochondria from filopodia impairs cellular motility.\",\n      \"method\": \"Fluorescence imaging of mitochondrial markers (MICOS, MCU, MYO19-GFP), filopodia length correlation analysis, mitochondria depletion from filopodia with motility assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, imaging-based localization with functional motility readout, single lab, no mechanistic dissection of MYO19 specifically\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MYO19 is a high-duty-ratio, actin-based myosin motor that is stably anchored to the outer mitochondrial membrane (OMM) via positively charged residues (R882/K883) in its MyMOMA tail domain, with additional OMM targeting mediated through nucleotide-state-dependent binding to the GTPase Miro2 (facilitated by metaxins); as a motor, MYO19 drives actin-dependent mitochondrial motility—transporting mitochondria to filopodia tips in response to ROS/starvation/EGF signals and tethering mitochondria to ER-associated actin (polymerized by INF2-CAAX and Spire1C) at ER-mitochondria contact sites to promote Drp1-mediated fission—and coordinates with microtubule-based motors (competing via Miro) to ensure symmetric mitochondrial partitioning during cytokinesis, with its unique motor kinetics (slow ADP release, high duty ratio) being essential for these transport functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO19 is an actin-based myosin motor that is stably anchored to the outer mitochondrial membrane and drives actin-dependent mitochondrial motility and positioning [#0, #2]. Membrane targeting is mediated by its C-terminal MyMOMA tail through two distinct mechanisms: direct insertion into the outer mitochondrial membrane via positively charged residues R882/K883 (whose mutation redirects the protein to the ER), and a nucleotide-state-dependent interaction with the mitochondrial GTPase Miro2 that stabilizes MYO19 at the membrane [#3, #6, #11]. Both anchoring modes display slow membrane dissociation kinetics, and the motor itself is a high-duty-ratio enzyme limited by slow ADP isomerization and ADP release; these kinetics, including a class-specific motor-domain tryptophan, are required for transporting mitochondria to the tips of filopodia in response to ROS and glucose-starvation signals [#3, #4, #5]. At ER–mitochondria contact sites, MYO19 tethers mitochondria to ER-associated actin polymerized by the formin INF2-CAAX and Spire1C—a function requiring ATPase activity and strong actin binding and controlled by metaxins—thereby promoting Drp1-mediated mitochondrial fission [#8]. During cell division MYO19 ensures symmetric mitochondrial partitioning to daughter cells; it competes with microtubule-motor adaptors for binding to Miro1/Miro2 and regulates mitochondrial levels of Drp1, dynactin, and TRAK1, with its loss causing mitotic fission failure, asymmetric partitioning, impaired respiration, elevated ROS, and cytokinesis defects [#1, #7]. MYO19 also physically binds the myosin light chain MYL9 [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing whether a dedicated motor links mitochondria to actin, this work identified MYO19 as a myosin whose tail is necessary and sufficient for mitochondrial localization and drives actin-dependent organelle movement.\",\n      \"evidence\": \"GFP-fusion deletion analysis with live imaging and latrunculin B treatment in CAD cells\",\n      \"pmids\": [\"19932026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular anchor on the membrane\", \"Motor kinetics uncharacterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Addressing how mitochondria are inherited during division, depletion showed MYO19 is required for symmetric mitochondrial partitioning and cytokinesis completion, linking the motor to mitotic organelle distribution.\",\n      \"evidence\": \"siRNA knockdown with high-content live imaging and epistasis with fission/fusion modulators\",\n      \"pmids\": [\"25447992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular receptor for MYO19 at the OMM still unknown\", \"Mechanism of competition with spindle-directed transport not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To localize the anchoring activity, a 30–45 residue tail motif was shown to stably attach MYO19 to the OMM and to direct mitochondria to starvation-induced filopodia tips.\",\n      \"evidence\": \"RNAi, GFP-truncation expression, and subcellular fractionation\",\n      \"pmids\": [\"26659663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific anchoring residues not yet identified\", \"Whether anchoring is via lipid or protein partner unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pinpointing the membrane-insertion determinant, alanine scanning identified R882/K883 as essential charged residues whose mutation redirects MYO19 to the ER, and kinetic assays showed slow membrane dissociation.\",\n      \"evidence\": \"Alanine-scanning mutagenesis of GFP-MyMOMA truncations with FRAP and PARF\",\n      \"pmids\": [\"27126804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether a protein receptor also contributes\", \"Lipid specificity of the insertion motif not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connecting motor enzymology to function, purified-motor kinetics and mutagenesis showed MYO19's high duty ratio (slow ADP isomerization/release) and a class-specific tryptophan are required for ROS- and starvation-driven mitochondrial transport to filopodia.\",\n      \"evidence\": \"Stopped-flow transient kinetics and ATPase assays on purified Myo19-3IQ plus site-directed mutagenesis and live imaging\",\n      \"pmids\": [\"28912530\", \"28912602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Number of motors needed for processive transport inferred, not directly measured\", \"How ROS signaling engages the motor mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolving the dual nature of OMM targeting, the MyMOMA domain was shown to use both membrane insertion and a nucleotide-state-dependent interaction with the GTPase Miro2 requiring conserved charged residues in both proteins.\",\n      \"evidence\": \"BioID, GFP-fragment recruitment assay, mutagenesis of MYO19 and Miro2, FRAP and PARF\",\n      \"pmids\": [\"31479585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of the two targeting modes in vivo not quantified\", \"Role of metaxins not yet implicated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining MYO19's role in mitotic mitochondrial dynamics, knockout showed it competes with microtubule-motor adaptors for Miro1/Miro2 and regulates Drp1/dynactin/TRAK1 levels, with loss causing fission failure, asymmetric partitioning, impaired respiration, and elevated ROS.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HEK293T with live imaging, Western blot, respiratory/ROS assays, and focal adhesion analysis\",\n      \"pmids\": [\"34013964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical competition with TRAK adaptors not reconstituted\", \"Mechanism linking MYO19 loss to focal adhesion defects unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing how MYO19 promotes fission, it was shown to tether mitochondria to ER-associated actin at contact sites in an ATPase- and actin-binding-dependent manner requiring INF2-CAAX, Spire1C, and metaxins.\",\n      \"evidence\": \"ATPase-dead and working-stroke mutants, super-resolution imaging, split-luciferase ER-mitochondria contact assay, and siRNA of actin nucleators/metaxins\",\n      \"pmids\": [\"36744380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How metaxins control MYO19 dispersal mechanistically not detailed\", \"Direct interaction between MYO19 and INF2/Spire1C not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a regulatory binding partner, MYL9 was shown to bind MYO19 directly and suppress MYO19-driven migration and EMT in NSCLC cells.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pull-down, scratch wound healing, and rescue overexpression\",\n      \"pmids\": [\"39437553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Whether MYL9 acts as a regulatory light chain on the motor not biochemically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Probing a possible link to cell-death regulation, knockdown placed MYO19 upstream of ferroptosis regulators ACSL4 and SLC7A11 in lung squamous carcinoma cells.\",\n      \"evidence\": \"Knockdown/overexpression with RSL3 induction, Western blot, and MDA/GSH measurement\",\n      \"pmids\": [\"41568382\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic link between MYO19 and ferroptosis machinery established\", \"Single-lab knockdown/overexpression with indirect readouts\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapping context-dependent interactomes, proximity proteomics revealed MYO19 associates with distinct mitochondrial trafficking, ER-contact, and MICOS/CIOS clusters between interphase and prometaphase, with Miro2 stabilizing MYO19 in a GTPase-state-dependent manner.\",\n      \"evidence\": \"TurboID proximity biotinylation/mass spectrometry with a Miro2 T18N GTPase-dead mutant\",\n      \"pmids\": [\"42102968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proximity associations not validated as direct interactions\", \"Functional consequence of cell-cycle-dependent partner switching not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream signals (ROS, EGF/calcium) are transduced to switch MYO19 between resting and transport-competent states, and how the motor's activity is regulated by light chains and Miro nucleotide cycling in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the autoinhibited or active motor\", \"Direct effect of calcium on MYO19 not demonstrated in vitro\", \"Light-chain regulation of duty ratio uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 4, 5, 8]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MIRO2\", \"MIRO1\", \"INF2\", \"SPIRE1\", \"MYL9\", \"DRP1\", \"TRAK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}