{"gene":"VPS13D","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2021,"finding":"VPS13D is recruited to mitochondria and peroxisomes by the outer mitochondrial membrane GTPase Miro (the Gem1 orthologue), and VPS13D in turn binds the ER via VAP proteins, thereby forming an ER-mitochondria/peroxisome lipid conduit at membrane contact sites.","method":"Co-immunoprecipitation, VAP-binding assays, subcellular fractionation, live-cell imaging; knockdown/rescue experiments in mammalian cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies (Miro recruits VPS13D; VPS13D binds VAP), multiple orthogonal methods, functionally validated ER-organelle tethering","pmids":["33891013"],"is_preprint":false},{"year":2018,"finding":"The UBA domain of Vps13D binds K63-linked ubiquitin chains; loss of the UBA domain causes defects in mitochondrial size, mitochondrial clearance, and semi-lethality in Drosophila, placing VPS13D downstream of DRP1 and MFF in mitochondrial fission and mitophagy.","method":"Ubiquitin-binding pulldown assay with K63 chains; UBA-domain deletion genetics in Drosophila; DRP1/MFF phosphorylation and mitochondrial association assays; suppression by reduced mitochondrial fusion gene function","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitin-binding assay plus domain-deletion genetics, epistasis with DRP1/MFF, suppression by fusion gene loss; single lab but multiple orthogonal methods","pmids":["29307555"],"is_preprint":false},{"year":2021,"finding":"VPS13D cooperates with the ESCRT-I protein TSG101 to remodel lipid-droplet membranes; the lipid-transfer domain of human VPS13D binds glycerophospholipids and fatty acids in vitro, and the VPS13 adaptor-binding domain of VPS13D directly interacts with TSG101. Together they facilitate fatty acid transfer from lipid droplets to mitochondria at mitochondria-LD membrane contact sites.","method":"In vitro lipid-binding assay (glycerophospholipids/FAs); co-IP (VPS13D–TSG101 interaction); LD membrane remodeling assay; siRNA depletion of VPS13D, TSG101, or ESCRT-III with FA trafficking readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro lipid-binding reconstitution, direct protein interaction, functional trafficking assay with RNAi, multiple orthogonal methods in one study","pmids":["33623047"],"is_preprint":false},{"year":2021,"finding":"VPS13D negatively regulates ER-mitochondria membrane contact sites (MCSs): VPS13D suppression causes extensive ER-mitochondria tethering that is rescued by co-suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with VCP/p97 and is required for the stability of p97, which controls VAPB levels at contacts.","method":"siRNA knockdown; co-IP (VPS13D–VCP/p97); quantitative MCS imaging (ER-mitochondria proximity assays); rescue by VAPB/PTPIP51 co-suppression","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction (Co-IP), functional rescue, multiple readouts; single lab","pmids":["34133214"],"is_preprint":false},{"year":2021,"finding":"Vps13D functions in a Pink1-dependent but Parkin/Park-independent mitophagy pathway in Drosophila: loss of vps13d and pink1 each cause equivalent defects in Atg8a localization, ubiquitin localization, and mitochondrial clearance, whereas loss of park does not phenocopy vps13d and contributes to mitochondrial clearance through a parallel pathway.","method":"Drosophila genetic epistasis (vps13d, pink1, park single and double mutants); autophagy reporter assays (Atg8a and ubiquitin localization); mitochondrial morphology imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis with multiple alleles, autophagy reporters, and morphological readouts; clearly dissects pathway position","pmids":["34459871"],"is_preprint":false},{"year":2021,"finding":"Vps13D functions downstream of Vmp1 and upstream of Marf/Mfn2 in regulating ER-mitochondria contact, mitochondrial fusion, and autophagy; vmp1 mutants phenocopy vps13d, loss of marf/MFN2 suppresses vps13d phenotypes including increased ER-mitochondria contact, and this pathway is conserved in human patient fibroblasts.","method":"Drosophila genetic epistasis (vmp1, vps13d, marf/MFN2 single and double mutants); ER-mitochondria contact-site quantification by imaging; patient fibroblast validation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis replicated in fly and human cells, suppression rescue, multiple readouts across two systems","pmids":["34019822"],"is_preprint":false},{"year":2021,"finding":"VPS13D loss leads to peroxisome biogenesis defects (partial or complete peroxisome loss) in HeLa cells, transformed cell lines, and patient fibroblasts, identifying VPS13D as a regulator of peroxisome biogenesis distinct from the mitochondrial phenotypes of other VPS13 paralogs.","method":"CRISPR knockout of each VPS13 gene in HeLa cells; immunofluorescence and marker quantification for peroxisomes; patient fibroblast analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype replicated across multiple cell lines and patient fibroblasts, systematic comparison across VPS13 family","pmids":["33891012"],"is_preprint":false},{"year":2021,"finding":"Vps13D has separable functions in mitochondrial fission and phagophore elongation in Drosophila neurons: Vps13D loss (unlike Drp1 loss) causes accumulation of compromised mitochondria within stalled mito-phagophores, demonstrating a role for Vps13D in completing mitophagy downstream of its role in fission.","method":"Drosophila neuronal genetics (vps13D and drp1 mutants); mitophagy reporter assays; autophagy intermediate characterization by imaging; epistasis analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection with reporters in neurons, distinct from Drp1 by multiple assays; single lab","pmids":["34383748"],"is_preprint":false},{"year":2021,"finding":"VPS13D interacts with Snhg1 lncRNA to promote IL-7Rα membrane localization in CD8 T cells, facilitating IL-7 signaling and memory CD8 T cell differentiation via STAT5-BCL-2 and STAT3-TCF1-Blimp1 axes.","method":"Snhg1-Vps13D interaction assay; IL-7Rα membrane localization by imaging; knockout/knockdown functional assays in CD8 T cell differentiation; signaling pathway analysis","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — protein-lncRNA interaction with functional downstream readout, but single lab and the mechanistic specificity to VPS13D protein function is partial","pmids":["33758164"],"is_preprint":false},{"year":2020,"finding":"A disease-causing VPS13D missense mutation maps to the conserved asparagine in repeat 6 of the VAB (Vps13 Adaptor Binding) domain; when modeled in yeast Vps13, this mutation blocks adaptor binding and Vps13 membrane recruitment, demonstrating that the VAB domain's last two repeats form the core adaptor-binding site.","method":"Systematic mutagenesis of yeast Vps13 VAB domain repeats; adaptor-binding assays; membrane recruitment assays; modeling of human VPS13D disease mutation in yeast","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis with direct binding and localization readouts, disease variant modeled and tested; single lab but rigorous mechanistic dissection","pmids":["31943017"],"is_preprint":false},{"year":2018,"finding":"Knockdown or knockout of Vps13D in Drosophila neurons causes changes in mitochondrial morphology and impaired mitochondrial distribution along axons; patient fibroblasts show altered mitochondrial morphology and reduced energy production, establishing VPS13D as required for mitochondrial homeostasis in neurons.","method":"Drosophila neuron-specific Vps13D knockdown/knockout; mitochondrial morphology and axonal distribution imaging; patient-derived fibroblast functional assays (energy production measurements)","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO in neurons plus patient fibroblast validation, multiple readouts; two independent groups reporting similar phenotypes","pmids":["29604224"],"is_preprint":false},{"year":2025,"finding":"CRISPR/Cas9-engineered SCAR4 missense mutations and C-terminal deletion in C. elegans vps-13D cause locomotion defects, abnormal mitochondrial morphology, and increased mitochondrial unfolded protein response (UPRmt), confirming conserved roles for VPS13D in mitochondrial proteostasis.","method":"CRISPR/Cas9 knock-in of patient missense mutations and C-terminal deletion in C. elegans; locomotion behavioral assays; mitochondrial morphology imaging; UPRmt reporter assays","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knock-in of specific disease alleles, multiple orthogonal phenotypic readouts; single study","pmids":["39957248"],"is_preprint":false},{"year":2023,"finding":"Adult-onset neuronal knockdown of Vps13D in Drosophila causes accumulation of mitophagy intermediates, progressive locomotor deficits, early lethality, and brain vacuolization, demonstrating that continuous VPS13D function in adult neurons is required to prevent neurodegeneration.","method":"Temporally controlled Gal4/UAS-Gal80-DD system for adult-onset Vps13D RNAi in Drosophila neurons; locomotion assays; histology for brain vacuolization; mitophagy reporter assays","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean temporal knockdown with multiple phenotypic readouts; single lab, single study","pmids":["37457002"],"is_preprint":false}],"current_model":"VPS13D is a large cytoplasmic lipid transfer protein that localizes to ER-mitochondria and ER-peroxisome membrane contact sites by binding the ER via VAP proteins and being recruited to mitochondria/peroxisomes by the GTPase Miro; at these contacts it transfers glycerophospholipids and fatty acids between organelles, and at lipid-droplet–mitochondria contacts it cooperates with the ESCRT-I protein TSG101 to remodel LD membranes for fatty acid transfer. VPS13D also negatively regulates ER-mitochondria tethering through interaction with VCP/p97 to control VAPB levels, binds K63-linked ubiquitin chains via its UBA domain to couple mitochondrial fission (acting downstream of DRP1/MFF) with autophagic clearance, and promotes mitophagy in a Pink1-dependent, Parkin-independent pathway by regulating Atg8a and ubiquitin localization and phagophore elongation; it additionally acts downstream of Vmp1 and upstream of Mfn2/Marf to control ER-mitochondria contact and mitochondrial fusion, and is required for peroxisome biogenesis. A conserved VAB-domain asparagine in repeat 6 is essential for adaptor binding and organelle targeting, and disease-causing mutations disrupt this site."},"narrative":{"mechanistic_narrative":"VPS13D is a large lipid transfer protein that operates at inter-organelle membrane contact sites to control mitochondrial homeostasis, lipid distribution, and mitophagy [PMID:33891013, PMID:33623047]. It bridges the ER to mitochondria and peroxisomes by binding the ER via VAP proteins while being recruited to mitochondria/peroxisomes through the outer-membrane GTPase Miro, forming a conduit through which its lipid-transfer domain moves glycerophospholipids and fatty acids [PMID:33891013, PMID:33623047]. At mitochondria–lipid droplet contacts it acts with the ESCRT-I protein TSG101 — which it binds through its VPS13 adaptor-binding domain — to remodel lipid-droplet membranes and route fatty acids to mitochondria [PMID:33623047]. VPS13D also negatively regulates ER–mitochondria tethering by interacting with VCP/p97 to control VAPB levels, with VAPB/PTPIP51 co-suppression reversing the excessive tethering caused by VPS13D loss [PMID:34133214]. A second function couples mitochondrial fission to clearance: its UBA domain binds K63-linked ubiquitin chains, and acting downstream of DRP1/MFF it is required to complete mitophagy through a Pink1-dependent, Parkin-independent pathway that controls Atg8a and ubiquitin localization and phagophore elongation, operating downstream of Vmp1 and upstream of Mfn2/Marf [PMID:29307555, PMID:34459871, PMID:34019822, PMID:34383748]. VPS13D is additionally required for peroxisome biogenesis, distinguishing it from other VPS13 paralogs [PMID:33891012]. Organelle targeting depends on a conserved asparagine in repeat 6 of the VAB adaptor-binding domain, and disease-causing missense mutations disrupt this adaptor-binding site, causing impaired mitochondrial morphology, energy production, and neurodegeneration [PMID:31943017, PMID:29604224, PMID:39957248].","teleology":[{"year":2018,"claim":"Established VPS13D as required for neuronal mitochondrial homeostasis and linked it to human disease, defining the cellular phenotype that motivated mechanistic dissection.","evidence":"Neuron-specific knockdown/knockout in Drosophila and patient fibroblast energy/morphology assays","pmids":["29604224"],"confidence":"Medium","gaps":["Did not define the molecular activity of VPS13D","Did not place VPS13D in a defined pathway"]},{"year":2018,"claim":"Identified a biochemical activity — K63-ubiquitin binding via the UBA domain — and positioned VPS13D downstream of DRP1/MFF in fission and mitophagy.","evidence":"K63 ubiquitin pulldown plus UBA-deletion genetics and fusion-gene suppression in Drosophila","pmids":["29307555"],"confidence":"High","gaps":["Did not identify the ubiquitinated substrate recognized","Did not establish the lipid-transfer role"]},{"year":2020,"claim":"Defined the structural basis of organelle targeting by showing the VAB domain's repeat-6 asparagine forms the adaptor-binding site disrupted by a disease mutation.","evidence":"Systematic VAB-domain mutagenesis in yeast Vps13 with adaptor-binding and membrane-recruitment readouts, modeling the human variant","pmids":["31943017"],"confidence":"High","gaps":["Tested in yeast Vps13 rather than human VPS13D directly","Did not identify the human adaptor binding repeat 6"]},{"year":2021,"claim":"Reconstituted the lipid-transfer function and contact-site architecture: VPS13D binds glycerophospholipids/fatty acids, is recruited by Miro and VAP, and cooperates with TSG101 to move fatty acids from lipid droplets to mitochondria.","evidence":"In vitro lipid binding, Co-IP, membrane remodeling and FA trafficking assays in mammalian cells","pmids":["33891013","33623047"],"confidence":"High","gaps":["Directionality and rate of in-cell lipid transfer not quantified","Did not resolve how lipid transfer relates to mitophagy function"]},{"year":2021,"claim":"Showed VPS13D negatively regulates ER–mitochondria tethering through VCP/p97 and VAPB, revealing a contact-site-limiting role.","evidence":"siRNA, VPS13D–VCP Co-IP, MCS imaging, and VAPB/PTPIP51 co-suppression rescue","pmids":["34133214"],"confidence":"Medium","gaps":["Mechanism by which VPS13D stabilizes p97 not defined","Single lab; reciprocal in-cell validation limited"]},{"year":2021,"claim":"Placed VPS13D in an ordered pathway (downstream of Vmp1, upstream of Mfn2/Marf) and in a Pink1-dependent/Parkin-independent mitophagy route, with a step in completing mitophagy distinct from fission.","evidence":"Genetic epistasis in Drosophila with autophagy/mitophagy reporters, replicated in patient fibroblasts","pmids":["34019822","34459871","34383748"],"confidence":"High","gaps":["Molecular link between fission completion and phagophore elongation unresolved","How Pink1 acts on VPS13D not defined"]},{"year":2021,"claim":"Distinguished VPS13D from other paralogs by establishing a requirement in peroxisome biogenesis.","evidence":"CRISPR knockout of each VPS13 gene in HeLa cells with peroxisome marker quantification and patient fibroblasts","pmids":["33891012"],"confidence":"High","gaps":["Step in peroxisome biogenesis affected not defined","Relationship to lipid-transfer activity at peroxisome contacts unclear"]},{"year":2021,"claim":"Reported a non-contact-site role: VPS13D interacts with Snhg1 lncRNA to promote IL-7Rα localization in CD8 T cells.","evidence":"Snhg1-Vps13D interaction and IL-7Rα localization/differentiation assays in CD8 T cells","pmids":["33758164"],"confidence":"Medium","gaps":["Specificity to VPS13D protein function partial","Single lab; not connected to its lipid-transfer/mitochondrial roles"]},{"year":2025,"claim":"Confirmed disease alleles cause conserved mitochondrial proteostasis defects, validating patient mutations in vivo.","evidence":"CRISPR knock-in of SCAR4 missense and C-terminal deletion alleles in C. elegans with UPRmt and behavioral readouts","pmids":["39957248","37457002"],"confidence":"Medium","gaps":["Mechanism linking mutations to UPRmt induction not defined","Single study per organism"]},{"year":null,"claim":"How VPS13D's lipid-transfer activity, ubiquitin-coupled mitophagy, and contact-site regulation are integrated into a single coordinated program — and the substrates/adaptors that switch between them — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling lipid transfer to mitophagy","Human in-cell adaptor and substrate identities incomplete","Directional lipid flux not quantified in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,4,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6]}],"complexes":[],"partners":["MIRO","VAPB","TSG101","VCP","PTPIP51"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5THJ4","full_name":"Intermembrane lipid transfer protein VPS13D","aliases":["Vacuolar protein sorting-associated protein 13D"],"length_aa":4388,"mass_kda":491.9,"function":"Mediates the transfer of lipids between membranes at organelle contact sites (By similarity). Functions in promoting mitochondrial clearance by mitochondrial autophagy (mitophagy), also possibly by positively regulating mitochondrial fission (PubMed:29307555, PubMed:29604224). Mitophagy plays an important role in regulating cell health and mitochondrial size and homeostasis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5THJ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS13D","classification":"Common Essential","n_dependent_lines":1045,"n_total_lines":1208,"dependency_fraction":0.8650662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VPS13D","total_profiled":1310},"omim":[{"mim_id":"608877","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG D; VPS13D","url":"https://www.omim.org/entry/608877"},{"mim_id":"607317","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 4; SCAR4","url":"https://www.omim.org/entry/607317"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS13D"},"hgnc":{"alias_symbol":["FLJ10619","KIAA0453","BLTP5D"],"prev_symbol":[]},"alphafold":{"accession":"Q5THJ4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5THJ4","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS13D","jax_strain_url":"https://www.jax.org/strain/search?query=VPS13D"},"sequence":{"accession":"Q5THJ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5THJ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5THJ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5THJ4"}},"corpus_meta":[{"pmid":"33891013","id":"PMC_33891013","title":"VPS13D bridges the ER to mitochondria and peroxisomes via Miro.","date":"2021","source":"The Journal of cell 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spastic paraplegia.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31876103","citation_count":37,"is_preprint":false},{"pmid":"31943017","id":"PMC_31943017","title":"A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31943017","citation_count":35,"is_preprint":false},{"pmid":"33758164","id":"PMC_33758164","title":"The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling.","date":"2021","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33758164","citation_count":34,"is_preprint":false},{"pmid":"34019822","id":"PMC_34019822","title":"Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and 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type 4 caused by novel VPS13D variants in Chinese.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39058251","citation_count":1,"is_preprint":false},{"pmid":"39896501","id":"PMC_39896501","title":"VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39896501","citation_count":0,"is_preprint":false},{"pmid":"37457002","id":"PMC_37457002","title":"An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37457002","citation_count":0,"is_preprint":false},{"pmid":"41288814","id":"PMC_41288814","title":"VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset.","date":"2025","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41288814","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.22.634397","title":"<i>VPS13D</i>  mutations affect mitochondrial homeostasis and locomotion in  <i>Caenorhabditis elegans</i>","date":"2025-01-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.22.634397","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.04.674037","title":"Lysosome-Dependent Sphingolipid Regulation as a potential therapeutic Target for Cohen Syndrome","date":"2025-09-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.04.674037","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17390,"output_tokens":3616,"usd":0.053205,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11272,"output_tokens":3264,"usd":0.06898,"stage2_stop_reason":"end_turn"},"total_usd":0.122185,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS13D is recruited to mitochondria and peroxisomes by the outer mitochondrial membrane GTPase Miro (the Gem1 orthologue), and VPS13D in turn binds the ER via VAP proteins, thereby forming an ER-mitochondria/peroxisome lipid conduit at membrane contact sites.\",\n      \"method\": \"Co-immunoprecipitation, VAP-binding assays, subcellular fractionation, live-cell imaging; knockdown/rescue experiments in mammalian cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies (Miro recruits VPS13D; VPS13D binds VAP), multiple orthogonal methods, functionally validated ER-organelle tethering\",\n      \"pmids\": [\"33891013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The UBA domain of Vps13D binds K63-linked ubiquitin chains; loss of the UBA domain causes defects in mitochondrial size, mitochondrial clearance, and semi-lethality in Drosophila, placing VPS13D downstream of DRP1 and MFF in mitochondrial fission and mitophagy.\",\n      \"method\": \"Ubiquitin-binding pulldown assay with K63 chains; UBA-domain deletion genetics in Drosophila; DRP1/MFF phosphorylation and mitochondrial association assays; suppression by reduced mitochondrial fusion gene function\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitin-binding assay plus domain-deletion genetics, epistasis with DRP1/MFF, suppression by fusion gene loss; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29307555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS13D cooperates with the ESCRT-I protein TSG101 to remodel lipid-droplet membranes; the lipid-transfer domain of human VPS13D binds glycerophospholipids and fatty acids in vitro, and the VPS13 adaptor-binding domain of VPS13D directly interacts with TSG101. Together they facilitate fatty acid transfer from lipid droplets to mitochondria at mitochondria-LD membrane contact sites.\",\n      \"method\": \"In vitro lipid-binding assay (glycerophospholipids/FAs); co-IP (VPS13D–TSG101 interaction); LD membrane remodeling assay; siRNA depletion of VPS13D, TSG101, or ESCRT-III with FA trafficking readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro lipid-binding reconstitution, direct protein interaction, functional trafficking assay with RNAi, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33623047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS13D negatively regulates ER-mitochondria membrane contact sites (MCSs): VPS13D suppression causes extensive ER-mitochondria tethering that is rescued by co-suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with VCP/p97 and is required for the stability of p97, which controls VAPB levels at contacts.\",\n      \"method\": \"siRNA knockdown; co-IP (VPS13D–VCP/p97); quantitative MCS imaging (ER-mitochondria proximity assays); rescue by VAPB/PTPIP51 co-suppression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction (Co-IP), functional rescue, multiple readouts; single lab\",\n      \"pmids\": [\"34133214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vps13D functions in a Pink1-dependent but Parkin/Park-independent mitophagy pathway in Drosophila: loss of vps13d and pink1 each cause equivalent defects in Atg8a localization, ubiquitin localization, and mitochondrial clearance, whereas loss of park does not phenocopy vps13d and contributes to mitochondrial clearance through a parallel pathway.\",\n      \"method\": \"Drosophila genetic epistasis (vps13d, pink1, park single and double mutants); autophagy reporter assays (Atg8a and ubiquitin localization); mitochondrial morphology imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis with multiple alleles, autophagy reporters, and morphological readouts; clearly dissects pathway position\",\n      \"pmids\": [\"34459871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vps13D functions downstream of Vmp1 and upstream of Marf/Mfn2 in regulating ER-mitochondria contact, mitochondrial fusion, and autophagy; vmp1 mutants phenocopy vps13d, loss of marf/MFN2 suppresses vps13d phenotypes including increased ER-mitochondria contact, and this pathway is conserved in human patient fibroblasts.\",\n      \"method\": \"Drosophila genetic epistasis (vmp1, vps13d, marf/MFN2 single and double mutants); ER-mitochondria contact-site quantification by imaging; patient fibroblast validation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis replicated in fly and human cells, suppression rescue, multiple readouts across two systems\",\n      \"pmids\": [\"34019822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS13D loss leads to peroxisome biogenesis defects (partial or complete peroxisome loss) in HeLa cells, transformed cell lines, and patient fibroblasts, identifying VPS13D as a regulator of peroxisome biogenesis distinct from the mitochondrial phenotypes of other VPS13 paralogs.\",\n      \"method\": \"CRISPR knockout of each VPS13 gene in HeLa cells; immunofluorescence and marker quantification for peroxisomes; patient fibroblast analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype replicated across multiple cell lines and patient fibroblasts, systematic comparison across VPS13 family\",\n      \"pmids\": [\"33891012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Vps13D has separable functions in mitochondrial fission and phagophore elongation in Drosophila neurons: Vps13D loss (unlike Drp1 loss) causes accumulation of compromised mitochondria within stalled mito-phagophores, demonstrating a role for Vps13D in completing mitophagy downstream of its role in fission.\",\n      \"method\": \"Drosophila neuronal genetics (vps13D and drp1 mutants); mitophagy reporter assays; autophagy intermediate characterization by imaging; epistasis analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection with reporters in neurons, distinct from Drp1 by multiple assays; single lab\",\n      \"pmids\": [\"34383748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VPS13D interacts with Snhg1 lncRNA to promote IL-7Rα membrane localization in CD8 T cells, facilitating IL-7 signaling and memory CD8 T cell differentiation via STAT5-BCL-2 and STAT3-TCF1-Blimp1 axes.\",\n      \"method\": \"Snhg1-Vps13D interaction assay; IL-7Rα membrane localization by imaging; knockout/knockdown functional assays in CD8 T cell differentiation; signaling pathway analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — protein-lncRNA interaction with functional downstream readout, but single lab and the mechanistic specificity to VPS13D protein function is partial\",\n      \"pmids\": [\"33758164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A disease-causing VPS13D missense mutation maps to the conserved asparagine in repeat 6 of the VAB (Vps13 Adaptor Binding) domain; when modeled in yeast Vps13, this mutation blocks adaptor binding and Vps13 membrane recruitment, demonstrating that the VAB domain's last two repeats form the core adaptor-binding site.\",\n      \"method\": \"Systematic mutagenesis of yeast Vps13 VAB domain repeats; adaptor-binding assays; membrane recruitment assays; modeling of human VPS13D disease mutation in yeast\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis with direct binding and localization readouts, disease variant modeled and tested; single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"31943017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown or knockout of Vps13D in Drosophila neurons causes changes in mitochondrial morphology and impaired mitochondrial distribution along axons; patient fibroblasts show altered mitochondrial morphology and reduced energy production, establishing VPS13D as required for mitochondrial homeostasis in neurons.\",\n      \"method\": \"Drosophila neuron-specific Vps13D knockdown/knockout; mitochondrial morphology and axonal distribution imaging; patient-derived fibroblast functional assays (energy production measurements)\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO in neurons plus patient fibroblast validation, multiple readouts; two independent groups reporting similar phenotypes\",\n      \"pmids\": [\"29604224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR/Cas9-engineered SCAR4 missense mutations and C-terminal deletion in C. elegans vps-13D cause locomotion defects, abnormal mitochondrial morphology, and increased mitochondrial unfolded protein response (UPRmt), confirming conserved roles for VPS13D in mitochondrial proteostasis.\",\n      \"method\": \"CRISPR/Cas9 knock-in of patient missense mutations and C-terminal deletion in C. elegans; locomotion behavioral assays; mitochondrial morphology imaging; UPRmt reporter assays\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knock-in of specific disease alleles, multiple orthogonal phenotypic readouts; single study\",\n      \"pmids\": [\"39957248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Adult-onset neuronal knockdown of Vps13D in Drosophila causes accumulation of mitophagy intermediates, progressive locomotor deficits, early lethality, and brain vacuolization, demonstrating that continuous VPS13D function in adult neurons is required to prevent neurodegeneration.\",\n      \"method\": \"Temporally controlled Gal4/UAS-Gal80-DD system for adult-onset Vps13D RNAi in Drosophila neurons; locomotion assays; histology for brain vacuolization; mitophagy reporter assays\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean temporal knockdown with multiple phenotypic readouts; single lab, single study\",\n      \"pmids\": [\"37457002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS13D is a large cytoplasmic lipid transfer protein that localizes to ER-mitochondria and ER-peroxisome membrane contact sites by binding the ER via VAP proteins and being recruited to mitochondria/peroxisomes by the GTPase Miro; at these contacts it transfers glycerophospholipids and fatty acids between organelles, and at lipid-droplet–mitochondria contacts it cooperates with the ESCRT-I protein TSG101 to remodel LD membranes for fatty acid transfer. VPS13D also negatively regulates ER-mitochondria tethering through interaction with VCP/p97 to control VAPB levels, binds K63-linked ubiquitin chains via its UBA domain to couple mitochondrial fission (acting downstream of DRP1/MFF) with autophagic clearance, and promotes mitophagy in a Pink1-dependent, Parkin-independent pathway by regulating Atg8a and ubiquitin localization and phagophore elongation; it additionally acts downstream of Vmp1 and upstream of Mfn2/Marf to control ER-mitochondria contact and mitochondrial fusion, and is required for peroxisome biogenesis. A conserved VAB-domain asparagine in repeat 6 is essential for adaptor binding and organelle targeting, and disease-causing mutations disrupt this site.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS13D is a large lipid transfer protein that operates at inter-organelle membrane contact sites to control mitochondrial homeostasis, lipid distribution, and mitophagy [#0, #2]. It bridges the ER to mitochondria and peroxisomes by binding the ER via VAP proteins while being recruited to mitochondria/peroxisomes through the outer-membrane GTPase Miro, forming a conduit through which its lipid-transfer domain moves glycerophospholipids and fatty acids [#0, #2]. At mitochondria–lipid droplet contacts it acts with the ESCRT-I protein TSG101 — which it binds through its VPS13 adaptor-binding domain — to remodel lipid-droplet membranes and route fatty acids to mitochondria [#2]. VPS13D also negatively regulates ER–mitochondria tethering by interacting with VCP/p97 to control VAPB levels, with VAPB/PTPIP51 co-suppression reversing the excessive tethering caused by VPS13D loss [#3]. A second function couples mitochondrial fission to clearance: its UBA domain binds K63-linked ubiquitin chains, and acting downstream of DRP1/MFF it is required to complete mitophagy through a Pink1-dependent, Parkin-independent pathway that controls Atg8a and ubiquitin localization and phagophore elongation, operating downstream of Vmp1 and upstream of Mfn2/Marf [#1, #4, #5, #7]. VPS13D is additionally required for peroxisome biogenesis, distinguishing it from other VPS13 paralogs [#6]. Organelle targeting depends on a conserved asparagine in repeat 6 of the VAB adaptor-binding domain, and disease-causing missense mutations disrupt this adaptor-binding site, causing impaired mitochondrial morphology, energy production, and neurodegeneration [#9, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established VPS13D as required for neuronal mitochondrial homeostasis and linked it to human disease, defining the cellular phenotype that motivated mechanistic dissection.\",\n      \"evidence\": \"Neuron-specific knockdown/knockout in Drosophila and patient fibroblast energy/morphology assays\",\n      \"pmids\": [\"29604224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular activity of VPS13D\", \"Did not place VPS13D in a defined pathway\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a biochemical activity — K63-ubiquitin binding via the UBA domain — and positioned VPS13D downstream of DRP1/MFF in fission and mitophagy.\",\n      \"evidence\": \"K63 ubiquitin pulldown plus UBA-deletion genetics and fusion-gene suppression in Drosophila\",\n      \"pmids\": [\"29307555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the ubiquitinated substrate recognized\", \"Did not establish the lipid-transfer role\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the structural basis of organelle targeting by showing the VAB domain's repeat-6 asparagine forms the adaptor-binding site disrupted by a disease mutation.\",\n      \"evidence\": \"Systematic VAB-domain mutagenesis in yeast Vps13 with adaptor-binding and membrane-recruitment readouts, modeling the human variant\",\n      \"pmids\": [\"31943017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tested in yeast Vps13 rather than human VPS13D directly\", \"Did not identify the human adaptor binding repeat 6\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted the lipid-transfer function and contact-site architecture: VPS13D binds glycerophospholipids/fatty acids, is recruited by Miro and VAP, and cooperates with TSG101 to move fatty acids from lipid droplets to mitochondria.\",\n      \"evidence\": \"In vitro lipid binding, Co-IP, membrane remodeling and FA trafficking assays in mammalian cells\",\n      \"pmids\": [\"33891013\", \"33623047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directionality and rate of in-cell lipid transfer not quantified\", \"Did not resolve how lipid transfer relates to mitophagy function\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed VPS13D negatively regulates ER–mitochondria tethering through VCP/p97 and VAPB, revealing a contact-site-limiting role.\",\n      \"evidence\": \"siRNA, VPS13D–VCP Co-IP, MCS imaging, and VAPB/PTPIP51 co-suppression rescue\",\n      \"pmids\": [\"34133214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which VPS13D stabilizes p97 not defined\", \"Single lab; reciprocal in-cell validation limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed VPS13D in an ordered pathway (downstream of Vmp1, upstream of Mfn2/Marf) and in a Pink1-dependent/Parkin-independent mitophagy route, with a step in completing mitophagy distinct from fission.\",\n      \"evidence\": \"Genetic epistasis in Drosophila with autophagy/mitophagy reporters, replicated in patient fibroblasts\",\n      \"pmids\": [\"34019822\", \"34459871\", \"34383748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between fission completion and phagophore elongation unresolved\", \"How Pink1 acts on VPS13D not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished VPS13D from other paralogs by establishing a requirement in peroxisome biogenesis.\",\n      \"evidence\": \"CRISPR knockout of each VPS13 gene in HeLa cells with peroxisome marker quantification and patient fibroblasts\",\n      \"pmids\": [\"33891012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step in peroxisome biogenesis affected not defined\", \"Relationship to lipid-transfer activity at peroxisome contacts unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reported a non-contact-site role: VPS13D interacts with Snhg1 lncRNA to promote IL-7Rα localization in CD8 T cells.\",\n      \"evidence\": \"Snhg1-Vps13D interaction and IL-7Rα localization/differentiation assays in CD8 T cells\",\n      \"pmids\": [\"33758164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity to VPS13D protein function partial\", \"Single lab; not connected to its lipid-transfer/mitochondrial roles\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed disease alleles cause conserved mitochondrial proteostasis defects, validating patient mutations in vivo.\",\n      \"evidence\": \"CRISPR knock-in of SCAR4 missense and C-terminal deletion alleles in C. elegans with UPRmt and behavioral readouts\",\n      \"pmids\": [\"39957248\", \"37457002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking mutations to UPRmt induction not defined\", \"Single study per organism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS13D's lipid-transfer activity, ubiquitin-coupled mitophagy, and contact-site regulation are integrated into a single coordinated program — and the substrates/adaptors that switch between them — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling lipid transfer to mitophagy\", \"Human in-cell adaptor and substrate identities incomplete\", \"Directional lipid flux not quantified in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MIRO\", \"VAPB\", \"TSG101\", \"VCP\", \"PTPIP51\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}