Affinage

VPS13D

Intermembrane lipid transfer protein VPS13D · UniProt Q5THJ4

Length
4388 aa
Mass
491.9 kDa
Annotated
2026-06-11
33 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2018 Medium

    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

    PMID:29604224

    Open questions at the time
    • Did not define the molecular activity of VPS13D
    • Did not place VPS13D in a defined pathway
  2. 2018 High

    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

    PMID:29307555

    Open questions at the time
    • Did not identify the ubiquitinated substrate recognized
    • Did not establish the lipid-transfer role
  3. 2020 High

    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

    PMID:31943017

    Open questions at the time
    • Tested in yeast Vps13 rather than human VPS13D directly
    • Did not identify the human adaptor binding repeat 6
  4. 2021 High

    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

    PMID:33623047 PMID:33891013

    Open questions at the time
    • Directionality and rate of in-cell lipid transfer not quantified
    • Did not resolve how lipid transfer relates to mitophagy function
  5. 2021 Medium

    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

    PMID:34133214

    Open questions at the time
    • Mechanism by which VPS13D stabilizes p97 not defined
    • Single lab; reciprocal in-cell validation limited
  6. 2021 High

    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

    PMID:34019822 PMID:34383748 PMID:34459871

    Open questions at the time
    • Molecular link between fission completion and phagophore elongation unresolved
    • How Pink1 acts on VPS13D not defined
  7. 2021 High

    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

    PMID:33891012

    Open questions at the time
    • Step in peroxisome biogenesis affected not defined
    • Relationship to lipid-transfer activity at peroxisome contacts unclear
  8. 2021 Medium

    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

    PMID:33758164

    Open questions at the time
    • Specificity to VPS13D protein function partial
    • Single lab; not connected to its lipid-transfer/mitochondrial roles
  9. 2025 Medium

    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

    PMID:37457002 PMID:39957248

    Open questions at the time
    • Mechanism linking mutations to UPRmt induction not defined
    • Single study per organism

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140104 molecular carrier activity 2 GO:0008289 lipid binding 1
Localization
GO:0005739 mitochondrion 3 GO:0005777 peroxisome 2 GO:0005783 endoplasmic reticulum 2 GO:0005811 lipid droplet 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-1430728 Metabolism 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
MIROPTPIP51TSG101VAPBVCP

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Co-immunoprecipitation, VAP-binding assays, subcellular fractionation, live-cell imaging; knockdown/rescue experiments in mammalian cells The Journal of cell biology High 33891013
2018 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. 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 Current biology : CB High 29307555
2021 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. 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 Nature communications High 33623047
2021 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. siRNA knockdown; co-IP (VPS13D–VCP/p97); quantitative MCS imaging (ER-mitochondria proximity assays); rescue by VAPB/PTPIP51 co-suppression Molecular biology of the cell Medium 34133214
2021 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. Drosophila genetic epistasis (vps13d, pink1, park single and double mutants); autophagy reporter assays (Atg8a and ubiquitin localization); mitochondrial morphology imaging The Journal of cell biology High 34459871
2021 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. Drosophila genetic epistasis (vmp1, vps13d, marf/MFN2 single and double mutants); ER-mitochondria contact-site quantification by imaging; patient fibroblast validation Current biology : CB High 34019822
2021 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. CRISPR knockout of each VPS13 gene in HeLa cells; immunofluorescence and marker quantification for peroxisomes; patient fibroblast analysis The Journal of cell biology High 33891012
2021 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. Drosophila neuronal genetics (vps13D and drp1 mutants); mitophagy reporter assays; autophagy intermediate characterization by imaging; epistasis analysis PLoS genetics Medium 34383748
2021 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. Snhg1-Vps13D interaction assay; IL-7Rα membrane localization by imaging; knockout/knockdown functional assays in CD8 T cell differentiation; signaling pathway analysis Signal transduction and targeted therapy Medium 33758164
2020 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. Systematic mutagenesis of yeast Vps13 VAB domain repeats; adaptor-binding assays; membrane recruitment assays; modeling of human VPS13D disease mutation in yeast Human molecular genetics High 31943017
2018 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. Drosophila neuron-specific Vps13D knockdown/knockout; mitochondrial morphology and axonal distribution imaging; patient-derived fibroblast functional assays (energy production measurements) Annals of neurology Medium 29604224
2025 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. CRISPR/Cas9 knock-in of patient missense mutations and C-terminal deletion in C. elegans; locomotion behavioral assays; mitochondrial morphology imaging; UPRmt reporter assays G3 (Bethesda, Md.) Medium 39957248
2023 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. Temporally controlled Gal4/UAS-Gal80-DD system for adult-onset Vps13D RNAi in Drosophila neurons; locomotion assays; histology for brain vacuolization; mitophagy reporter assays Frontiers in neuroscience Medium 37457002

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 VPS13D bridges the ER to mitochondria and peroxisomes via Miro. The Journal of cell biology 142 33891013
2018 Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Annals of neurology 136 29604224
2018 Vps13D Encodes a Ubiquitin-Binding Protein that Is Required for the Regulation of Mitochondrial Size and Clearance. Current biology : CB 130 29307555
2021 An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions. Nature communications 113 33623047
2018 Recessive mutations in VPS13D cause childhood onset movement disorders. Annals of neurology 108 29518281
2021 VPS13D promotes peroxisome biogenesis. The Journal of cell biology 57 33891012
2021 Vps13D functions in a Pink1-dependent and Parkin-independent mitophagy pathway. The Journal of cell biology 43 34459871
2019 VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia. Molecular genetics & genomic medicine 37 31876103
2020 A VPS13D spastic ataxia mutation disrupts the conserved adaptor-binding site in yeast Vps13. Human molecular genetics 35 31943017
2021 The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling. Signal transduction and targeted therapy 34 33758164
2021 Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease. Current biology : CB 31 34019822
2021 VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions. Molecular biology of the cell 24 34133214
2021 Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons. PLoS genetics 18 34383748
2023 Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder. International journal of molecular sciences 15 36768210
2022 Autosomal recessive spinocerebellar ataxia type 4 with a VPS13D mutation: A case report. World journal of clinical cases 13 35097097
2022 Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia. BMC neurology 13 35151251
2015 VPS13D Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock. Journal of innate immunity 12 25896417
2018 Mitophagy: Vps13D Couples Mitochondrial Fission and Autophagic Clearance. Current biology : CB 9 29374445
2024 VPS13D affects epileptic seizures by regulating mitochondrial fission and autophagy in epileptic rats. Genes & diseases 7 39286655
2022 VPS13D-based disease: Expansion of the clinical phenotype in two brothers and mutation diversity in the Turkish population. Revue neurologique 7 36156252
2023 Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders. Gene 6 38160741
2023 RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature. Molecular genetics and genomics : MGG 5 37340120
2024 A Novel Mutation of VPS13D-related Disorders with Parkinsonism. Internal medicine (Tokyo, Japan) 3 38369353
2024 New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants. International journal of molecular sciences 3 38791166
2024 Autosomal recessive spinocerebellar ataxia type 4 due to a novel homozygous mutation in the VPS13D gene in a Saudi family. Clinical neurology and neurosurgery 2 38569247
2023 A boy with a progressive neurologic decline harboring two coexisting mutations in KMT2D and VPS13D. Brain & development 2 37599126
2025 VPS13D-related disorders: a severe case, review, and genotype-phenotype correlation. Neurocase 1 39814591
2025 VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans. G3 (Bethesda, Md.) 1 39957248
2024 Clinical, genetic, and neuroimaging profiles of autosomal recessive spinocerebellar ataxia type 4 caused by novel VPS13D variants in Chinese. American journal of medical genetics. Part A 1 39058251
2022 Bombyx mori Vps13d is a key gene affecting silk yield. PloS one 1 35797274
2025 VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans. bioRxiv : the preprint server for biology 0 39896501
2025 VPS13D-Related Disorders: Description of New Variant and Phenotypic Spectrum Based on Age of Onset. Cerebellum (London, England) 0 41288814
2023 An optimized temporally controlled Gal4 system in Drosophila reveals degeneration caused by adult-onset neuronal Vps13D knockdown. Frontiers in neuroscience 0 37457002

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