ATP6V0A1

ATP6V0A1 encodes the a1-subunit of the V0 domain of the vacuolar H+-ATPase, the proton-translocating component that drives acidification of the endolysosomal compartment and is enriched in neurons (PMID:33833240). Through this acidifying function it sustains lysosomal hydrolysis, autophagic flux, and mTORC1 signaling, and is required for proper neurotransmitter loading of synaptic vesicles and synaptic connectivity (PMID:33833240). Loss of acidification capacity is the unifying consequence of perturbing ATP6V0A1: missense variants impair lysosomal acidification and cause a developmental and epileptic encephalopathy in humans, recapitulated in cell, mouse, and C. elegans models showing autophagic dysfunction and lysosomal accumulation (PMID:33833240, PMID:34909687). The same acidification-dependent control of endolysosomal maturation and autophagy underlies its roles in diverse cell contexts, including RABGEF1-dependent endosome maturation and cholesterol trafficking (PMID:38971819), NCOA4-mediated ferritinophagy and ferroptosis (PMID:41161393), and hepatic autophagic flux governing triglyceride homeostasis (PMID:41722762). Beyond pumping protons, ATP6V0A1 also acts at ER-lysosome contact sites, where it directly binds ryanodine receptors to suppress RYR-mediated Ca2+ release and restrain lysosomal secretion, preserving the intracellular lysosomal pool for autophagy (PMID:42087556). It additionally controls secretory granule pH and the regulated exocytotic pathway, where altered expression impairs CHGA processing and CGRP-dependent vesicle release (PMID:21558123, PMID:36232740).

1. 2007 Medium

   Establishing where the a1 isoform resides distinguished it from other V-ATPase a-subunits and indicated a distinct, non-apical-restricted membrane role.

   Evidence Isoform-specific immunolocalization in mouse kidney with AE1/pendrin co-markers and expression qPCR

   PMID:17595521

   Open questions at the time

   • No functional perturbation of ATP6V0A1 specifically
   • Localization established only in kidney epithelia, not neurons
2. 2011 Medium

   Linking ATP6V0A1 dosage to granule pH connected the subunit to control of the regulated secretory pathway, beyond bulk lysosomal acidification.

   Evidence 3'-UTR miR-637 reporter assays, granule pH imaging, and CHGA processing analysis in PC12 cells

   PMID:21558123

   Open questions at the time

   • Mechanism tested via a single regulatory variant in one cell line
   • Does not address neuronal phenotypes
3. 2021 High

   Demonstrating that pathogenic missense variants impair lysosomal acidification and produce neuronal dysfunction in vivo established ATP6V0A1 as the disease-causing acidifying subunit in neurons.

   Evidence Missense mutant acidification assays plus knock-in mouse models with mTORC1, synaptic, and neurotransmitter readouts; patient cells and C. elegans autophagy assays

   PMID:33833240 PMID:34909687

   Open questions at the time

   • Structural basis of how specific residues impair proton transport not resolved
   • Mechanism linking acidification loss to seizure phenotype unspecified
4. 2022 Medium

   Knockdown experiments tied ATP6V0A1 to vesicle exocytosis and CGRP secretion, extending its role to NGF-driven neuropeptide release.

   Evidence shRNA knockdown in trigeminal ganglia and SH-SY5Y neurons with FM1-43 vesicle release and CGRP ELISA

   PMID:36232740

   Open questions at the time

   • Whether the effect is via acidification or another mechanism not separated
   • Single lab
5. 2024 Medium

   Placing ATP6V0A1 upstream of RABGEF1-dependent endosome maturation connected its acidifying function to cholesterol trafficking and tumor immunosuppression.

   Evidence Gain/loss of function in colorectal cancer cells with cholesterol assays, 24-OHC quantification, LXR reporters, and CD8+ T cell co-culture

   PMID:38971819

   Open questions at the time

   • Direct RABGEF1 binding versus functional dependence not fully disentangled
   • Single cancer-cell context
6. 2025 Medium

   Cadmium-driven upregulation experiments showed ATP6V0A1-dependent acidification promotes ferritinophagy and ferroptosis, generalizing its lysosomal role to iron metabolism.

   Evidence siRNA knockdown in Ramos B cells with lysosomal pH, Fe2+ flow cytometry, NCOA4-FTH1 Co-IP, and in vivo transcriptomics

   PMID:41161393

   Open questions at the time

   • Whether ATP6V0A1 directly regulates NCOA4-FTH1 or acts only via acidification unclear
   • Single lab
7. 2026 Medium

   Showing cadmium destabilizes ATP6V0A1 protein and that overexpression rescues autophagic flux and triglyceride accumulation established it as a post-transcriptionally regulated node controlling hepatic autophagy.

   Evidence Knockdown/overexpression in hepatocytes with pH probes, autophagic flux assays, proteasome/lysosome inhibitors, and serum metabolomics in mice

   PMID:41722762

   Open questions at the time

   • Identity of the degradation machinery targeting ATP6V0A1 not defined
   • Single lab
8. 2026 Medium

   Identifying a direct ATP6V0A1-RYR interaction at ER-lysosome contacts revealed a proton-pumping-independent function regulating Ca2+ release and lysosomal secretion.

   Evidence Direct binding assay and RYR-derived decoy peptide disruption with Ca2+, lysosomal secretion, and autophagic flux readouts in human iPSC cortical neurons

   PMID:42087556

   Open questions at the time

   • Binding interface and stoichiometry not mapped
   • Single Co-IP-type binding assay without reciprocal structural validation

• How the proton-pumping and RYR-binding/Ca2+-regulatory functions of ATP6V0A1 are coordinated, and which contributes to the human encephalopathy phenotype, remains unresolved.
• No structure of the variant-affected residues
• Relative contribution of pump versus contact-site function to disease unknown