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  organism: human
  gene_id: P27449
  gene_symbol: ATP6V0C
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## Question

# Gene Research for Functional Annotation

Please provide a comprehensive research report on the gene ATP6V0C (P27449) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function. 

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

## Output

# Overview of ATP6V0C and the V-ATPase Complex

**ATP6V0C** (also known as *V-ATPase 16 kDa proteolipid subunit c*, UniProt P27449) encodes the **c subunit of the vacuolar H^+-ATPase (V-ATPase)** in humans ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=thereby%20creating%20the%20proton%2FpH%20gradient,conducted%20in%20Saccharomyces%20cerevisiae%20revealed)) ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function)). V-ATPase is a large multi-subunit enzyme complex that uses the energy from ATP hydrolysis to pump protons (H^+) across intracellular membranes, thereby acidifying organelles such as lysosomes, endosomes, and the Golgi apparatus ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=V,resorption%20compartment%20to%20solubilize%20bone)) ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function)). This proton transport activity of V-ATPase is essential for maintaining **pH homeostasis** in cells and for creating the proton gradients required by many cellular processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,silico%20modelling%20suggested%20that%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Vacuolar,impair%20brain%20development%20and%20synaptic)). In certain specialized cells, V-ATPases are also targeted to the plasma membrane, where they actively acidify the extracellular environment (for example, in osteoclast-mediated bone resorption or renal acid secretion) ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=complex%20,By%20similarity%29%20Specific%20Function)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=include%20acidifying%20an%20extracellular%20resorption,9)).

**Key Functional Role:** ATP6V0C’s gene product is a **proton-conducting, pore-forming subunit** of the V-ATPase **V0 domain** ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function)). Within the V-ATPase complex, the V0 domain is the membrane-embedded sector that translocates protons, while the V1 domain is the peripheral sector that hydrolyzes ATP to power proton transport ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=conservation%2C%20transmembrane%20transport%2C%20acidification%20of,subunits%2C%20forms%20the%20hydrogen%20pore)). The ATP6V0C-encoded subunit *c* forms part of the **rotary proton pump mechanism**: ATP hydrolysis in V1 drives rotation of a ring of *c* subunits in V0, which shuttles protons from the cytosol into the organelle lumen against the electrochemical gradient ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205)) ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function)). In biochemical terms, V-ATPase activity can be viewed as **ATP hydrolysis coupled to H^+ transport** – i.e. ATP6V0C is not an enzyme on its own, but an integral component of the **transmembrane proton channel** that is driven by the enzyme’s catalytic subunits. The substrate of this transporter is the proton (H^+), and the pumping cycle typically translocates multiple H^+ per ATP hydrolyzed via a rotary mechanism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1)).

# Structure and Mechanism of the V0 *c* Subunit

**Protein Features:** The human V0 *c* subunit is a small **155-amino-acid** protein with **four transmembrane helices**, characteristic of a hydrophobic proteolipid ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved)). It is highly conserved evolutionarily – for instance, the human *c* subunit shares ~72% amino acid identity with its yeast ortholog, underscoring the conserved structure and function of this protein across species ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved)). The subunit is encoded by a gene on chromosome 16p13.3 consisting of three exons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=ATP6V0C%2C%20a%20three,4)) (two other loci on chromosomes 6 and 17 encode non-functional pseudogene copies ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=of%20five%20different%20subunits%3A%20a%2C,provided%20by%20RefSeq%2C%20Nov%202010))). Alternative splicing of ATP6V0C can produce transcript variants, but all encode the same core protein product ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=of%20five%20different%20subunits%3A%20a%2C,provided%20by%20RefSeq%2C%20Nov%202010)).

**Assembly in V-ATPase:** Multiple *c* subunits assemble together with related proteolipids to form the **c-ring** rotor within the V0 membrane domain. High-resolution structural studies indicate that in the human V-ATPase, the c-ring is composed of **10 proteolipid subunits** in total: **nine copies of the ATP6V0C-encoded subunit c** and **one copy of the related “cʺ” subunit (encoded by ATP6V0B)** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1)). These subunits arrange in a ring within the lipid bilayer, and each *c* subunit contributes a proton-binding site. A key conserved residue in subunit c is **glutamate 139 (E139)**, which plays a critical role in binding and releasing protons during the transport cycle ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=c%E2%80%B2%E2%80%B2,1)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=ATP6V0C%2C%20a%20three,4)). The rotary mechanism can be summarized as follows: the V1 domain hydrolyzes ATP and drives rotation of the c-ring; as the ring turns, each subunit c carries a proton from the cytosolic side to the luminal side of the membrane. The *c* subunits interact with the V0 **subunit a** (product of ATP6V0A genes), which provides two half-channels for proton entry and exit and contains a crucial **arginine residue (R735)**. Proton translocation relies on a **charge shuttle between E139 in subunit c and R735 in subunit a**: a proton binds to E139 in a *c* subunit on the cytosolic side, the ring rotates and delivers that proton to the luminal half-channel where R735 in subunit a helps facilitate proton release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=the%20movement%20of%20protons%20across,1)). This coordinated hand-off mechanism is analogous to that of the F-ATP synthase in mitochondria, reflecting the conserved rotary ATPase design ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205)).

**Bafilomycin Binding:** Notably, ATP6V0C is identified as the **binding target of bafilomycin A1**, a well-known macrolide inhibitor of V-ATPases ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=ATP6V0C%20is%20the%20bafilomycin%20A1,by%20a%20significant%20decrease%20in)). Bafilomycin and related inhibitors (like concanamycin) bind the c-ring proteolipid subunits and block proton translocation, causing a collapse of organelle pH gradients. This reveals that the *c* subunit’s proton channel region is the pharmacological point of inhibition for these compounds ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=ATP6V0C%20is%20the%20bafilomycin%20A1,by%20a%20significant%20decrease%20in)). Experimentally, treating cells with bafilomycin or knocking down ATP6V0C produces similar phenotypes of organelle de-acidification – for example, loss of lysosomal acidity, impaired protein degradation, and stalled autophagic flux ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=shown%20previously%20that%20bafilomycin%20A1,terminal%20fragments%2C%20and%20inhibited)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did)). These observations underscore the c subunit’s central role in V-ATPase activity and its potential as a drug target in diseases where modulation of vesicular pH is therapeutic.

# Biological Processes and Pathways Involving ATP6V0C

**Organelle Acidification and Trafficking:** The primary role of ATP6V0C (as part of V-ATPase) is to **acidify intracellular organelles**, and this acidification is *absolutely critical* for a host of cellular processes. V-ATPase–dependent luminal acidification is required for **endocytic trafficking and protein sorting** (e.g. dissociating ligands from receptors in endosomes), for **zymogen activation** in secretory granules (e.g. activation of pro-enzymes in endocrine and digestive cells), and for the generation of proton gradients in secretory vesicles ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=,This%20gene%20encodes%20the%20V0)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=essential%20housekeeping%20enzymes%20in%20eukaryotic,and%20pumping%20protons%20across)). For instance, the low pH in Golgi and secretory granules facilitates proper protein processing (such as glycosylation steps and precursor cleavage), and late endosomes/lysosomes must be acidified for **protease activation and substrate degradation** by hydrolases ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=V,resorption%20compartment%20to%20solubilize%20bone)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=essential%20housekeeping%20enzymes%20in%20eukaryotic,and%20pumping%20protons%20across)). **Receptor-mediated endocytosis** also requires V-ATPase function: as early endosomes mature and acidify, the pH drop triggers conformational changes that cause receptors to release their cargo (e.g. LDL from its receptor) and primes cargo for sorting or degradation ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=,This%20gene%20encodes%20the%20V0)). In *yeast* and other model systems, loss of V-ATPase activity leads to defects in sorting of vacuolar enzymes and accumulation of cargo in aberrant compartments, highlighting its fundamental role in vesicle trafficking ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC360825/#:~:text=Role%20of%20vacuolar%20acidification%20in,1)).

**Autophagy and Lysosomal Function:** **Macroautophagy** (the self-degradative pathway for recycling cellular components) is strongly dependent on ATP6V0C and V-ATPase function. The lysosome is the terminal organelle where autophagic cargo is degraded, and a **highly acidic lumen (pH ~4.5–5)** is required for lysosomal enzymes to function. **Catabolic processes such as autophagic degradation strictly rely on V-ATPase-driven acidification** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Vacuolar,impair%20brain%20development%20and%20synaptic)). If ATP6V0C function is lost or inhibited, lysosomal pH rises and **autophagic flux is blocked**, meaning cells accumulate autophagosomes and undegraded substrates ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did)). Experimental knockdown of ATP6V0C in human neuroblastoma cells, for example, caused increased LC3-II levels and build-up of proteins like α-synuclein and amyloid precursor fragments, indicating **impaired autophagosome-lysosome clearance** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did)). These cells also showed reduced viability and neurite degeneration, especially under stress, consistent with failure of the autophagy-lysosome system ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did)). Thus, through its role in V-ATPase, ATP6V0C is intimately tied to cellular clearance pathways; this has implications for neurodegenerative conditions where defective lysosomal acidification can lead to toxic protein accumulation.

**Synaptic Vesicle Loading:** In neurons, V-ATPases (containing ATP6V0C subunits) are crucial for neurotransmission. They **acidify synaptic vesicles**, creating an electrochemical proton gradient that is harnessed by neurotransmitter transporters to fill the vesicles with neurotransmitters. The human brain expresses high levels of V-ATPase, and **synaptic vesicle acidification by V-ATPase is required to load various neurotransmitters into vesicles** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=%28Supplementary%20Table%201%20%29,presentations%20when%20compared%20to%20patients)). For example, vesicular glutamate transporters use the proton gradient (exchanging lumenal H^+ for cytosolic glutamate) to concentrate glutamate inside synaptic vesicles. If the V0 *c* subunit or other V-ATPase components are dysfunctional, synaptic vesicles cannot accumulate neurotransmitters properly, leading to synaptic transmission defects. This dependency links ATP6V0C to **neurophysiological processes** like synaptic plasticity and neural circuit function. Indeed, genetic and pharmacological disruptions of V-ATPase in neurons cause seizures and neurodevelopmental anomalies (discussed further below), underlining the importance of ATP6V0C for normal nervous system activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=,with%20a%20novel%20syndrome%20of)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Dmel,hypothesis%20that%20haploinsufficiency%20of%20ATP6V0C)).

**Specialized Roles (Bone Resorption and pH Homeostasis):** In certain cell types, V-ATPases perform “specialized” physiological roles beyond routine vesicle acidification. Osteoclasts (bone-resorbing cells) use plasma-membrane V-ATPases to pump protons into the sealed resorption lacuna between the cell and bone surface, thereby **acidifying the extracellular compartment to dissolve bone mineral** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9)). The *c* subunit is a part of these osteoclast V-ATPases, and **mutations in other V-ATPase subunits (like ATP6V0A3, the osteoclast-specific a3 subunit) cause osteopetrosis** due to failure of bone acidification, implying that ATP6V0C is also essential in this process as a core component of the proton pump ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9)). In the kidneys, **intercalated cells of the distal nephron** have V-ATPases on their apical membrane to secrete protons into the urine, regulating systemic acid–base balance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=include%20acidifying%20an%20extracellular%20resorption,cells%20also%20have%20plasma%20membrane)). ATP6V0C contributes to these pumps, meaning it indirectly supports **systemic pH homeostasis**. In immune cells like neutrophils and macrophages, V-ATPases help acidify phagosomes and granules (e.g. azurophil granules) for microbial killing – consistent with GO annotations localizing subunit c to **phagolysosomal and granule membranes** ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane)). These examples illustrate that ATP6V0C-containing V-ATPase complexes are not only housekeeping proton pumps but also facilitators of specialized physiological processes that require controlled acidification.

**Cell Signaling and Metabolic Pathways:** Beyond its direct role in proton transport, emerging evidence links V-ATPase (and by extension ATP6V0C) to **cellular signaling pathways**. One prominent example is the mTORC1 nutrient-sensing pathway: the lysosomal V-ATPase works in concert with the Ragulator complex to signal amino acid availability to mTORC1. The **V-ATPase–Ragulator complex is essential for mTORC1 activation** on the lysosome; in response to amino acids, this complex helps recruit and activate mTORC1, promoting anabolic growth signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=%2832%20%2C%2031%29%2C%20NHE,The%20papillomavirus%20E5%20oncoprotein)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25002183/#:~:text=AMPK%20and%20mTOR%20play%20principal,also%20uncovered%20that%20AMPK%20is)). Although ATP6V0C is a structural subunit, the intact proton pump seems necessary for this signaling function – in fact, some studies suggest that the proton gradient or V-ATPase conformational state may act as a cue for mTORC1 activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=%2832%20%2C%2031%29%2C%20NHE,The%20papillomavirus%20E5%20oncoprotein)). Additionally, V-ATPase activity can impact **Wnt/β-catenin signaling** and other pathways indirectly by modulating the trafficking of receptors and the pH of endo-lysosomal compartments where signaling components are processed ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=There%20are%20now%20strong%20evidences,17)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=proteins%2C%20a%20number%20of%20other,The%20papillomavirus%20E5%20oncoprotein)). There are also links to cellular metabolism: for example, cancer cells often upregulate V-ATPase subunits to maintain an acidic microenvironment and promote glycolysis. A 2019 study showed that silencing ATP6V0C in highly metastatic esophageal cancer cells attenuated their **aerobic glycolysis (Warburg effect)** and invasive growth – likely by disrupting cytosolic pH and enzyme activities – and reduced tumor cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6830105/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,uptake%20and%20decreased%20lactate%20and)). Thus, while ATP6V0C’s primary role is structural (enabling proton transport), this function intersects with numerous signaling and metabolic pathways that depend on proper organelle acidification and pH dynamics.

# Subcellular Localization

**Membrane Localization:** The ATP6V0C protein is an **integral membrane protein** that localizes to the membranes of acidic organelles and certain specialized membranes, consistent with the distribution of V-ATPase complexes. UniProt annotations and cell imaging studies indicate that subunit c is found in **lysosomal and endosomal membranes**, **trans-Golgi network membranes**, and in the membranes of secretory vesicles (e.g. **synaptic vesicles, endocrine secretory granules**) ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=%2A%20Cytoplasmic%20vesicle%2C%20clathrin,ECO%3A0000250%20UniProtKB%3AP63081%20%7C%20ECO%3A0000255)) ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane)). For example, the Human Protein Atlas detects ATP6V0C in cytoplasmic vesicle structures, reflecting its presence in vesicle membranes. V-ATPase containing ATP6V0C is also present on **clathrin-coated vesicles** that bud from the plasma membrane or Golgi, suggesting it is poised to acidify endocytic vesicles soon after they form ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=%2A%20Cytoplasmic%20vesicle%2C%20clathrin,ECO%3A0000250%20UniProtKB%3AP63081%20%7C%20ECO%3A0000255)). 

Within these membranes, ATP6V0C’s 4-pass transmembrane topology means it spans the lipid bilayer multiple times, likely arranging such that both the N- and C-termini face the cytosolic side (as shown for homologous proteolipid subunits) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved)). The crucial proton-binding residue (E139) lies in the transmembrane segment and faces the lipid/rotor interface where proton transfer occurs ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=the%20movement%20of%20protons%20across,1)).

**Plasma Membrane Occurrence:** Under typical conditions, most V-ATPases reside on intracellular organelles, but in specific cell types or stimuli, ATP6V0C-containing V-ATPases are targeted to the plasma membrane. This occurs in osteoclasts and kidney intercalated cells as discussed, and also in certain tumor cells and specialized epithelia. **Compartments.jensenlab** computational localization scores give high confidence for ATP6V0C at the **lysosome (score 5)** and **plasma membrane (score 5)**, with slightly lower scores for Golgi and endosomes ([www.genecards.org](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=Compartment%20%20%7C%20Confidence%20,2)). Indeed, immunolabeling in osteoclasts shows a ruffled-border plasma membrane localization of V0 subunits during active bone resorption ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9)). In cancer cell lines, V-ATPase subunits (including c) have been detected at the cell surface, where their activity correlates with an acidic pericellular milieu that facilitates invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=for%20loading%20neurotransmitters%20in%20neurons,6)). It’s worth noting that reversible **relocalization of V-ATPase** is a known regulatory mechanism: for instance, in response to cellular cues, V-ATPases can be trafficked to or from the plasma membrane. An example is in *macrophages*, where V-ATPases are stored on vesicles and deployed to the phagosome membrane upon ingestion of pathogens, acidifying the phagosome to kill microbes. Thus, ATP6V0C’s localization is dynamic, but always associated with membranes where proton pumping is needed. Consistent with this, gene ontology annotations list ATP6V0C as an integral component of membranes like **lysosomal, endosomal, phagosomal, secretory granule, and **synaptic vesicle** membranes ([go.drugbank.com](https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane)). No evidence suggests ATP6V0C ever exists in a soluble form; it is invariably membrane-bound and usually found as part of the assembled V0 complex.

# Clinical Significance and Recent Research Developments

**Disease Associations:** Given its fundamental role in organelle acidification, it is not surprising that defects in ATP6V0C can have serious consequences. For many years, direct mutations in ATP6V0C were not widely reported in human disease (possibly because complete loss of such an essential subunit might be embryonically lethal). However, **recent genetic studies (2020–2023)** have uncovered multiple cases linking *de novo* ATP6V0C mutations to a pediatric neurodevelopmental syndrome. In 2023, Mattison *et al.* reported **27 patients** from unrelated families harboring heterozygous missense variants in ATP6V0C, presenting with a syndromic neurodevelopmental disorder characterized by **early-onset epilepsy, developmental delay, intellectual disability, and often corpus callosum hypoplasia** ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=thereby%20creating%20the%20proton%2FpH%20gradient,conducted%20in%20Saccharomyces%20cerevisiae%20revealed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=ATP6V0C%20%28NM_001694.4%29%20%20,gait%20ataxia%2C%20nonspecific%20dysmorphic%20features)). Notably, many of these mutations clustered in the fourth transmembrane region of the protein (which includes the critical Glu-139), suggesting that they disrupt proton translocation. The researchers demonstrated in yeast and *C. elegans* models that patient-derived ATP6V0C variants **impair V-ATPase function**, leading to reduced lysosomal acidification and cellular growth defects ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=patient%20variants%20interfere%20with%20the,clinical%20features%20of%20the%20associated)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=,with%20a%20novel%20syndrome%20of)). In a *Drosophila* knockdown model, loss of the ATP6V0C ortholog caused seizure-like activity that could be suppressed by existing anti-epileptic drugs, consistent with a hyperexcitability phenotype due to lysosomal dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=interfered%20with%20the%20interactions%20between,Caenorhabditis%20elegans%20led%20to%20motor)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Dmel,hypothesis%20that%20haploinsufficiency%20of%20ATP6V0C)). These findings firmly establish ATP6V0C as a **disease gene (OMIM #620465)**: even a partial loss of function (haploinsufficiency) in humans can lead to neurological disorders. Intriguingly, earlier studies of chromosomal microdeletions involving ATP6V0C (e.g. 16p13.3 deletions) also pointed to **haploinsufficiency of ATP6V0C as the likely driver of epilepsy, microcephaly, and developmental delay** in those patients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=match%20at%20L410%20of%20TBC1D24%2C,was%20proposed%20as%20the%20primary)). A subsequent case in 2020 identified a de novo stop-loss mutation in ATP6V0C in an individual with epilepsy and intellectual disability, further implicating this gene in epilepsy pathogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=match%20at%20L415%20,with%20a%20novel%20syndrome%20of)). Now, with dozens of cases reported, ATP6V0C joins other V-ATPase subunit genes (such as ATP6V1A, ATP6V0A1, ATP6V1B2) that are linked to neurological disorders, underscoring the unique vulnerability of neurons to endo-lysosomal dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Catabolic%20processes%2C%20such%20as%20endocytic,genetic%20and%20functional%20evidence%20linking)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=%28Supplementary%20Table%201%20%29,variants%20in%20ATP6V1B2%20can%20cause)).

Beyond the nervous system, ATP6V0C might play roles in other diseases, though these are less well characterized. There is evidence that aberrant regulation of V-ATPase subunits is involved in cancer invasiveness, as mentioned. High ATP6V0C expression has been observed in some tumors and is correlated with aggressive behavior, presumably because it helps tumor cells survive in acidic, low-nutrient environments. Functional studies in esophageal cancer cells (KYSE lines) showed that **silencing ATP6V0C suppressed glycolytic flux and cell invasiveness**, hinting that targeting V0 subunits could be a strategy to impair cancer metabolism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6830105/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,uptake%20and%20decreased%20lactate%20and)). In the context of kidney disease, a 2022 study suggested ATP6V0C downregulation may contribute to defective autophagy and fibrosis in renal tubular cells, via interaction with SNARE proteins required for autophagosome–lysosome fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10929200/#:~:text=Impaired%20TFEB,Google)). These are areas of ongoing research.

**Expert Insights and Therapeutic Potentials:** As a central component of V-ATPase, ATP6V0C is considered a potential **therapeutic target** in certain conditions. Pharmacologically, *general* V-ATPase inhibitors like bafilomycin are too toxic for systemic use, but researchers are exploring ways to target specific V-ATPase isoforms or accessory interactions. For example, one approach has been to disrupt the interaction of V-ATPase with the actin cytoskeleton in osteoclasts to treat osteoporosis. Small molecules such as enoxacin were found to selectively inhibit the V-ATPases in osteoclasts by blocking the binding of the V1 sector to microfilaments, thereby reducing bone resorption without globally inhibiting all V-ATPases ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=identified%20unexpected%20roles%20for%20V,enoxacin%20have%20proven)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=are%20two%20molecules%20that%20emerged,prove%20useful%20in%20the%20clinic)). This specificity arises because the osteoclast V-ATPase uses a particular isoform composition (including ATP6V0C plus the a3 subunit and others) that associates with actin. Enoxacin and related compounds showed efficacy in animal models of osteoporosis and bone metastasis, hinting that *selective V-ATPase modulators* could have clinical benefit ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=efforts%20to%20identify%20small%20molecule,ATPases%20may)). Another emerging strategy is exploiting the dependence of cancer cells on V-ATPase: some tumors rely on plasma-membrane V-ATPase to acidify the tumor microenvironment, so inhibiting V-ATPase can reduce metastasis and make the environment less favorable for invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=include%20acidifying%20an%20extracellular%20resorption,9)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=for%20loading%20neurotransmitters%20in%20neurons,6)). While no ATP6V0C-specific inhibitor exists, the subunit is part of the drug-binding c-ring, so any V0-directed inhibitor would act on it. Researchers are also interested in **ATP6V0C as a biomarker**: for instance, elevated expression of V0 subunits might predict tumors that would respond to pH-disrupting therapies, or mutations in ATP6V0C could be diagnostic for certain neurodevelopmental disorders.

**Current and Future Directions:** The latest research (2022–2024) continues to deepen our understanding of ATP6V0C. Structural biologists achieved near-atomic resolution structures of the human V-ATPase in 2020, revealing how subunit *c* and its partners assemble and indicating conformational changes during rotary catalysis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=,Google%20Scholar)). These structures confirm the 1:1:10 stoichiometry of a:a2:c-ring subunits (consistent with 9 c and 1 cʺ in the ring) and provide templates for modeling disease mutations. On the clinical side, ongoing genotype-phenotype mapping of ATP6V0C variants (including studies in 2022 and 2023) is defining the spectrum of neurological disease and may uncover milder phenotypes or tissue-specific effects of partial V-ATPase dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=match%20at%20L1164%20Zhang%20Y,Google%20Scholar)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=match%20at%20L1169%20Liang%20M,1.%20%5BDOI%5D%20%5BPubMed%5D%20%5BGoogle%20Scholar)). There is also growing interest in how **modulating V-ATPase activity** can influence age-related diseases: for example, activating V-ATPase (to boost lysosomal degradation) is being explored in neurodegenerative disease models, whereas inhibiting V-ATPase in certain contexts (like tumor microenvironments or bone turnover) is desired in oncology and orthopedics ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=Vacuolar%20H%5E%7B%2B%7D,nutrient%20and%20energy%20sensing%2C%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=identified%20unexpected%20roles%20for%20V,which%20relates%20to%20the%20specialized)). 

In summary, **ATP6V0C is a vital component of the proton pump that acidifies cellular organelles**, enabling diverse physiological processes from nutrient processing to synaptic signaling. Its protein product is a multi-pass membrane subunit that forms the proton-conducting rotor of V-ATPase, working in concert with other subunits to pump H^+ ions using ATP energy. This action underlies critical pathways such as lysosomal degradation, autophagy, and neurotransmitter storage. ATP6V0C predominantly localizes to endo-lysosomal membranes (and specialized plasma membranes), reflecting the sites of acidification in the cell. Disruption of ATP6V0C can derail these processes, as evidenced by recent discoveries linking *ATP6V0C mutations to human disease*. Ongoing research and expert analyses emphasize that **proper regulation of V-ATPase (and thus ATP6V0C) is central to cellular homeostasis**, and manipulating this proton pump – whether by genetic means or targeted drugs – holds potential for treating diseases ranging from epilepsy to cancer ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Catabolic%20processes%2C%20such%20as%20endocytic,genetic%20and%20functional%20evidence%20linking)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=Vacuolar%20H%5E%7B%2B%7D,nutrient%20and%20energy%20sensing%2C%20and)).

**References:** *(Publication dates and sources are included in citations for verification.)*

## Citations

1. AnnotationURLCitation(end_index=395, start_index=206, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=thereby%20creating%20the%20proton%2FpH%20gradient,conducted%20in%20Saccharomyces%20cerevisiae%20revealed')
2. AnnotationURLCitation(end_index=516, start_index=396, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function')
3. AnnotationURLCitation(end_index=881, start_index=746, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=V,resorption%20compartment%20to%20solubilize%20bone')
4. AnnotationURLCitation(end_index=1002, start_index=882, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function')
5. AnnotationURLCitation(end_index=1337, start_index=1178, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,silico%20modelling%20suggested%20that%20the')
6. AnnotationURLCitation(end_index=1477, start_index=1338, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Vacuolar,impair%20brain%20development%20and%20synaptic')
7. AnnotationURLCitation(end_index=1821, start_index=1697, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=complex%20,By%20similarity%29%20Specific%20Function')
8. AnnotationURLCitation(end_index=1962, start_index=1822, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=include%20acidifying%20an%20extracellular%20resorption,9')
9. AnnotationURLCitation(end_index=2212, start_index=2092, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function')
10. AnnotationURLCitation(end_index=2534, start_index=2407, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205')
11. AnnotationURLCitation(end_index=2731, start_index=2535, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=conservation%2C%20transmembrane%20transport%2C%20acidification%20of,subunits%2C%20forms%20the%20hydrogen%20pore')
12. AnnotationURLCitation(end_index=3116, start_index=2989, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205')
13. AnnotationURLCitation(end_index=3237, start_index=3117, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=Proton,By%20similarity%29%20Specific%20Function')
14. AnnotationURLCitation(end_index=3744, start_index=3656, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1')
15. AnnotationURLCitation(end_index=4103, start_index=3962, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved')
16. AnnotationURLCitation(end_index=4460, start_index=4319, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved')
17. AnnotationURLCitation(end_index=4652, start_index=4543, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=ATP6V0C%2C%20a%20three,4')
18. AnnotationURLCitation(end_index=4904, start_index=4733, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=of%20five%20different%20subunits%3A%20a%2C,provided%20by%20RefSeq%2C%20Nov%202010')
19. AnnotationURLCitation(end_index=5188, start_index=5017, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=of%20five%20different%20subunits%3A%20a%2C,provided%20by%20RefSeq%2C%20Nov%202010')
20. AnnotationURLCitation(end_index=5682, start_index=5594, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1')
21. AnnotationURLCitation(end_index=6059, start_index=5953, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=c%E2%80%B2%E2%80%B2,1')
22. AnnotationURLCitation(end_index=6169, start_index=6060, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=ATP6V0C%2C%20a%20three,4')
23. AnnotationURLCitation(end_index=6967, start_index=6879, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=V,1')
24. AnnotationURLCitation(end_index=7093, start_index=6968, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=the%20movement%20of%20protons%20across,1')
25. AnnotationURLCitation(end_index=7364, start_index=7237, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,1%20%2C%205')
26. AnnotationURLCitation(end_index=7672, start_index=7514, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=ATP6V0C%20is%20the%20bafilomycin%20A1,by%20a%20significant%20decrease%20in')
27. AnnotationURLCitation(end_index=8123, start_index=7965, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=ATP6V0C%20is%20the%20bafilomycin%20A1,by%20a%20significant%20decrease%20in')
28. AnnotationURLCitation(end_index=8526, start_index=8356, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=shown%20previously%20that%20bafilomycin%20A1,terminal%20fragments%2C%20and%20inhibited')
29. AnnotationURLCitation(end_index=8697, start_index=8527, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did')
30. AnnotationURLCitation(end_index=9616, start_index=9493, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=,This%20gene%20encodes%20the%20V0')
31. AnnotationURLCitation(end_index=9786, start_index=9617, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=essential%20housekeeping%20enzymes%20in%20eukaryotic,and%20pumping%20protons%20across')
32. AnnotationURLCitation(end_index=10187, start_index=10052, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=V,resorption%20compartment%20to%20solubilize%20bone')
33. AnnotationURLCitation(end_index=10357, start_index=10188, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=essential%20housekeeping%20enzymes%20in%20eukaryotic,and%20pumping%20protons%20across')
34. AnnotationURLCitation(end_index=10749, start_index=10626, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=,This%20gene%20encodes%20the%20V0')
35. AnnotationURLCitation(end_index=11096, start_index=10970, title='Role of vacuolar acidification in protein sorting and zymogen activation: a genetic analysis of the yeast vacuolar proton-translocating ATPase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC360825/#:~:text=Role%20of%20vacuolar%20acidification%20in,1')
36. AnnotationURLCitation(end_index=11682, start_index=11543, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Vacuolar,impair%20brain%20development%20and%20synaptic')
37. AnnotationURLCitation(end_index=12017, start_index=11847, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did')
38. AnnotationURLCitation(end_index=12429, start_index=12259, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did')
39. AnnotationURLCitation(end_index=12751, start_index=12581, title='ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3973706/#:~:text=knockdown%20was%20validated%20by%20quantitative,A1%2C%20a%20concentration%20that%20did')
40. AnnotationURLCitation(end_index=13606, start_index=13439, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=%28Supplementary%20Table%201%20%29,presentations%20when%20compared%20to%20patients')
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42. AnnotationURLCitation(end_index=14555, start_index=14412, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Dmel,hypothesis%20that%20haploinsufficiency%20of%20ATP6V0C')
43. AnnotationURLCitation(end_index=15090, start_index=14959, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9')
44. AnnotationURLCitation(end_index=15530, start_index=15399, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9')
45. AnnotationURLCitation(end_index=15884, start_index=15706, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=include%20acidifying%20an%20extracellular%20resorption,cells%20also%20have%20plasma%20membrane')
46. AnnotationURLCitation(end_index=16392, start_index=16225, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane')
47. AnnotationURLCitation(end_index=17311, start_index=17159, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=%2832%20%2C%2031%29%2C%20NHE,The%20papillomavirus%20E5%20oncoprotein')
48. AnnotationURLCitation(end_index=17463, start_index=17312, title='The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/25002183/#:~:text=AMPK%20and%20mTOR%20play%20principal,also%20uncovered%20that%20AMPK%20is')
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51. AnnotationURLCitation(end_index=18371, start_index=18210, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=proteins%2C%20a%20number%20of%20other,The%20papillomavirus%20E5%20oncoprotein')
52. AnnotationURLCitation(end_index=18959, start_index=18804, title='Vacuolar H+-ATPase Subunit V0C Regulates Aerobic Glycolysis of Esophageal Cancer Cells via PKM2 Signaling - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6830105/#:~:text=The%20vacuolar%20H%5E%7B%2B%7D,uptake%20and%20decreased%20lactate%20and')
53. AnnotationURLCitation(end_index=19875, start_index=19687, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=%2A%20Cytoplasmic%20vesicle%2C%20clathrin,ECO%3A0000250%20UniProtKB%3AP63081%20%7C%20ECO%3A0000255')
54. AnnotationURLCitation(end_index=20043, start_index=19876, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane')
55. AnnotationURLCitation(end_index=20562, start_index=20374, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=%2A%20Cytoplasmic%20vesicle%2C%20clathrin,ECO%3A0000250%20UniProtKB%3AP63081%20%7C%20ECO%3A0000255')
56. AnnotationURLCitation(end_index=20944, start_index=20803, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=shares%2072,affected%20residues%20that%20are%20conserved')
57. AnnotationURLCitation(end_index=21212, start_index=21087, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=the%20movement%20of%20protons%20across,1')
58. AnnotationURLCitation(end_index=21897, start_index=21769, title='ATP6V0C Gene - GeneCards | VATL Protein | VATL Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP6V0C#:~:text=Compartment%20%20%7C%20Confidence%20,2')
59. AnnotationURLCitation(end_index=22165, start_index=22034, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=to%20the%20housekeeping%20functions%2C%20some,9')
60. AnnotationURLCitation(end_index=22488, start_index=22354, title='Vacuolar H+-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6448788/#:~:text=for%20loading%20neurotransmitters%20in%20neurons,6')
61. AnnotationURLCitation(end_index=23345, start_index=23178, title='V-type proton ATPase 16 kDa proteolipid subunit c | DrugBank Online', type='url_citation', url='https://go.drugbank.com/polypeptides/P27449#:~:text=azurophil%20granule%20membrane%20%2F%20endosome,membrane%20%2F%20tertiary%20granule%20membrane')
62. AnnotationURLCitation(end_index=24547, start_index=24358, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=thereby%20creating%20the%20proton%2FpH%20gradient,conducted%20in%20Saccharomyces%20cerevisiae%20revealed')
63. AnnotationURLCitation(end_index=24721, start_index=24548, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=ATP6V0C%20%28NM_001694.4%29%20%20,gait%20ataxia%2C%20nonspecific%20dysmorphic%20features')
64. AnnotationURLCitation(end_index=25279, start_index=25107, title='ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10319782/#:~:text=patient%20variants%20interfere%20with%20the,clinical%20features%20of%20the%20associated')
65. AnnotationURLCitation(end_index=25398, start_index=25280, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=,with%20a%20novel%20syndrome%20of')
66. AnnotationURLCitation(end_index=25804, start_index=25627, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=interfered%20with%20the%20interactions%20between,Caenorhabditis%20elegans%20led%20to%20motor')
67. AnnotationURLCitation(end_index=25948, start_index=25805, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=Dmel,hypothesis%20that%20haploinsufficiency%20of%20ATP6V0C')
68. AnnotationURLCitation(end_index=26526, start_index=26370, title='V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11393946/#:~:text=match%20at%20L410%20of%20TBC1D24%2C,was%20proposed%20as%20the%20primary')
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