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Open access peer-reviewed chapter

Vacuolar ATPase (V-ATPase) Proton Pump and Its Significance in Human Health

Written By

Anuj Tripathi and Smita Misra

Submitted: 15 June 2022 Reviewed: 28 July 2022 Published: 23 August 2022

DOI: 10.5772/intechopen.106848

Ion Transporters IntechOpen
Ion Transporters From Basic Properties to Medical Treatment Edited by Zuzana Sevcikova Tomaskova

From the Edited Volume

Ion Transporters - From Basic Properties to Medical Treatment

Edited by Zuzana Sevcikova Tomaskova

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Abstract

Vacuolar H + -ATPases (V-ATPase), is an ATP-dependent proton transporter that transports protons across intracellular and cellular plasma membranes. V-ATPase is a multi-protein complex, which functions as an ATP-driven proton pump and is involved in maintaining pH homeostasis. The V-ATPase is a housekeeping proton pump and is highly conserved during evolution. The proton-pumping activity of V-ATPases allows acidification of intracellular compartments and influences a diverse range of cellular and biological processes. Thus, V-ATPase aberrant overexpression, mis-localization, and mutations in the genes for subunits are associated with several human diseases. This chapter focuses on a detailed view of V-type ATPase, and how V-ATPase contributes to human health and disease.

Keywords

  • pH
  • homeostasis
  • V-ATPases
  • proton pump
  • human health

1. Introduction

The maintenance of pH homeostasis is vital for the survival of all cells and organisms. Changes in intracellular pH affect the acid-base balance of the cells, and dictates the protonation state of different acid-base groups present on the macromolecules. This greatly influences their biochemical properties and function. Deregulation of the pH homeostasis affects enzymatic functions affecting the cell cycle and other biochemical processes and can be deleterious for cellular health and survival. In addition to the cytosol, each organelle has its specific pH requirement to function normally. The pH within the cytosol and the organelles can vary up to 3 units ranging from nearly neutral to highly acidic. To maintain the pH all eukaryotic cells, have a large regulatory network of secretory pathways within the cell cytosol and organelles including the nucleus, and outside the plasma membrane [1, 2]. These secretory pathways, from plasma membrane to organelles and nucleus are well connected by continuous exchange of nutrients, signaling molecules, membrane proteins, and lipids. The maintenance and assembly of these complexes and pathways is highly energy consuming for cells. Cellular energy requirements for these processes are partly fulfilled by local cytoplasmic metabolic energy, but a larger extent of the energy required for development and homeostasis maintenance of the cytosol and organelle lumen is provided by ion pumps [3, 4].

Proton pumping ATPases are a class of these membrane transporters that act as master players in the transport of protons across membranes from Archaea to humans. pH homeostasis is achieved via proton influx and efflux by the proton pumping ATPases. These ATPases either actively transport proton deriving energy from ATP hydrolysis, or they use the proton gradient for ATP synthesis to perform multiple cellular functions. The ATPases are broadly classified into four classes: the F- and A-type ATP synthases, the V-type transporters, the P-type transporters, and the ATP binding cassette (ABC) multidrug efflux pumps. The A-type ATPase, which are present in archaea and bacteria, help survive the extreme conditions and act by synthesizing ATP coupling with H+ or Na+. F-type ATPase are well conserved among species and are the primary source of cellular energy production in the living organisms. They act as ATP synthases. The P-type ATPases, also known as E1–E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. The P-ATPase are essential for cell survival, and they maintain the gradient of many crucial ions including Na+, Ca+, K+, and H+ using ATP hydrolysis. There are different type of P-type ATPases. ABC-transporters utilize the energy of ATP binding and hydrolysis to transport various substrates across cellular membranes. ABC-transporters are importers of nutrients and other molecules, or as exporters of toxins and drugs, among others. V-type ATPase is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. They couple ATP-hydrolysis with H+ pumping.

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2. Vacuolar-type ATPase (V-ATPase)

The Vacuolar proton-translocating ATPase (V-ATPase) is a highly conserved and highly efficient ATP driven proton pump and a member of the rotary ATPase protein family [5, 6]. V-ATPase are ubiquitous multi-subunit complexes composed of two large domains: the soluble V1 domain, which hydrolyzes ATP, and the membrane-embedded V0 domain, which transports protons [5, 7, 8, 9]. V-ATPase were first discovered in vacuoles of yeast and plants. V-ATPase perform active proton transport across membranes by coupling it with ATP hydrolysis. V-ATPase are also identified in the lysosomes, clathrin-coated vesicles, secretory vesicles, endosomes, Golgi-derived vesicles and other subcellular locations. They are also present on the plasma membrane. V-ATPase acidifies lysosomes/vacuoles, Golgi, and the endosomal compartments of all eukaryotes. The plasma membrane V-ATPase present on certain specialized mammalian cells aid in proton export from the cell [10]. In intracellular compartments, V-ATPase is critical for multiple cellular processes, this includes protein processing and secretion, endocytosis and vesicle trafficking, zymogen activation, and autophagy [5, 10]. V-ATPase was initially identified and characterized for its role in the acidification of intracellular vesicles and organelles, which is necessary for many essential cell biological events to occur [9, 10, 11]. In addition to its housekeeping cellular function, many specialized cell types in various organ systems such as the kidney, bone, male reproductive tract, inner ear, olfactory mucosa, and others, use plasma membrane V-ATPases to perform specific activities that depend on extracellular acidification [12, 13, 14, 15, 16].

Finally, and importantly, it is increasingly apparent that V-ATPases are central players in other normal and pathophysiological processes that directly contribute to human health in many different and sometimes unexpected ways. This chapter will cover the basic knowledge of V-ATPase, its physiological contribution and recently emerging unconventional roles of the V-ATPase in human health.

2.1 Structure and role of V-ATPases

V-ATPase are multi-subunit protein complex with two domains the V1-domain and V0-domain. The peripheral domain V1, is cytosolic and responsible for ATP hydrolysis, and an integral domain V0, is embedded in the membrane and is involved in proton translocation across the membrane [17]. The mammalian V-ATPase is composed of 13 subunits in total. Of these 13 subunits, V1 domain has 8 peripheral proteins and the V0 domain has 5 membrane intrinsic proteins (Figure 1) [17]. The V1 domain performs ATP binding, hydrolysis and drives the active proton translocation from the V0 domain. Alternate arrangement of V1A and V1B subunits forms the hexameric core of the V1 domain. The V0 core ring domain is made up of subunits V0c, V0c’ and V0c”. The V0 core ring domain is located next to the V0a and V0e subunits. The V0 and V1 domains are connected by a central stalk. The central stalk is composed of the V1D, V1F and V0d and is supported by the peripheral stalk domain. The peripheral stalk is made from the subunits V1C, V1E, V1G V1H and the N-terminal of the V0a. V0a is a key subunit of the V0 domain. It has a bi-lobed N-terminal which interacts with the V1H and V1C near the membrane interface and V1A on the outer surface [18, 19, 20]. Arginine at position 735 and two hemi channels of the V0a subunits are crucial for its proton pumping function.

Figure 1.

Structure of vacuolar ATPase (V-ATPase): The V-ATPase is made of a peripheral V1 domain that hydrolyzes ATP and an integral V0 domain that translocated protons across the membranes. Structural model of the vacuolar V-ATPase showing subunit composition. The transmembrane domain (V0) consists of the subunits a–d with several isoforms of the c subunit (denoted in small letters) and the cytosolic domain (V1) made up of the A, B, C, D, E, F, G, and H subunits. Hydrolyzation of ATP is done on the intersection of the V1A and V1B subunits, and generated power rotate V-ATPase rotor formed by the V0d, V1D, and V1F subunits. The “c-ring” couples the energy generation by ATP hydrolysis and translocation of the protons from the cytosol to the lumen.

Although V-ATPase subunits are highly conserved, some subunits have cell/tissue specific isoforms that govern V-ATPase subcellular localization. These isoforms are associated with subsets of V-ATPases that perform specialized functions. However, specialized V-ATPases represent a mixture of cell type selective isoforms and ubiquitous isoforms [13, 21, 22, 23]. Mammals have different isoforms for subunits V0a, V0d, V1B, V1C, V1E, and V1G, besides the ubiquitous ones. Subunit V0a is most important in determining the subcellular localization of the V-ATPase, it has four isoform in humans which are found in different tissues and guide the subcellular locations of the V-ATPase. Isoform V0a1 is present in the V-ATPase of the presynaptic plasma membrane and synaptic vesicles [24]. V0a2 is found on the plasma membrane of the mammary epithelial cells [25]. V0a2 is also found on the renal proximal tubule cells [26] and sperm acrosomes [27]. V0a3 is found in the V-ATPase on the plasma membrane in the ruffled borders of the osteoclast [28], secretory endocrine tissues [29], pancreatic islets [22] and premature melanosomes [30, 31]. While V0a4 is found in the renal intercalated cells [31] and clear cells of epididymis [32]. V0a3 and V0a4 isoforms are also overexpressed in tumor tissues, with V0a4 primarily present on the plasma membrane and responsible for acidification of the extracellular matrix [33]. Other subunits in mammals that have multiple isoforms are V1G, which has three and V1B, V1C, V1E and V0d all have two [34]. V1B1 is expressed in renal and epididymal cells [35], while V1E1 in testis and acrosome [27]. V1C2 in the lungs and kidneys [36], V1G3 in kidneys [36] and V0d2 in kidneys and bones [37].

V-ATPase are responsible for acidification of endosomal, lysosomal compartments in the cell. In addition, they participate in other biological processes, such as toxin delivery, viral entry, membrane targeting, apoptosis, regulation of cytoplasmic pH, proteolytic process, and acidification of intracellular systems, are important roles of V-ATPases. Plasma membrane V-ATPase are responsible for the acidification of the urine in kidney and the FVreabsorption of bicarbonate ions. They help in bone resorption in osteoclast and facilitate tumor metastasis. Maintain the acidification of the sperm acrosome and activation of the different hydrolytic enzymes to ensure fertilization with the ovum.

2.2 V-ATPase regulation

Transmembrane proton transport by the V-ATPase is regulated in several different ways to modify pH in extracellular compartments or within intracellular vesicles. It is regulated by assembly process to form the holoenzyme and/or by trafficking to the appropriate cellular location.

2.2.1 Reversible assembly and disassembly

V-ATPase is a multi-subunit complex comprising of two distinct domains, the membrane integrated domain V0, responsible for proton pumping and the free cytosolic domain V1, which carries out the ATP-binding and hydrolysis. As the V0 domain is membrane integrated, its subunits are polymerized on the rough endoplasmic reticulum during the translation process and are processed via the vesicular transport pathway. Whereas the subunits of the V1 domain are synthesized on the free cytosolic ribosomes. Different subunits of each domain assemble to form the V1 and V0 domain before the formation of the V-ATPase holoenzyme. To form the complete functional V-ATPase holoenzyme the association of the V0 and V1 domain is essential. The efficiency of the V-ATPase function is dependent on its assembly process, as the V1 and V0 domain independently are incapable of performing ATP hydrolysis and proton pumping, which are their respective functions [38, 39]. The phenomenon of the reversible assembly and disassembly of the V1 and V0 was first described for yeast, where it was noted that the V1 domain dissociates from the V0 domain in a reversible manner in the absence of glucose [20]. In one study with the Manduca sexta larval midgut the authors reported that the goblet cells of the apical membrane lose the proton pumping activity of the plasma membrane V-ATPase upon dissociation of its V1 domain [40]. It is also known that the levels of cAMP and hormone induced protein kinase A (PKA) can regulate the plasma membrane V-ATPase assembly and activity in the blowfly salivary glands [41, 42]. It is shown that for the exocytosis of the presynaptic vesicles in the neuronal cells the V1 disassembly is required on the mature exosomes, which fuse with the plasma membrane in the active zone and releases the exosomal contents in synaptic cleft [43]. The V1 domain reassembles to V0 on the neural membrane post release [43]. Using the cultured hamster kidney cells and sub cellular fractionation of different endosomal vesicles during maturation, it is known that the level of acidification in the lumen directly correlates with the level of V-ATPase of the isolated vesicles [4]. Glucose also affects the assembly of V-ATPase in human cells. Glucose starvation affects the V-ATPase assembly and activation by AMP kinase and phosphatidylinositide 3-kinase (PI3K)/Akt signaling pathway [44, 45]. The level of V-ATPase also goes high in lysosomes during dendritic cell maturation [46]. Although the mechanistic understanding of the assembly process is not well understood and needs more research to decipher it, however it is shown that subunit V1C plays a central role in establishing interaction between the V1 and V0 domain during assembly assisted by their RAVE (regulator of the ATPase of vacuolar and endosomal membranes) complex in yeast [47, 48, 49].

2.2.2 Regulated trafficking of the V-ATPase

A second mechanism of controlling V-ATPase activity is via regulated trafficking of the functional holoenzyme. This occurs primarily in acid-secreting cells in a variety of different tissues [8, 50]. In proton-secreting intercalated cells of the kidney collecting duct and analogous organs in lower vertebrates and amphibian epidermis, regulation of transepithelial proton secretion is achieved by the exo- and endocytotic recycling of tubulovesicular structures containing high levels of V-ATPase holoenzymes in their membranes [8]. Trafficking of the V-ATPase to the plasma membrane and organelle membrane is also used by osteoclast [51] and the epididymal cells [52] to maintain the acidic pH of the extra cellular space and epididymal fluid respectively. The assembly and localization of V-ATPase are linked processes and are regulated by cellular needs. Although more studies are needed to establish the mechanism of assembly and trafficking process, but it is shown that the disassembly of V1 from holocomplex is required for endosomal vesicles to localize the cargo to the plasma membrane and then V1 is reassembled to form the holoenzyme complex [43].

Apart from the signaling molecules mentioned above there are other kinases and proteases that are also involved in the assembly and trafficking of V-ATPase. In the intercalated renal cells G-protein coupled receptor Gpr116 is shown to negatively regulate the surface expression of proton pump V-ATPase [53]. Cytoskeletal proteins have a well-established role in trafficking the cargo from cytosol to the plasma membrane and vice versa. It has been shown that subunits V1B and V1C are associated with the actin of cytoskeleton and are essential for the movement of the V-ATPase cargo to the plasma membrane [54]. Profilin is a protein involved in actin polymerization. Subunits V1B1 and V1B2 also have a profilin-like domain [55]. Research has shown that use of microtubule depolymerizing drugs colchicine and vinblastine on turtles inhibits the excretion of protons in their urine upon carbon dioxide exposure, which alters the plasma pH [56]. Microtubule depolymerizing drugs also inhibit the V-ATPase localization and function in the renal intercalated cells [57] and epididymal clear cells [58]. PKA mediated phosphorylation of the subunits V1A and V1C upon increase in cAMP levels is necessary for the increase in the expression levels of V-ATPase on cell surface [12, 42, 59]. Activation of PKA upon bicarbonate stimulation is also essential for sensing acid-base balance and proton excretion by the kidneys [60, 61]. Furthermore, AMP kinase also phosphorylates the V-ATPase subunit V1A and regulates its trafficking in renal epithelial cells [62]. The regulation of V-ATPase by phosphorylation is an interesting area for understanding the many different patterns of expression and regulation of V-ATPase activity in a variety of cells and tissues, as well as its pathophysiological dysfunction leading to human disease.

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3. Physiological function of V-ATPase

3.1 Function of intracellular V-ATPases

The pH of cell and organelle lumen is an important governing parameter for the function of various organelles and is mainly controlled by V-ATPase-dependent proton transport. Receptor recycling and release of the ligands internalized via the receptor mediated endocytosis requires acidic pH of the endosomal lumen, which is maintained by the V-ATPase [63]. Density of the V-ATPase receptor on the cell surface is also synchronized by receptor recycling and it impacts the response and sensitivities for hormones and growth factors. In many cases ligand-receptor dissociation allows both protease delivery to lysosomes and the return of Mannose 6-phosphate receptors (MPRs) to the trans-Golgi network [64]. Acidification of endosomal lumen also plays important role in the formation of certain carrier vesicles, for transport of the cargo in the endocytic and secretory pathways [65]. When low pH is found within endosomes many pathogens take entry in cytoplasm. Low endosomal pH also promotes the entry of pathogenic agents such as diphtheria toxin and anthrax toxin, which first enter endosomes and then are released from late endosomes [66]. Acidic pH of the cytoplasm helps in fusion of enveloped viruses such as Influenza and Ebola, which is required for the insertion of viral genomes into the cytosol [67]. Some secretory vesicles are acidified by the V-ATPase to facilitate the proteolytic processing in prohormones such as proinsulin [68], in dendritic cell lysosomes [69], and in neurotransmitter antiporters [5, 70]. In lysosomes, a variety of proton/amino acid symporters use the proton gradient to drive amino acid efflux [71]. Lysosomal enzymes require acidic pH for activity, and for proper degradation of macromolecules [72]. These macromolecules are brought to lysosomes either endocytically via chaperone-mediated autophagy, or through macroautophagy, a catabolic program for recycling cellular components [73, 74, 75]. During autophagy process, acidification is essential for both autophagosomes and lysosome fusion as well as subsequent breakdown of luminal contents [76, 77, 78]. In normal condition, autophagy occurs at low basal levels but can be upregulated during times of energy stress or starvation (Figure 2) [79].

Figure 2.

The physiological importance of V-ATPase expression in membranes of different organs and tissues. Specific V-ATPase holoenzymes are expressed typically at the apical surface of proton-secreting cells in numerous tissues throughout the body and plays unique roles on place. Change in expression level of V-ATPase in specific tissues effected unique physiological role of these tissues/organs.

3.2 Function of plasma membrane V-ATPases

Renal α-intercalated cells, osteoclasts, cells of the epididymis, sustentacular cells of the olfactory epithelium and many polarized animal cell’s plasma membrane have V-ATPases for transport of protons to the extracellular space [5, 52, 80]. Mutations in subunit V0a3, of the plasma membrane V-ATPase of osteoclasts cause severe congenital form of osteopetrosis in humans [81, 82]. Renal α-intercalated cells respond to alterations in plasma pH by rapidly adjusting the density of apical V-ATPases to pump out the excess acid from the blood into the urine to be excreted out and restore the plasma pH. Studies have shown that distal renal tubular acidosis is associated with mutations in the plasma membrane V-VATPase subunit of the α-intercalated cells [31, 83]. Similarly clear cells of the epididymal epithelium regulate the acidic pH of the epididymal fluid to keep the spermatozoa in quiescent stage for storage and proper maturation [5, 52]. Loss of V-ATPase from the plasma membrane of epididymis results in increased epididymal fluid pH, defective sperms and renders the mice infertile [14]. The V-ATPase are also significant in cancer progression and metastasis [84]. Figure 2 summarizes the broad localization and function of V-ATPases.

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4. Emerging functions of the V-ATPase

4.1 Role in cancers

Recent studies revealed the role and significance of V-ATPase in cancer. It is shown that the plasma membrane V-ATPase help maintain an alkaline intracellular environment favorable for growth and an acidic extracellular environment favorable for invasion by proton efflux from the cell [85]. V-ATPase are shown to have higher expression in proliferating cancer cells of breast, prostate, lung, ovarian, liver, pancreatic, melanoma and esophageal cancers [10]. Increased expression of V-ATPase on the plasma membrane of the breast cancer cells correlates with increased invasiveness and metastatic potential of the breast cancer cell lines [86]. The increased metastatic potential is due to decreased pH of the extracellular matrix activating the proteases that degrade the extracellular matrix and aids in epithelial mesenchymal transition.

4.2 Immunomodulation

The V0a2 isoform of Vacuolar ATPase has an immunomodulatory role in cancer and pregnancy. Research has shown that V0a2 is required for normal sperm maturation and production in addition to embryo implantation [87, 88]. In the tumor microenvironment, the N terminal domain of V0a2 polarizes monocytes to become tumor-associated macrophages (M2 type) and stimulates different monocyte subsets through the endocytosis pathway [89]. Studies demonstrated that V0a2 deficiency in tumor cells alters the resident macrophage population in the tumor microenvironment and affects in vivo tumor growth [90]. Subunit V0a2 is expressed on the primary granules of neutrophils and maintains the pH in exocytotic pathway for neutrophil activation [91]. These studies indicate V-ATPase importance as an immunomodulator in immune responses.

4.3 Warburg effect

Shifting of cancer cells from oxidative phosphorylation to aerobic glycolysis for energy production is referred as the Warburg effect [92]. Robust glycolytic cancer cells produce lots of acid and need an efficient proton pumping system to restore the intracellular pH homeostasis. Several studies have shown that for this purpose cancer cells rely on V-ATPase more than any other proton exchangers like Na+H+ exchangers, bicarbonate transporters and proton-lactate symporters to restore the alkaline intracellular pH [93]. V-ATPase also facilitate the activation of hypoxia induced factor 1 (HIF-1) in glycolytic cancer cells which promotes their growth [94].

4.4 Acid proteases

Dissolution of extracellular matrix is an essential process needed for the initiation of cancer invasion and metastasis. Proteases including cathepsins, metal requiring matrix metalloproteinases (MMP) and gelatinases carry out dissolution of extracellular matrix [95, 96, 97]. All these proteases are proenzymes that need an acidic pH for activation. The V-ATPase are involved in acidification of the extracellular space around the tumor to activate these proteinases and thus facilitate tumor invasion.

4.5 Drug resistance and V-ATPase inhibitors

Change in pH of microenvironment may influence sensitivity of tumor cells to chemotherapeutic drugs [98]. Recent studies suggests that the use of V-ATPase inhibitors not only causes cytosolic pH alterations leading to cell death but also enhances drug uptake, thereby making an effective component of combinatorial treatment to cancer [99]. In ovarian cancer, V0a2 expression contributes in cisplatin mediated drug resistance and selective inhibition of V0a2 could serve as an efficient strategy to treat chemo-resistant [100]. Currently, Apicularen and archazolids are reported to be potent and specific inhibitors of V-ATPase [101]. Thus combinatorial use of small molecule inhibitors for V-ATPase along with cancer drugs will be an effective strategy to treat/combat multi drug resistance cancers [102].

4.6 Autophagy

Autophagy is the natural process of selective degradation or recycling of macromolecules by autophagosomes to lysosomes [103]. In tumors, cells show dependency on autophagy as tumor progress from primary metastatic stage [104]. The proton pumping activity of V-ATPase is responsible for activation of lysosomal acid hydrolases, which degrade cargo uptake from autophagosomes [105]. Reports confirm the requirement of functional V-ATPase for autophagy [106]. Additionally V-ATPase inhibitor Bafilomycin is used as classic inhibitor of autophagy [107], but the exact role of V-ATPase in membrane dynamics of autophagy flux is not clear.

4.7 Signaling

The endo-lysosomal pathway is important for both positive and negative regulation of signaling pathways [108, 109]. The involvement of V-ATPase in signaling was first reported, by showing that inhibition of V-ATPase by Bafilomycin affected internalization of the epidermal growth factor receptor (EGFR) [77]. Studies demonstrated, V-ATPase has been also involved in multiple signal transduction pathways [110] like Notch, Wnt, transforming growth factor-β (TGF-β) and mammalian Target Of Rapamycin (m-TOR). Notch signaling depends on the endolysosomal pathway for its activation, maintenance and degradation of its key pathway mediators [111, 112, 113]. Some reports show that through its involvement in acidification of endolysosomal pathway, V-ATPase is required for the activation of Notch in endosomes as well as for its degradation in the lysosomes of Drosophila and mammalian cells [48, 114, 115, 116, 117]. V-ATPase and Notch crosstalk is significantly important for normal growth as well as in Alzheimer’s and cancer [118]. Wnt signaling pathway regulates numerous physiological processes. Dysregulation of Wnt pathway is linked to various pathologies including tumor metastasis [119, 120, 121]. The ATP6ap2 acts as an adaptor molecule between V-ATPase and Wnt receptor complex LRP 5/6 [122]. Furthermore, V-ATPase indirectly regulates Wnt signaling mediator β-catenin through Notch mediator NICD and autophagy [119, 123]. Mutations in V0a2 are associate with elevated TGFβ signaling in patients with Cutis Laxa disease due to glycosylation defects [124]. V0a2 inhibition activates Wnt signaling in a specific subtype of breast cancer called triple negative breast cancer (TNBC) and TGF-β pathway in mammary epithelial cells [25, 125]. mTOR regulates cellular growth during stress. Upon stimulation by amino acids during stress, V-ATPase activate the cascade of signaling events via RagA and RagC followed by GTP hydrolysis and loading of the mTOR-complex1 (mTORC1) to the lysosomal surface and activated mTORC1 switches the antigrowth to pro-growth signals [126, 127, 128, 129].

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5. V-ATPases in human disease

5.1 Cancer

As mentioned above the role of V-ATPase in cancer is evident. V-ATPases contribute to the survival and spread of cancer cells through several mechanisms. One of the ways that V-ATPases have been proposed to promote tumor cell survival is by maintaining an alkaline cytosolic pH, in contrast to normal cells which use the Na+K+ proton pump to maintain their pH. Tumor cells with hypoxia and high glycolytic metabolic stage have elevated levels of cytosolic acid [130]. Reports indicates that cancer cells increase V-ATPase biosynthesis and its targeting to the plasma membrane in order to secrete this increased proton extracellularly and restore the intracellular pH to support cell growth [131]. Studies have shown that V-ATPase is localized in plasma membrane of human breast tumors, lung tumors, osteosarcoma and numerous other cancer cell lines, including Ewing sarcoma, melanoma, breast, liver, pancreatic, prostate and ovarian cancer [33, 86, 99, 100, 132, 133, 134, 135, 136, 137]. Blocking acid extrusion from the cancer cells after treating with V-ATPAse inhibitors has shown to increase apoptosis of these cells [138, 139, 140, 141]. Decreased pH of the extracellular milieu driven by the V-ATPase of the cancer cells, can modify chemotherapeutic drugs by protonation [98], reduces drug uptake, its retention in the cytosol and cytotoxic effect on tumor [142, 143]. Thus, there is an enhanced efficacy of the chemotherapeutic drugs when used in combination with V-ATPase inhibitors [144, 145]. Some V-ATPase mediated mechanisms can be cancer subtype specific, as seen for prostate cancer. Prostate cancer cells need androgen receptor for proliferation. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcriptional repressor for androgen receptors [146, 147]. A recent study showed that inhibition of V-ATPase, reduces prostate cancer growth by reducing the iron-dependent hydroxylation followed by degradation of HIF1α [146]. Overexpression of cathepsins, is associated with worse prognosis for different human cancers [148]. Inhibition of cathepsins reduces metastasis and spread of breast cancer in mice [149, 150]. Activation of secreted cathepsins happens in the acidic extracellular space, which are acidified by the plasma membrane V-ATPase. V-ATPases have been detected at the plasma membrane of numerous invasive cancer cell lines. Since plasma membrane targeting is controlled by isoforms of subunit a, it is likely that cancer cells will upregulate particular isoforms in order to increase localization of V-ATPases to the plasma membrane [33, 151]. Immunofluorescence studies in breast carcinoma showed that the levels of V0a3 isoform are higher in the invasive tumor cells relative to non-invasive and normal breast tissues [132], and inhibition of V0a3 reduces metastasis of murine melanoma [137]. Study with prostate cancer cell line PC3, demonstrate that there is an increased expression of V0a1 and V0a3 isoforms on the plasma membrane and siRNA mediated knock down of these isoforms reduces it growth and in-invasion in cell culture [136]. While V0a2 is expressed in ovarian cancer cell lines [100], V0a4 is shown to be overexpressed in metastatic breast cancer cell line MDA-MB231 [33]. Inhibition of V-ATPase hinders the activity of matrix metalloproteinase (MMP) MMP2 and MMP9 in different cancers in vitro [100, 135] and in vivo [137]. Significance of the V0a4 isoform in invasion and metastasis of breast tumors is established by the CRISPR/ Cas9 mediated knock down of the ATP6V0A4 gene in the murine breast cancer cell line 4 T1 and loss of its metastatic ability [152]. Different subunits have significance for specific cancer’s, V1G1 is necessary for stem cell in neurospheres [153], V1E1 in pancreatic cancer cells [135] and V1A1 for gastric cancer [154].

5.2 Osteoporosis and Osteopetrosis

Healthy bone mass contributes to a healthy skeleton, which is based on the synchronized activity of the osteoblasts (the bone forming cells) and osteoclast (the cells for dissolution and reabsorption of the bone matrix). Osteoclasts are multinucleated cells that attaches to the bone surface with their ruffled borders and create a very acidic compartment called resorption lacunae. It is in the resorption lacunae that solubilization and degradation of the extracellular matrix, collagen fibers and the bone matrix happens. V-ATPase are located in the ruffle borders of the osteoclast and are responsible for the maintaining the acidity of the resorption lacunae. The acidic pH of the resorption lacunae is important for activation of the multiple hydrolases needed for bone dissolution. Lack of osteoclast functioning can cause increased bone density, diminished bone strength and several skeletal defects, a condition referred as osteopetrosis. V0a3 is overexpressed in the highly resorptive osteoclast [155]. V1C1 is also present with V0a3 in the ruffle borders of the osteoclast [156]. As shown by RNAi studies the isoforms V0a3 and V1C1 are essential for the acidic pH of the resorption lacunae [156]. Isoform V0d2 is needed for cell fusion during osteoclast maturation [157] and V1B2 is also expressed in the ruffle borders [158]. Mutations in the gene TCIRG1 that encodes V0a3 are the primary cause of infantile malignant autosomal recessive osteopetrosis (present in about 50% of the cases), a rare congenital disease caused by the failure of osteoclasts function.

Another disorder associated with V-ATPase in osteoclast is osteoporosis, which is characterized by low bone mineral density due to increased bone degradation by osteoclast and low bone formation by osteoblast. Single nucleotide polymorphism in the ATP6V1G1 gene, which encodes V1G1 and total or partial loss of function of V1H subunit are shown to have association with osteoporosis [159, 160, 161].

5.3 Neurodegenerative diseases

Mutations in V-ATPase subunits isoforms are cause of different neurodegenerative disorders. Autophagy is a housekeeping process involved in the removal of abnormal and misfolded proteins and damaged organelles from the cells. Autophagy is dependent on the lysosomal function, which are heavily dependent on the acidic pH of the lysosomal compartments maintained by the V-ATPases. Autophagy is very important for terminally differentiated neuronal cells as shown by neurodegeneration in the mice upon inhibition of autophagic process [162, 163]. Many neurodegenerative disorders including Alzheimer’s disease (AD) are characterized by pathological hallmark, like increase in the misfolded protein aggregates in the brain. AD is characterized by the extracellular plagues made up of insoluble amyloid β (Aβ) fibers [164]. Proteases α, β and γ-secretase are needed for proper processing of amyloid protein. Presenilin-1 (PS1) is a cofactor for γ-secretase and mutations in PS1 gene are associated with familial AD [165]. PS1 is also needed for accurate subcellular trafficking of V0a1 to the neuronal lysosomes. Mutation in PS1 also affect V0a1 trafficking and lysosomal acidification, rescue of lysosomal acidification in PS1 knock out cells reduces Aβ build up [118]. Parkinsons, another neurodegenerative disorder is caused by buildup of α-synuclein aggregates [166]. The ATP6AP2 gene encodes the accessory subunit for V-ATPase. Mutation in ATP6AP2, also known as Renin/Prorenin receptor, causes X-linked Parkinsonism with spasticity, an early-onset form of Parkinsonism with defective lysosomal acidification [167]. Mutation in ATP6AP2 is also associated with the Wolfram syndrome, a neurodegenerative disorder characterized by endoplasmic reticulum stress, childhood diabetes mellitus, severe neurological disabilities [168] and X-linked mental retardation Hedera type (MRXSH), a congenital disorder of intellectual disability, delayed motor and speech development and epilepsy [169, 170]. Many other neurodegenerative disorders which are not directly caused by V-ATPase defects nevertheless exhibit lysosomal impairment [171]. Restoration of lysosomal function therefore represents an attractive therapeutic concept that should be investigated further.

5.4 Distal renal tubular acidosis (DRTA) and hearing loss

Intercalated cells of the kidney are the primary regulators of the physiological urine acidification. They sense the physiological changes in the acidosis/alkalosis levels and balance it by reorganize the V-ATPase on the apical membrane. The V-ATPase on the plasma membrane is responsible for acidification of the urine and maintainence of the physiological pH by the kidneys [23, 80, 172]. The isoforms V1B1 and V0a4 are characteristics of the apical membrane V-ATPase [173, 174]. As these V-ATPase are needed for urine acidification, mutation in the genes ATP6V1B1 and ATP6V0A4 encoding the renal isoforms leads to an autosomal recessive genetic disease called DRTA [83, 175]. It has been shown that the mutation in the genes causes V0a4 retention in the endoplasmic reticulum and not being able to perform the protonation of the urine is the cause for DRTA onset [176]. It has also been shown that mice lacking V1B1 and V0a4 develop symptoms similar to human DRTA like metabolic acidosis, hypokalemia and hearing loss [177, 178, 179]. This is treated by administering bicarbonates to regulate metabolic acidosis. Patients with ATP6V0A4 mutation also present with hearing loss. V1B1 and V0a4 isoforms are also expressed in the human inner ear and maintain the endolymph pH homeostasis, necessary for mechano transduction sensitivity and auditory function. V0a4 knockout mice present severe deafness associated with enlarged cochlear and endolymphatic compartments [178]. Alkali treatment does not help restore the deafness; the conition is treated by the use of hearing devices.

5.5 Cutis laxa (CL) and wrinkly skin syndrome (WSS)

Cutis laxa is a skin condition, characterized by loss of elasticity in the skin tissue. Skin losses its strength to stretch and instead hangs in loose folds, becomes saggy and gives wrinkled appearance to the face and others parts of the body. CL is also associated with variable neurological and skeletal alterations. CL can be both inherited and/or acquired and is caused by autosomal recessive inheritance of V-ATPase subunit mutations. It is characterized by impaired Golgi function, glycosylation defects and delayed retrograde transport from Golgi to endoplasmic reticulum, thus resulting in abnormal elastic fibers that affect the skin and internal organs [180, 181]. WSS is also a type of CL caused by mutation in ATP6V0A2 gene. Besides V0a2 mutations, mutations in ATP6V1E1 and ATP6V1A, were also recently associated with CL. However, each mutation result in CL, but they vary in clinical manifestation, as it is multi-systemic and also includes risk of cardiopulmonary problems [181].

5.6 Other roles of V-ATPase

Subunit V0a4 also targets the V-ATPase to the apical membrane of epididymal clear cells, but its association with male fertility are not well understood for patients with V0a4 mutations [8]. Some studies have shown that the levels of the V0a2 is higher in the fertile male compared to infertile. Study also shows that the higher levels of V0a2 are associated with Sperm capacitation [88]. Zimmermann-Laband syndrome (ZLS) is a rare genetic disorder characterized by gingival fibromatosis (abnormally large gum), defects in craniofacial features, nails, ear and nose. In some cases, ZLS is also associated with mental retardation. Two patient suffering with ZLS showed mutation in the ATP6V1B2 gene resulting in substitution of proline instead of arginine in the V1B2 subunit.

Viruses like influenzas virus [182], Sindbis virus [183],and West Nile virus [184] use the endosomal route for infecting the host cells and delivering its genetic material. Host V-ATPase are needed for endosomal compartment acidification, which also facilitates the uncoating of the virus and release of its genetic material. Pathogenic fungi use its V-ATPase in establishing the infection, as demonstrated that impairment of V-ATPase activity, either by V-ATPase inhibitors or deletion of specific subunits/assembly factors, dramatically diminishes or inhibits virulence-associated traits [185, 186]. For example, knocking down VPH2 in Candida albicans reduced candidiasis in mice model [185]. Other examples are the V0c subunit for C. albicans [186], V0a for Cryptococcus neoformans [187] that affects fungal infectivity and thus the fungal V-ATPase subunits can be used as therapeutic targets.

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6. Conclusions

V-ATPase are proton pumping ATPase with a housekeeping role of maintaining the pH of the cytosol, organelle lumen and extracellular space. V-ATPase is a multi-subunit complex with highly regulated assembly and trafficking to the right compartment. Its multi-subunit complex and different isoforms are the basis for its diverse location. It works by the rotary mechanism, has two domains: one membrane embedded, responsible for proton transport and other cytosolic, which carries out ATP hydrolysis. The reduced pH is in turn, required for processes that involve the trafficking of intracellular vesicles to their correct destination, post-translational modification of proteins in cellular compartments and the plasma membrane and activation of different proteases. It is needed for lysosomal function, autophagy, immunomodulation and endosomal maturation. V-ATPase are a key component of the renal apical layer and assist in maintaining the physiological pH and preventing metabolic acidosis. They are essential for osteoclast functioning which provides proper skeletal health by working in symphony with osteoblast. Increased plasma membrane activity of the V-ATPase is the reason for cancer metastasis. V-ATPase are also required for giving the proper skin texture. As discuss above, the V-ATPase is clearly involved in many aspects of normal physiological function, and mutation in the gene for different subunits either leading to lack of proper protein-protein interaction and/or assembly, mis-localization, loss of function of the subunits, or hyperactivity are attribute to different human diseases. There are lot of therapeutic opportunities for V-ATPases-directed therapies. Using inhibitors for the plasma membrane V-ATPase for cancer and osteoclast is a promising strategy for treating cancer metastasis and osteoporosis. Restoring the intracellular V-ATPase function could be a good approach for helping the neurodegenerative disorders associated with loss or reduced autophagy. Additionally targeting the endosomal V-ATPase can help reduce viral infection. Combating V-ATPase of the fungal pathogen can be an effective strategy to use as an antifungal drug. Although V-ATPases are known to play a role in sperm maturation and fertilization, their association to male fertility needs more research. Most of the treatment option for the V-ATPase mediated diseases are focused on elevating the symptoms not focused on eliminating the root cause. Thus, research is needed to focus on ways to rescue the activity of these disease associated mutants. Finding effective inhibitors for V-ATPase has been challenging due to their ubiquitous role, so far developed V-ATPase inhibitors are toxic and have off target effects. Thus rigorous research is needed to find effective inhibitors as increasing evidence is building, highlighting the role of V-ATPase in different human diseases.

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Anuj Tripathi and Smita Misra

Submitted: 15 June 2022 Reviewed: 28 July 2022 Published: 23 August 2022

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