Abstract
BackgroundLysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway. This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen. Lysosome pH gradients are mainly maintained by the vacuolar (H+) ATPase (or V-ATPase), which pumps protons into lysosomal lumen by consuming ATP. Dysfunction of V-ATPase affects lysosomal acidification, which disrupts the clearance of substrates and leads to many disorders, including neurodegenerative diseases.Main bodyAs a large multi-subunit complex, the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis. The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic, protein processing and degradation, synaptic vesicle loading, and coupled transport. The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion, pH sensing, amino-acid-induced activation of mTORC1, and scaffolding for protein-protein interaction. In response to various stimuli, V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport. Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases, including neurodegenerative disorders such as Alzheimer disease, Parkinson’s disease, amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.ConclusionV-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells. Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases, further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.
Highlights
ConclusionV-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells
Lysosome function Lysosomes degrade a broad range of substrates including DNA, RNA, proteins, and lipid
The most well-known diseases related to lysosomes are lysosomal storage disorders (LSDs) [7], a family of disorders caused by inherited gene mutations of lysosomal and non-lysosomal proteins, including the resident hydrolytic enzymes inside the lysosome [8]
Summary
V-ATPase complex is a universal proton pump and plays important roles in lysosome acidification for all cell types, the most profound impact of VATPase dysfunction appears to manifest in the central nervous system as neurodegeneration. Studies have demonstrated that FK506 exerts neuroprotective effects by binding with ATP6V1A and induces autophagy. This provides a new and attractive strategy for treating neurodegenerative diseases [204]. The bafilomycin A1-binding subunit ATP6V0C may serve as a therapeutic target to enhance substrate degradation in age-related neurodegenerative disease [207]. In this regard, it is worth noting that the diversity of subunit isoforms existed for the V-ATPases in different organs and organelles should offer the opportunities for selectively targeting particular V-ATPase complexes that are involved in certain disease processes.
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