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Review
. 2016 Dec:32:75-88.
doi: 10.1016/j.arr.2016.05.004. Epub 2016 May 16.

Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease

Daniel J Colacurcio  1 , Ralph A Nixon  2
Affiliations
Review

Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease

Daniel J Colacurcio et al. Ageing Res Rev. 2016 Dec.

Abstract

Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson disease and Alzheimer disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal hydrolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

Keywords: Acidification; Alzheimer’s disease; Autophagy; Calcium; Caloric restriction; Cathepsin; Endocytosis; Lysosomal storage disease; Lysosome; Parkinson’s disease; TFEB; mTORC; pH; v-ATPase.

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Figures

Figure 1
Figure 1. The Lysosomal System
The lysosomal system refers to the autophagic pathway and the endocytic pathway, and mediates the transport and proteolytic degradation of cellular waste. In the endocytic pathway, early endosomes (EE) mature into late endosomes (LE) prior to full acidification (Lysosome). In the autophagic (macroautophagy) pathway, a preautophagosomal structure (PAS) is formed, enveloping an area of cytoplasm or a selected substrate, and developing into a double-membrane autophagosome (AP). Lysosomes fuse with autophagosomes, generating single-membrane autolysosomes (AL), and ultimately lysosomes. Upon fusion with autophagosomes, lysosomes introduce proteolytic enzymes which carry out the degradation of substrates as the compartment becomes more acidic. The acidification of these compartments is mediated by the v-ATPase. Chaperone-mediated autophagy (CMA) is another type of autophagy, during which a chaperone protein complex (Hsc70 complex) recognizes a cytoplasmic target protein via a KFERQ motif, and shuttles the target protein to the lysosomal lumen for digestion via interaction with the LAMP2 protein complex, which serves as the lysosomal CMA receptor. (Figure modified from Nixon, 2013, Nat Med).
Figure 2
Figure 2. v-ATPase structure and regulation by dissociation
The v-ATPase promotes the acidification of lysosomes via ATP-dependent transport of protons across the lysosomal membrane. The v-ATPase is a multimeric complex composed of two sub-complexes, the cytosolic V1, and the membrane-bound V0. These two sub-complexes can reversibly dissociate, which diminishes v-ATPase activity. In mammalian cells, v-ATPase assembly is induced by glucose, leading to a feedback mechanism by which lysosomal acidification is modulated by intracellular nutrient availability. v-ATPase assembly is also regulated by several other factors, allowing v-ATPase function and lysosomal acidification to be regulated by various intracellular signaling pathways.
Figure 3
Figure 3. v-ATPase defects and associated neurodegenerative diseases
Shown in the left column are disease-associated mutations in the genes encoding for individual v-ATPase subunits (bold). Shown in the right column are changes in v-ATPase-related proteins (bold) and corresponding neurodegenerative diseases. *ATP13A2, while not directly linked to v-ATPase function, is shown due to its suspected role in lysosomal acidification and its implication in both Kufor-Rakeb Syndrome and Parkinson Disease.
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