Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

Abstract

The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1–a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2–a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation.

Neuroinflammation and Lysosomal Abnormalities Characterise the Essential Role for Oxidation Resistance 1 in the Developing and Adult Cerebellum

“…Of note, we observe the upregulation of several lysosomal enzymes in the transcriptomic data from the Oxr1 KO cerebellum, as well as the presence of aberrant lipid droplets and membranous structures by EM that are also indicative of dysfunction in and around the endo-lysosomal and autophagy systems. How these pathways are interrelated in the context of normal and disrupted OXR1 function requires further study, in particular given the striking overlap in clinical outcomes related to TLDc proteins and v-ATPase subunit variants in disease, including seizures, cerebellar pathology and hearing loss [ 50 , 51 , 52 ].…”

Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review

“…These H + discharged outside the tumor cells will enter the normal cell tissues with the concentration gradient and accumulate in large quantities, activating the enzyme cascade reaction leading to cell necrosis or apoptosis, which is more conducive to the spread and metastasis of the tumor. In addition, studies have shown that the acidic environment of tumor microenvironments can induce increased lysosome secretion and activation and activate proteolytic enzymes to promote the degradation and remodeling of the extracellular matrix (ECM), which contributes to tumor invasion and metastasis [69]. In addition, this enzyme is also related to membrane traffic, protein degradation, autophagy, and the coupled transport of small molecules.…”