ATP6V0A1, encoding the a1-subunit of the V0 domain of vacuolar H + -ATPases, is crucial for transporting protons across cellular membranes to acidify organelles like endosomes and lysosomes [2,4,5]. It is strongly expressed in neurons and is involved in various cellular processes such as autophagy, protein trafficking, and endocytosis [4].

In colorectal cancer, ATP6V0A1 drives exogenous cholesterol-induced immunosuppression. It facilitates cholesterol absorption through RABGEF1-dependent endosome maturation, leading to cholesterol-related immunosuppressive signaling that inactivates memory CD8 + T cells [1].

In brain development, homozygous mutant mice with human-like variants (Atp6v0a1R741Q and Atp6v0a1A512P) show embryonic lethality or early postnatal mortality. The A512P variant leads to lysosomal dysfunction, cell death, reduced mTORC1 signaling, and synaptic connectivity in the brain [2].

Mutations in zebrafish Atp6v0a1 cause phagosome accumulation in microglia due to defective transition from early to late phagosomes [3].

In humans, variants in ATP6V0A1 are associated with progressive myoclonus epilepsy and developmental and epileptic encephalopathy. The R740Q mutation in C. elegans impairs lysosomal hydrolysis and causes autophagic dysfunction [4].

In conclusion, ATP6V0A1 is essential for normal physiological functions, especially in neurons and cellular membrane-related processes. Gene-knockout models in mice and other organisms have revealed its critical roles in diseases such as colorectal cancer, neurological disorders including epilepsy and encephalopathy, and in processes like cholesterol-mediated immunosuppression and phagosome maturation [1,2,3,4].