Atp6v0c, encoding the c-subunit in the membrane-bound integral domain of the vacuolar H⁺-ATPase (V-ATPase), is crucial for the function of this enzymatic complex. V-ATPase pumps protons across membranes in an ATP-dependent manner, acidifying organelles and creating the proton/pH gradient essential for membrane trafficking by various transporters [1]. It is also involved in processes like autophagy-lysosome fusion, antibacterial autophagy (xenophagy), and may regulate HIF-1α expression [2,3,6].

Heterozygous point variants in ATP6V0C in 27 patients led to neurodevelopmental abnormalities, often with epilepsy, as well as corpus callosum hypoplasia and cardiac abnormalities in some. In silico modelling indicated interference with interactions between ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Functional analyses in Saccharomyces cerevisiae showed decreased vacuolar H⁺-ATPase activity, and knockdown in Drosophila increased seizure-like behavior duration, while expression of patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction, and lifespan [1]. In renal fibrosis, impaired TFEB-mediated autophagosome-lysosome fusion promoted tubular cell cycle G2/M arrest by suppressing ATP6V0C expression [2]. A bacterial effector SopF targeted Gln124 of ATP6V0C for ADP-ribosylation, blocking xenophagy [3,5]. In neuroblastoma cells, ATP6V0C knockdown altered autophagy-lysosome pathway function and metabolism of proteins associated with neurodegenerative diseases [4].

In conclusion, Atp6v0c is essential for V-ATPase function and involved in multiple biological processes. Research using genetic models like Drosophila, C. elegans, and yeast has revealed its role in neurodevelopmental disorders, especially those associated with epilepsy, as well as in renal fibrosis and antibacterial autophagy. Understanding Atp6v0c contributes to insights into disease mechanisms and potential therapeutic targets for these conditions.