The diagram shows how lysosomal damage triggers cellular responses. Pathogens, fibrils, and toxins exert pressure on the lysosomal limiting membrane. This stress activates TMEM63A, leading to the release of lysosomal ions alongside VRAC channel activity. Subsequently, luminal water efflux occurs, helping relax and stabilize the membrane. The illustration also proposes an additional role for TMEM63A in lipid transport, possibly functioning as a lipid scramblase at endoplasmic reticulum and lysosome contact sites. This coordinated response links membrane damage to ion flux, water movement, and lipid redistribution, contributing to membrane repair, homeostasis, and adaptation to cellular stress conditions.
Lysosomal mechanoresilience prevents membrane rupture. Lysosome-damaging stimuli (including pathogens, protein fibrils, and toxic chemicals) increase lumenal pressure and thereby elevate tension on the lysosomal membrane. In response to this tension, TMEM63A, a mechanosensitive cation channel, opens and allows cations to exit the lysosomal lumen into the cytosol; anions must follow through channels such as VRAC to maintain ionic balance. Ion efflux drives water out of the lysosome, possibly through a water channel, resulting in an acute reduction in lysosomal volume and hydrostatic pressure. In this way, TMEM63A-dependent solute efflux helps prevent lysosomes from rupture. Because TMEM63A has also recently been reported to possess lipid scramblase activity, it may additionally help facilitate bulk lipid transport from the endoplasmic reticulum (ER) during lysosomal mechanical stress.