Mechanoresilience of lysosomes conferred by TMEM63A

Lysosomes are subject to perturbations that can cause damage to their limiting membrane. Osmotic shifts, pore-forming toxins, and the growth of luminal polymers or pathogens all stand to increase lysosomal membrane tension and/or disrupt the bilayer. In some contexts, this leads to lysosomal rupture and cell death. Here, we describe a mechanism that enables lysosomes to sense and respond to acute increases in tension of their limiting membrane. We report that the lysosome-resident nonselective cation channel, TMEM63A, can drive the directional flux of monovalent cations, major osmoticants, out of the lumen when gated by mechanical tension on the organelle. This results in the ability for lysosomes to relieve hydrostatic pressure and, proportionally, membrane tension, affording lysosomes the time to acquire additional lipids. Lysosomes without this mechanism-either because TMEM63A is deleted or in the case when cells express disease-causing variants of TMEM63A-are an order of magnitude more sensitive to lysis upon increases to their membrane tension when compared with their WT counterparts. These findings suggest that lysosomes are capable of regulating hydrostatic pressure and volume in response to high tension.