Biophysical and molecular mechanisms of lysosomal mechanoresilience: Membrane tension, TMEM63A, and cellular injury.

Lysosomal membrane failure contributes to cellular injury by disrupting degradation, metabolism, immune signaling, and compartmental integrity, yet the physical principles that determine whether a mechanically loaded lysosome adapts or ruptures remain incompletely resolved. This review integrates biophysical and molecular evidence to examine lysosomal membrane tension as an organelle-state variable and TMEM63A as an emerging determinant of lysosomal mechanoresilience. We distinguish membrane tension from hydrostatic and osmotic pressure, organelle volume, membrane permeabilization, and rupture, and evaluate how surface-area-to-volume constraints, luminal solute accumulation, ion and water flux, membrane potential, lipid composition, and force-from-lipid gating shape mechanical failure thresholds. The strongest evidence comes from Drosophila TMEM63 and mouse TMEM63A lysosomal mechanosensitivity and macrophage models in which TMEM63A-dependent cation efflux lowers acute membrane tension and rupture susceptibility. Together, these findings support a pressure-relief model coupling mechanically activated conductance to lysosomal membrane stability. Evidence from lysosome-related organelles, lipid scrambling, myelination, infection, and pressure-sensitive mTORC1-TFEB/TFE3 signaling broadens the mechanistic scope without establishing a universal TMEM63A-dependent pathway. Accordingly, TMEM63A is best viewed as a system- and condition-dependent regulator of acute lysosomal mechanical vulnerability, not a general lysosomal controller or validated therapeutic target. Importantly, TMEM63A-linked disease phenotypes in humans and Tmem63a-deficient mice have not been causally linked to impaired lysosomal mechanoresilience, and the macrophage pressure-relief mechanism remains unvalidated in vivo. Resolving these uncertainties will require simultaneous, time-resolved measurements of tension, geometry, ion composition, membrane potential, permeability, and repair, combined with compartment-specific localization and rescue using wild-type, pore-defective, localization-defective, and disease-associated variants.