TMEM63A encodes a mechanosensitive cation channel with high activation thresholds that functions as a critical regulator of respiratory and neurological homeostasis 1. The channel localizes to lamellar body and lysosomal membranes, where it mediates mechanosensitivity in response to mechanical stretch and osmotic stress 2. During lung inflation, TMEM63A activation in alveolar epithelial cells conducts cation currents that trigger lamellar body exocytosis and surfactant secretion, essential for the first breath and lifelong respiration 1. TMEM63A also functions in myelination as an oligodendrocyte-autonomous regulator; its presence at both plasma membrane and lysosomes modulates myelin production in response to mechanical cues 3. Structurally, TMEM63A exhibits a proteo-lipidic pore architecture where lipids participate in ion permeation, with a surface-proximal hydrophobic latch serving as a putative force-sensing module 4. Disease-associated mutations in TMEM63A cause infantile hypomyelinating leukodystrophy 19 (HLD19), characterized by reduced CNS white matter and neurological symptoms 3. Patient-derived variants impair membrane trafficking and function as loss-of-function mutations, leading to delayed oligodendrocyte differentiation and transient hypomyelination 5. Unlike TMEM63B, TMEM63A does not exhibit phospholipid scramblase activity 4.