Cells sense physical forces and convert them into electrical or chemical signals, a process known as mechanotransduction. Whereas extensive studies focus on mechanotransduction at the plasma membrane, little is known about whether and how intracellular organelles sense mechanical force and the physiological functions of organellar mechanosensing. Here we identify the Drosophila TMEM63 (DmTMEM63) ion channel as an intrinsic mechanosensor of the lysosome, a major degradative organelle. Endogenous DmTMEM63 proteins localize to lysosomes, mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function. Tmem63 mutant flies exhibit impaired lysosomal degradation, synaptic loss, progressive motor deficits and early death, with some of these mutant phenotypes recapitulating symptoms of TMEM63-associated human diseases. Importantly, mouse TMEM63A mediates lysosomal mechanosensitivity in Neuro-2a cells, indicative of functional conservation in mammals. Our findings reveal DmTMEM63 channel function in lysosomes and its physiological roles in vivo and provide a molecular basis to explore the mechanosensitive process in subcellular organelles.

细胞感知物理力并将其转化为电或化学信号，这一过程称为机械转导。尽管广泛的研究集中在质膜的机械转导上，但对于细胞内细胞器是否以及如何感知机械力以及细胞器机械传感的生理功能知之甚少。在这里，我们将果蝇TMEM63 ( Dm TMEM63) 离子通道确定为溶酶体（一种主要的降解细胞器）的内在机械传感器。内源性Dm TMEM63 蛋白定位于溶酶体，介导溶酶体机械敏感性并调节溶酶体形态和功能。Tmem63突变果蝇表现出溶酶体降解受损、突触丧失、进行性运动缺陷和早期死亡，其中一些突变表型重现了 TMEM63 相关人类疾病的症状。重要的是，小鼠 TMEM63A 介导 Neuro-2a 细胞中的溶酶体机械敏感性，表明哺乳动物的功能保守。我们的研究结果揭示了溶酶体中的Dm TMEM63 通道功能及其在体内的生理作用，并为探索亚细胞器中的机械敏感过程提供了分子基础。