Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels

• Published in: Nature cell biology Vol. 26; no. 3; pp. 393 - 403
• Main Authors: Li, Kai, Guo, Yanmeng, Wang, Yayu, Zhu, Ruijun, Chen, Wei, Cheng, Tong, Zhang, Xiaofan, Jia, Yinjun, Liu, Ting, Zhang, Wei, Jan, Lily Yeh, Jan, Yuh Nung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2024; Nature Publishing Group
• Subjects: 13/109; 13/51; 14/19; 14/34; 38/35; 42/41; 45/29; 631/45/269; 631/80/642; 64/24; 82/80; 9/74; Animals; Biomedical and Life Sciences; Cancer Research; Cell Biology; Developmental Biology; Drosophila; Drosophila - metabolism; Fruit flies; Humans; Insects; Ion channels; Ion Channels - genetics; Ion Channels - metabolism; Life Sciences; Lysosomes; Lysosomes - metabolism; Mammals - metabolism; Mechanotransduction; Mechanotransduction, Cellular; Mice; Morphology; Mutants; Organelles; Phenotypes; Physiology; Signs and symptoms; Stem Cells
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-024-01353-7

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 ( Dm TMEM63) ion channel as an intrinsic mechanosensor of the lysosome, a major degradative organelle. Endogenous Dm TMEM63 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 Dm TMEM63 channel function in lysosomes and its physiological roles in vivo and provide a molecular basis to explore the mechanosensitive process in subcellular organelles. Li, Guo, Wang and colleagues show that the ion channels TMEM63 in Drosophila and TMEM63A in mouse mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function.