{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:26:39Z","timestamp":1792211199594,"version":"4.4.0"},"posted":{"date-parts":[[2025,7,4]]},"group-title":"Neuroscience","reference-count":94,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["DC000096"],"award-info":[{"award-number":["DC000096"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DC015271"],"award-info":[{"award-number":["DC015271"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,4]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>TMC1 and TMC2, the pore-forming subunits of the mechanoelectrical transduction (MET) complex in inner ear sensory hair cells, are essential for auditory and vestibular function. Pathogenic mutations in TMC1 are a leading cause of genetic hearing loss, but their underlying cellular mechanisms remain poorly understood. Here, we reveal that TMC1 and TMC2 are cholesterol-regulated lipid scramblases whose activity modulates plasma membrane asymmetry. Using reconstituted proteoliposomes and molecular dynamics simulations, we demonstrate that both proteins facilitate phospholipid translocation across membrane bilayers, a process tuned by cholesterol and enhanced by deafness-causing TMC1 mutations. We show that this scramblase activity correlates with TMC1-dependent externalization of phosphatidylserine and membrane blebbing in murine auditory hair cells, linking TMC1-dependent membrane homeostasis dysregulation to auditory sensory cell pathology. These findings identify TMCs as a novel family of lipid scramblases, advancing our understanding of MET complex biology and offering mechanistic insight into membrane-driven forms of hereditary deafness.<\/jats:p>","DOI":"10.1101\/2025.07.03.663083","type":"posted-content","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T17:41:29Z","timestamp":1751650889000},"source":"Crossref","is-referenced-by-count":4,"title":["TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells"],"prefix":"10.64898","author":[{"given":"Hubert","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yein Christina","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haosheng","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harper 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