TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells 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. ### Competing Interest Statement The authors have declared no competing interest. National Institute on Deafness and Other Communication Disorders, https://ror.org/04mhx6838, DC000096, DC015271

Excited to share our first pre-print from the new SSPB section at the NIDCD!🥳
We hope you find it interesting and inspiring for future research. Thanks to our team, colleagues, mentors and collaborators 🔥 💪 🙏 .
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www.biorxiv.org/content/10.1...