Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing

ABSTRACT The mechanoelectrical transduction (MET) channel complex of auditory hair cells converts sound into electrical signals, allowing us to hear. After decades of research, the transmembrane-like channel 1 and 2 (TMC1 and TMC2) have been recently identified as pore-forming subunits of the MET channels, but the molecular peculiarity that differentiates these two proteins and makes TMC1 essential for hearing remains elusive. Here, we show that TMC1, but not TMC2, is essential for membrane remodeling triggered by a decrease in intracellular calcium concentration. We demonstrate that inhibition of MET channels or buffering of intracellular calcium lead to pronounced phosphatidylserine externalization, membrane blebbing and ectosome release at the hair cell sensory organelle, culminating in the loss of TMC1 protein. Moreover, three TMC1 deafness-causing mutations cause constitutive phosphatidylserine externalization that correlates with the deafness phenotype, suggesting that the mechanisms of hearing loss involve alterations in membrane homeostasis.