Regulation of Tmem30b-mediated apical membrane homeostasis in auditory outer hair cells is critical for hearing
Abstract
Mechanotransduction within the cochlea depends on the precise architecture of hair bundles, yet our comprehension of the mechanisms that govern the formation and maintenance of the sound-receptive structure is still limited. Here, we identify Tmem30b, a phospholipid-flippase chaperone, as a critical regulator expressed in outer hair cells (OHCs). Although initially localized to the nuclear membrane at P5, Tmem30b translocates to and stabilizes within the stereocilia and the underlying cuticular plate during maturation. The Tmem30b −/− mice exhibit an early-onset hearing loss with preserved vestibular and retinal functions. Notably, the disorganization of OHC stereocilia in mutants initiates at P7, coinciding with the initial presence of Tmem30b in stereocilia. Mechanistically, Tmem30b partners with Atp8b1 to regulate phospholipid asymmetry; disruption of this complex destabilizes OHC bundles. Crucially, AAV-mediated delivery of Tmem30b t o hair cells alleviates stereocilia defects in both Tmem30b −/− and Atp8b1 −/− mice. Furthermore, hair cell specific overexpression of Tmem30b protects mice from noise-induced and aminoglycoside-induced hearing loss. In summary, our findings establish Tmem30b as a pivotal organizer of OHC hair bundles and highlight Tmem30b–Atp8b1–mediated lipid regulation as a therapeutic target for hearing loss.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Miao Chang
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Guodong Hong
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Shan Gao
Cheng Cheng
Jia Yuan
Key Laboratory of Seed Innovation, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences
Yu Xiao
Ruifeng Qiao
Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Ear, Nose and Throat Hospital, Cheeloo College of Medicine, Shandong University
Jing Ke
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Xinhao Wu
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Tiancheng Zhang
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Siwei Guo
Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs
Runze Jiang
Department of Tissue Regeneration and Wound Repair, Traditional Chinese Medicine Innovation Research Institute, Shandong University of Traditional Chinese Medicine
Ziyi Liu
New Energy Research Institute, School of Environment and Energy
Jing Zhou
Zhejiang Institute of Photoelectronics
Xiaohan Zhang
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Yunhao Wu
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Xiaoxu Zhao
Wen Li
Shuyuan Shen
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Zuhong He
Xiuli Bi
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Renjie Chai
Xiaolong Fu