mTOR signaling in the mammalian inner ear

Sensorineural hearing loss affects millions of people worldwide. Yet, current treatment options are mostly limited to prosthetic devices. Despite decades of research efforts, molecular mechanisms of sensorineural hearing loss are only sparsely understood. However, deciphering and precisely understanding molecular mechanisms of auditory (dys)function are key to design novel treatment options. Most causes of sensorineural hearing loss reside in the peripheral hearing organ, the inner ear. Mechanoreceptive sensory hair cells (HCs) in the inner ear are essential for hearing and among the most vulnerable cells of the inner ear. Apart from the cochlea, the hearing organ, the inner ear also contains a vestibular organ for balance perception, which also relies on mechanosensory HCs.
The mammalian Target of Rapamycin (mTOR) kinase regulates fundamental cellular processes such as growth, metabolism, and aging. It forms the core of two structurally and functionally distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTORC2. Each of these complexes signals via individual signaling pathways. mTORC1 inhibition with rapamycin has been shown to protect against hearing loss. Nevertheless, the precise function of mTOR signaling in the inner ear, particularly in sensory HCs, remains unknown.
To investigate specific roles of mTORC1 and mTORC2 in sensory HCs, we generated HC-specific Raptor (HC-RapKO) and Rictor (HC-RicKO) knockout mice, respectively. HC-RapKO mice display accelerated age-related hearing loss and vestibular dysfunction. HC-RicKO mice exhibit early-onset, progressive, and profound hearing loss. In addition, HC-RicKO mice show shortened outer HC stereocilia, reduced synapse numbers, and an altered organization of the actin cytoskeleton and Ca2+ channels at inner HC synapses. In contrast to HC-RapKO mice, the vestibular function is not affected in HC-RicKO mice.
To conclude, mTORC1 signaling in HCs is key for maintaining normal auditory and vestibular HC function with age. mTORC2 regulates auditory HC structure and function and is essential for hearing. Thus, both mTOR complexes are critical for normal auditory HC function. These results provide novel insights on mTOR signaling in the mammalian inner ear, which might open new perspectives to treat hearing loss.