Nox3-Derived Superoxide in Cochleae Induces Sensorineural Hearing Loss

• Published in: The Journal of neuroscience Vol. 41; no. 21; pp. 4716 - 4731
• Main Authors: Mohri, Hiroaki, Ninoyu, Yuzuru, Sakaguchi, Hirofumi, Hirano, Shigeru, Saito, Naoaki, Ueyama, Takehiko
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 26.05.2021
• Subjects: Age; Aging - pathology; Animals; Biosynthesis; Cisplatin; Cisplatin - toxicity; Cochlea; Cochlea - metabolism; Cochlea - pathology; Cre recombinase; Ear; Female; Gene Knock-In Techniques; Hair; Hair cells; Hearing; Hearing loss; Hearing Loss, Noise-Induced - metabolism; Hearing Loss, Sensorineural - etiology; Hearing Loss, Sensorineural - metabolism; Hearing Loss, Sensorineural - pathology; Hearing protection; Inner ear; Male; Mice; Mice, Inbred C57BL; NAD(P)H oxidase; NADPH Oxidases - metabolism; Noise; Noise - adverse effects; Outer hair cells; Reactive oxygen species; Spiral ganglion; Superoxide; Superoxides - metabolism; noise-induced hearing loss; drug-induced hearing loss; hearing loss; NADPH oxidase; age-related hearing loss; reactive oxygen species
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2672-20.2021

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3-dependent SNHL remains unclear and warrants further investigation. We generated knock-in mice, in which Nox3 was replaced with ( ). Using mice of either sex, in which tdTomato is expressed under the control of the promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3-expressing cells in the cochlea included various types of supporting cells, outer hair cells, inner hair cells, and spiral ganglion neurons. Nox3 expression increased with cisplatin, age, and noise insults. Moreover, increased Nox3 expression in supporting cells and outer hair cells, especially at the basal turn of the cochlea, played essential roles in ROS-related SNHL. The extent of Nox3 involvement in SNHL follows the following order: cisplatin-induced hearing loss > age-related hearing loss > noise-induced hearing loss. Here, on the basis of , which can be used as a reporter system ( and ), and -KO ( ) mice, we demonstrate that Nox3 inhibition in the cochlea is a promising strategy for ROS-related SNHL, such as cisplatin-induced HL, age-related HL, and noise-induced HL. We found Nox3-expressing regions and cell types in the inner ear, especially in the cochlea, using mice, a reporter system generated in this study. Nox3 expression increased with cisplatin, age, and noise insults in specific cell types in the cochlea and resulted in the loss (apoptosis) of outer hair cells. Thus, Nox3 might serve as a molecular target for the development of therapeutics for sensorineural hearing loss, particularly cisplatin-induced, age-related, and noise-induced hearing loss.