Pou4f3 gene mutation promotes autophagy and apoptosis of cochlear hair cells in cisplatin-induced deafness mice

Abstract

Pou4f3 plays an important role in the development of hair cells in the inner ear sensory epithelia. Autophagy is related to the auditory damage. However, the role and mechanism of Pou4f3 on drug-induced ototoxicity are incompletely understood. Hence, this study aimed to explore the effects of Pou4f3 on the apoptosis of cochlear hair cells (CHCs) and to explore whether autophagy was involved in this process. The cisplatin was used to produce a loss of CHCs to create a murine model of deafness. The AAV vectors were delivered into the scala media through the lateral wall. Compared with the control mice, the cisplatin-treated mice exhibited significantly enhanced apoptosis and autophagy in the cochleae, accompanied by a notably decreased Pou4f3 levels. Both mutation and knockdown of Pou4f3 promoted the apoptosis- and autophagy-related protein levels, and enhanced the cisplatin-induced levels of apoptosis- and autophagy-related proteins. Furthermore, the autophagy activator rapamycin promoted the apoptosis and autophagy in the cochlea. In addition, the autophagy inhibitor 3-MA overturned the promoting effect of Pou4f3 knockdown on the apoptosis and autophagy. Collectively, in cisplatin-induced deafness mice, the Pou4f3 gene mutation facilitated apoptosis of cochlear hair cells, at least partially, through inducing autophagy.