Bmi1 regulates auditory hair cell survival by maintaining redox balance.

Y Chen,W Ni,S Sun,D Miao,H Li,R Chai,L Li,Y Zhang

doi:10.1038/cddis.2014.549

Abstract

Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1−/− mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1−/− mice compared with that in wild-type controls both in vivo and in vitro, indicating Bmi1−/− hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1−/− mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1−/− hair cells due to the aggravated disequilibrium of antioxidant–prooxidant balance. Furthermore, the antioxidant N-acetylcysteine rescued Bmi1−/− hair cells from neomycin injury both in vitro and in vivo, suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1−/− hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.

Highlights

Hearing loss is one of the most common sensory disorders in humans
We found that Bmi[1] is expressed in the hair cells and supporting cells, and can regulate the redox balance and Reactive oxygen species (ROS) levels, having an important role in the survival and sensitivity to ototoxic drug of auditory hair cells in mice cochleae
Auditory brain stem response (ABR) measurement revealed that hearing threshold at 8, 16, 24 and 32 KHz significantly increased in postnatal day 22 (P22) and postnatal day 30 (P30) Bmi1− / − mice compared with WT littermate (Figure 2d) (n = 6, Po0.05), indicating severe hearing loss in Bmi1− / − mice

Summary

Introduction

Hearing loss is one of the most common sensory disorders in humans. Hair cells in the inner ear have an essential role in converting mechanical sound movement to neural signals for hearing and balance. Previous studies have reported that several genes involved in the survival of hair cells, including Pou4f3 (Xiang et al.1), Barhl[1] (Li et al.2), Gfi[1] (Wallis et al.3), Rb1 (Sage et al.4), Tmprss[3] (Fasquelle et al.5), Eya[1] (Lozlowki et al.6) and AMPK.[7] Deficiency of these genes in hair cells lead to the loss of hair cells via lack of neurotrophic factors,[8] disorder of cell cycle[4] and dysfunction of cellular energy production.[7] Reactive oxygen species (ROS) have important roles in noise- and ototoxic drug-induced hair cell damage and hearing loss.[9] ROS include less-reactive ROS and high ROS (hROS); high levels of both less-reactive ROS and hROS can oxidize cell constituents, including DNA, proteins and lipids and active multiple apoptosis pathways including mitogen-activated protein kinase, Fas-FasL, NF-. We found that Bmi[1] is expressed in the hair cells and supporting cells, and can regulate the redox balance and ROS levels, having an important role in the survival and sensitivity to ototoxic drug of auditory hair cells in mice cochleae

Methods

Results

Conclusion