Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage via the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway.

Wenqi Liang,Zijing Yang,Zhongrui Chen,Chunli Zhao,Ke Liu,Shusheng Gong

doi:10.3389/fcell.2021.766512

Abstract

Mitochondrial oxidative stress is involved in hair cell damage caused by noise-induced hearing loss (NIHL). Sirtuin-3 (SIRT3) plays an important role in hair cell survival by regulating mitochondrial function; however, the role of SIRT3 in NIHL is unknown. In this study, we used 3-TYP to inhibit SIRT3 and found that this inhibition aggravated oxidative damage in the hair cells of mice with NIHL. Moreover, 3-TYP reduced the enzymatic activity and deacetylation levels of superoxide dismutase 2 (SOD2). Subsequently, we administered adeno-associated virus-SIRT3 to the posterior semicircular canals and found that SIRT3 overexpression significantly attenuated hair cell injury and that this protective effect of SIRT3 could be blocked by 2-methoxyestradiol, a SOD2 inhibitor. These findings suggest that insufficient SIRT3/SOD2 signaling leads to mitochondrial oxidative damage resulting in hair cell injury in NIHL. Thus, ameliorating noise-induced mitochondrial redox imbalance by intervening in the SIRT3/SOD2 signaling pathway may be a new therapeutic target for hair cell injury.

Highlights

Noise is a worldwide public health problem and an important risk factor for sensorineural hearing loss (SNHL)
Using the auditory brainstem response (ABR) test, we found that the hearing thresholds of mice receiving a single NE increased transiently after NE and decreased, which were not significantly different from those of the control group mice at 2 weeks after NE, indicating that a single NE caused a hearing temporary threshold shift (TTS) (Figure 1C)
Compared with the control group mice, the TTS group mice showed no significant loss of outer hair cells (OHCs) in either the apical, middle or basal turns, whereas the permanent threshold shift (PTS) group mice showed significant OHC loss (Figures 2A,B)

Summary

Introduction

Noise is a worldwide public health problem and an important risk factor for sensorineural hearing loss (SNHL). Oxidative stress-induced hair cell damage plays an important role in its development (Zhang et al, 2019). Noise exposure (NE) causes oxidative stress, elevates reactive oxygen species (ROS) levels, and causes hair cell damage, which further contributes to hearing loss (Delmaghani et al, 2015). Several studies in the past decades have focused on countering noise-induced hair cell damage by interfering with ROS, there are no clinically relevant intervention targets to date. Key targets in the pathogenesis of noise-induced hearing loss (NIHL) should be explored. Mitochondrial abnormalities caused by ROS accumulation play an important role in the pathogenesis of NIHL (Ding et al, 2020; Zhong et al, 2020). Autophagy and apoptosis are often simultaneously triggered by similar stimuli, such as oxidative stress, in both hair cells and spiral ganglion neurons (SGNs)

Methods

Results

Conclusion