Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice

Abstract

Atg7 is an indispensable factor that plays a role in canonical nonselective autophagy. Here we show that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage, somatic electromotility disturbances, and presynaptic ribbon degeneration over time, which led to the gradual wholesale loss of OHCs and subsequent early-onset profound hearing loss. Impaired autophagy disrupted OHC mitochondrial function and triggered the accumulation of dysfunctional mitochondria that would otherwise be eliminated in a timely manner. Atg7-independent autophagy/mitophagy processes could not compensate for Atg7 deficiency and failed to rescue the terminally differentiated, non-proliferating OHCs. Our results show that OHCs orchestrate intricate nonselective and selective autophagic/mitophagy pathways working in concert to maintain cellular homeostasis. Overall, our results demonstrate that Atg7-dependent autophagy plays a pivotal cytoprotective role in preserving OHCs and maintaining hearing function.

CCDC154 Mutant Caused Abnormal Remodeling of the Otic Capsule and Hearing Loss in Mice

“…Many genes are crucial for the development and survival of hair cells. Zhou et al (2020) reported that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage and electromotility disturbances, which led to the degeneration of OHCs and subsequent early-onset profound hearing loss. Disrupted function of slc4a2b resulted in a decreased number of HCs in zebrafish neuromasts due to increased HC apoptosis ( Qian et al, 2020 ).…”

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

“…Maintaining the structural and functional integrity of the basilar membrane in the cochlea, is known to require a highly orchestrated process for the elimination of damaged OHCs ( Hu et al, 2018 ; Li et al, 2018b ; Zhou et al, 2020 ). This process has been shown to always involve the activation of neighbor cells or professional scavengers, such as macrophages.…”

“…Noise-induced hearing loss (NIHL) is the most common type of sensorineural hearing loss, ranking first among occupational diseases, seriously affecting the lives of patients, and greatly increasing the social burden ( Carroll et al, 2017 ; Murphy et al, 2018 ). The mechanisms underlying noise-induced damage to critical cochlear cells have been reported to include oxidative damage, mechanical shearing forces, and glutamate excitotoxicity ( Zhou et al, 2020 ), which eventually induce apoptotic cell death in HCs, especially the outer HCs of the basal turn ( Sun et al, 2014 ; Yu et al, 2017 ; Li et al, 2018a ; Zhang et al, 2019 ).…”

Differences in Calcium Clearance at Inner Hair Cell Active Zones May Underlie the Difference in Susceptibility to Noise-Induced Cochlea Synaptopathy of C57BL/6J and CBA/CaJ Mice

“…Hearing loss is often caused by the death of sensory hair cells (HCs) in the inner ear, which function in transducing the sound waves into electric signals (Wang et al, 2017 ; Zhu et al, 2018 ; Liu et al, 2019d ; Qi et al, 2019 , 2020 ). Damages from a variety of intrinsic and extrinsic sources can impair inner ear function, including mutations in deafness genes, exposure to ototoxic drugs, aging, chronic cochlear infections, and environmental noise overexposure (Kujawa and Liberman, 2009 ; Gao et al, 2019 ; Zhang et al, 2019 , 2020 ; He et al, 2020 ; Qian et al, 2020 ; Zhong et al, 2020 ; Zhou et al, 2020 ), among which, noise-induced hearing loss (NIHL) is the most common form of non-hereditary sensorineural hearing loss, with the incidence increasing annually in our aging society.…”