OSBPL2 deficiency impaired autophagy and induced apoptosis in auditory cells via AMPK-TFEB signalling pathway

OSBPL2 was identified as a causal gene responsible for autosomal dominant non-syndromic hearing loss. Previous study revealed that OSBPL2-mediated AMPK signalling was crucial for cholesterol-homeostasis in inner ear. AMPK is the downstream component of a kinase cascade as the key regulator of autophagy, metabolism, cell growth and apoptosis, etc. In addition, OSBPL2 deficiency could lead to autophagy impairment in auditory cells, indicating the potential role of OSBPL2-mediated AMPK signalling in autophagy. In the present study, autophagy function was characterized in hair cells (HCs) of Osbpl2-knockout mice and in Osbpl2-knockdown HEI-OC1 cells. The results showed that OSBPL2 deficiency impaired autophagy by inhibiting AMPK-TFEB signalling, resulting in aberrant accumulation of lipid droplets and apoptosis in auditory cells, which could be partially reversed by trehalose treatment. This study revealed the implications of OSBPL2 for autophagy in auditory cell and contributed to elucidating the pathogenesis of OSBPL2 mutations in hearing loss.