Cdk5 regulatory subunit-associated protein 1 knockout mice show hearing loss phenotypically similar to age-related hearing loss

Molecular Brain

Kazuhito Tomizawa¹  Fan-yan Wei²  Toru Miwa³ 

[1] Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, 1-1-1- Honjo, Chuo-ku, 8608556, Kumamoto, Japan;Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, 1-1-1- Honjo, Chuo-ku, 8608556, Kumamoto, Japan;Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo, Aoba-ku, 9808575, Sendai, Miyagi, Japan;Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, 6068507, Kyoto, Japan;Department of Otolaryngology-Head and Neck Surgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20 Ougimaci, Kita-ku, 5308480, Osaka, Japan;

关键词: Auditory brainstem responses;    Cdk5rap1;    Endocochlear potentials;    Hearing loss;    Mitochondrial tRNA;    Spiral ligament of cochlea;   

DOI  :  10.1186/s13041-021-00791-w

来源: Springer

【 摘 要 】

Mitochondrial dysfunction is associated with aging and age-related hearing loss (AHL). However, the precise mechanisms underlying the pathophysiology of hearing loss remain unclear. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) enables efficient intramitochondrial translation by catalyzing the deposition of 2-methylthio modifications on mitochondrial tRNAs. Here we investigated the effect of defective mitochondrial protein translation on hearing and AHL in a Cdk5rap1 deficiency C57BL/6 mouse model. Compared to control C57BL/6 mice, Cdk5rap1-knockout female mice displayed hearing loss phenotypically similar to AHL from an early age. The premature hearing loss in Cdk5rap1-knockout mice was associated with the degeneration of the spiral ligament and reduction of endocochlear potentials following the loss of auditory sensory cells. Furthermore, cultured primary mouse embryonic fibroblasts displayed early onset of cellular senescence associated with high oxidative stress and cell death. These results indicate that the CDK5RAP1 deficiency-induced defective mitochondrial translation might cause early hearing loss through the induction of cellular senescence and cochlear dysfunction in the inner ear. Our results suggest that the accumulation of dysfunctional mitochondria might promote AHL progression. Furthermore, our findings suggest that mitochondrial dysfunction and dysregulated mitochondrial tRNA modifications mechanistically cause AHL. Understanding the mechanisms underlying AHL will guide future clinical investigations and interventions in the attempt to mitigate the consequences of AHL.

【 授权许可】

CC BY