The pathogenesis of age‐related hearing loss (ARHL) remains unclear. OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D‐gal‐induced senescent HEI‐OC1 cells and the cochlea of C57BL/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR/Cas9 technology. We found enhanced L‐OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI‐OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL.

Cell death mediated by the abnormal activation of autophagy has been observed in many neurodegenerative diseases. Dual leucine zipper kinase (DLK), a member of the mitogen‐activated protein kinase cascade, plays a key role in regulating cellular autophagy and the progression of neurodegenerative diseases. However, its role in age‐related hearing loss has not been reported. In this study, we found that DLK, phosphorylated c‐Jun N‐terminal kinase (p‐JNK), and JNK3 expression increased in the cochleae of C57BL/6J mice during aging. The DLK/JNK pathway and autophagy are excessively activated in the House Ear Institute‐Organ of Corti 1 (HEI‐OC1) senescent hair cell line. After DLK was upregulated in HEI‐OC1 cells, autophagy was activated, and cell aging was initiated. Inhibiting the DLK/JNK pathway in senescent HEI‐OC1 cells can reduce autophagy activation and senescence, and inhibiting autophagy activation can also alleviate senescence. The inhibition of DLK or JNK3 in vivo significantly reduced age‐related cochlear structural damage and hearing loss in C57BL/6J mice. The results of the present study showed that DLK/JNK3 may play a key role in cochlear hair cell senescence and age‐related hearing loss through the abnormal activation of autophagy within cochlear hair cells, suggesting that DLK or JNK3 may be potential targets for alleviating age‐related hearing loss.

Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings.Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD.Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p.Trp441Arg). The same variant was also found in the proband’s sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband’s daughter and parents.Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described.

The c-Jun N-terminal kinase (JNK) pathway is a vital component of the mitogen-activated protein kinase cascade, which regulates cell death and survival. The present study aimed to explore the Spatio-temporal changes in all JNK isoforms in the cochleae of C57/BL6J mice with age-related hearing loss. Changes in the three isoforms of JNKs in the cochleae of an animal model with presbycusis and the senescent HEI-OC1 cell line were tested by immunohistochemistry staining and western blotting. Our results demonstrated that all three JNK isoforms are distributed in the cochleae, and the expression patterns of JNK1, JNK2, and JNK3 differed in hair cells, spiral ganglion neurons, and stria vascularis, with great significance in the cochleae of adult C57BL/6J mice. The levels of JNK1, JNK2, and JNK3 showed various spatio-temporal changes in the aging mice. In a senescent hair cell model, changes in JNK1, JNK2, and JNK3 expression levels were similar to those observed in the cochleae. Our study is the first to show that JNK3 is highly expressed in the hair cells of C57BL/6J mice and further increases in conjunction with age-related hearing loss, suggesting that it may play a more critical role than previously believed in hair cell loss and spiral ganglion degeneration.