2. Academic Validation
  3. Cochlear endoplasmic reticulum stress causes connexin 26 degradation is involved in age-related hearing loss

Cochlear endoplasmic reticulum stress causes connexin 26 degradation is involved in age-related hearing loss

  • iScience. 2025 Oct 28;28(12):113891. doi: 10.1016/j.isci.2025.113891.
Xue Bai 1,  Bing Liao 1,  Wen-Hui Hu 1,  Mei-Qun Wang 1,  Yu Sun 2,  Xu-Bo Chen 1,  Kai Xu 1
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Head and Neck Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 2 Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 41321625 DOI: 10.1016/j.isci.2025.113891
Abstract

Age-related hearing loss (ARHL) represents a progressive auditory disorder. Growing evidence indicates that degradation of connexin 26 (Cx26) in cochlear may constitute one of the pathogenic mechanisms in ARHL. However, the molecular mechanisms underlying age-related Cx26 degradation remain unclear. We systematically analyzed Cx26 expression patterns in C57BL/6J mice across different age groups and confirmed an age-dependent downregulation of Cx26 in the mouse cochlea. Notably, we observed concurrent upregulation of endoplasmic reticulum (ER) stress markers Glucose-regulated protein 78 (GRP78) and protein disulfide isomerase (PDI) in aged cochlear tissues. Furthermore, in vitro experiments demonstrated that ER stress significantly reduced Cx26 protein levels in cochlear explants. Mechanistically, we observed enhanced expression of ubiquitination-related proteins Nedd4 and Eps15 with evident colocalization with Cx26 in an ER stress mouse model. In summary, our findings demonstrate that Cx26 ubiquitination mediated by cochlear ER stress is the main cause of Cx26 degradation in the cochlea of aged mice.

Keywords

cell biology; molecular biology; neuroscience.

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