JOURNAL ARTICLE

Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice

Bei Chen, Hongen Xu, Yanfang Mi, Wei Jiang, Dan Guo, Jinhui Zhang, Yulin Zhao, Wenxue Tang
American Journal of Physiology. Cell Physiology 2020 August 5
32755449
Mutations in Connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain response and endocochlear potential at postnatal day 18, Cx30-/- mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30-/- mice might be explained in part by an increase in reactive oxygen species generation beginning at postnatal day 10. The expression of oxidative stress genes was increased in Cx30-/- mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18, as assessed by decreased ATP levels and decreased expression of mitochondria Complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30-/- mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, pro-apoptotic proteins, including Bax, Bad and Caspase-3 were upregulated at postnatal day 18, providing a molecular basis to explain the loss of hearing that occurs prior to hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30-/- mice that is coincident with hearing loss but precedes hair cell loss.

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