Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice
- 1 September 2020
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 319 (3), C569-C578
- https://doi.org/10.1152/ajpcell.00483.2019
Abstract
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.Keywords
This publication has 35 references indexed in Scilit:
- Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral LineJournal of the Association for Research in Otolaryngology, 2013
- SLC26A4 Genotypes and Phenotypes Associated with Enlargement of the Vestibular AqueductCellular Physiology and Biochemistry, 2011
- Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochleaJournal of Comparative Neurology, 2009
- Gap Junction Mediated Intercellular Metabolite Transfer in the Cochlea Is Compromised in Connexin30 Null MicePLOS ONE, 2008
- Connexin30 deficiency causes instrastrial fluid–blood barrier disruption within the cochlear stria vascularisProceedings of the National Academy of Sciences of the United States of America, 2007
- Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafnessProceedings of the National Academy of Sciences of the United States of America, 2007
- Connexins: functions without junctionsCurrent Opinion in Cell Biology, 2004
- Gap junctions in the inner ear: Comparison of distribution patterns in different vertebrates and assessement of connexin composition in mammalsJournal of Comparative Neurology, 2003
- Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potentialHuman Molecular Genetics, 2003
- High carrier frequency of the 35delG deafness mutation in European populationsEuropean Journal of Human Genetics, 2000