Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Abstract

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.

The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity

“…The major results indicated that polyphenols administrated in conjunction with cisplatin can exert both anti-oxidant and pro-oxidant effects; however, the polyphenolic compounds show different mechanisms of action depending on cell context and dosage. In fact, cisplatin in the cochlea causes an excessive ROS production resulting in redox imbalance and cell death similarly to what occurs in noise-induced hearing loss and presbycusis 21,[34][35][36][37] . Here, we demonstrated that the increase of Nrf-2 nuclear translocation and HO-1 fluorescence in hair cells and spiral ganglion neurons (Fig.…”

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca2+ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

“…This stands out a key open question for cochlear physiopathology, as connexin expression and spontaneous Ca 2+ signaling in the GER are essential for normal development of the sensory epithelium, hair cell functional maturation, hearing acquisition, [20][21][22][23] redox homeostasis and age-related hearing loss. 24 We are confident that the technological advances presented here have the potential to shed light on this as well as a plethora of other unrelated open issues that concern the role of paracrine signaling in physiology and pathology 93 and cannot be addressed with standard methods.…”

Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation

“…The null Cx26 can induce apoptosis and oxidative damage in the cochlear duct, reduce the release of glutathione from connexin hemichannels, and decrease nutrient delivery to the sensory epithelium via cochlear gap junctions, thereby leading to HL. Cx26-deficient mouse models showed congenital HL and cochlear developmental disorders [ 53 – 55 ]. GJB2 -related HL is usually binaural [ 42 , 56 ], as in all 244 patients in this study.…”