Noise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakin-deficient (Pjvk^−/−), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubule-associated protein 1 light chain 3β) to peroxisomes in wild-type, but not Pjvk^−/−, mice. We also show that pejvakin–LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin–LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk^−/− mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins. Significance Noise-induced hearing loss is a highly prevalent form of sensorineural hearing impairment affecting individuals of all ages. Noise exposure triggers a rapid increase in reactive oxygen species (ROS) levels, causing oxidative damage to auditory hair cells and resulting in hearing loss. Here we describe a novel mechanism of protection against noise-induced auditory hair cell damage. In response to sound exposure, pejvakin, a peroxisome-associated protein, acts as an ROS sensor and recruits the autophagy machinery to trigger the degradation of peroxisomes (pexophagy) damaged by oxidative stress. We characterized the pejvakin interactions involved in this process. We provide evidence that pejvakin-mediated pexophagy plays a key role in controlling peroxisome proliferation and protecting auditory hair cells against noise-induced damage.

In mammals, cochlear sensory hair cells that are responsible for hearing are postmitotic and are not replaced after loss. One of the most promising strategies to regenerate hair cells is to identify and inhibit the factors preventing the conversion of adjacent non-sensory supporting cells into hair cells. Here we demonstrate that mammalian hair cells can be directly generated from supporting cells by inhibition of ephrin-B2 signalling. Using either ephrin-B2 conditional knockout mice, shRNA-mediated gene silencing or soluble inhibitors, we found that downregulation of ephrin-B2 signalling at embryonic stages results in supporting cell translocation into hair cell layers and subsequent switch in cell identity from supporting cell to hair cell fate. As transdifferentiation is here a result of displacement across boundary, this original finding presents the interest that newly generated hair cells directly integrate either hair cell layer, then would be likely more rapidly able to fit into functional circuitry.

In mammals, sensorineural deafness results from damage to the auditory receptors of the inner ear, the nerve pathways to the brain or the cortical area that receives sound information. In this review, we first focused on the cellular and molecular events taking part to spiral ganglion axon growth, extension to the organ of Corti, and refinement. In the second half, we considered the functional maturation of synaptic contacts between sensory hair cells and their afferent projections. A better understanding of all these processes could open insights into novel therapeutic strategies aimed to re-establish primary connections from sound transducers to the ascending auditory nerve pathways.