Editors' ChoicePhysiology

Peroxisomes respond to sound

Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ec346
DOI: 10.1126/scisignal.aad9148

Individuals with mutations in DFNB59, which is also known as PJVK and which encodes the protein pejvakin, have a form of hearing impairment caused by defects in the neural transmission of auditory signals. The extent of hearing loss in DFNB59 patients is variable. By measuring auditory brainstem response (ABR) thresholds, Delmaghani et al. (see also Mardones and Hetz) found that the hearing sensitivity of Pjvk–/– mice also varied, suggesting that additional factors contributed to the phenotype. The extent of loss in hearing sensitivity correlated to the amount of acoustic energy to which the Pjvk–/– pups were exposed. Inner hair cells in the cochlea are auditory sensory receptors and outer hair cells function as amplifiers. Controlled sound exposure attenuated the responses of the outer and inner hair cells in Pjvk–/– mice. Action potential propagation in the cochlear neurons of these mice in response to controlled sound exposure or electrical stimulation was defective, which was rescued by neuronal expression of pejvakin. Sound-induced hearing loss involves oxidative damage to cochlear tissue by reactive oxygen species (ROS), and the cochleas of Pjvk–/– mice showed decreased expression of genes encoding antioxidant proteins and exhibited evidence of oxidative stress, as demonstrated by increases in the ratio of reduced to oxidized glutathione and in lipid peroxidation. Pejvakin associated with peroxisomes, organelles that contain various antioxidant enzymes, and the outer hair cells of Pjvk–/– mice had fewer peroxisomes than those of Pjvk+/+ mice. Hydrogen peroxide induced peroxisome proliferation in embryonic fibroblasts from Pjvk+/+ mice but not in those from Pjvk–/– mice, and HeLa cells expressing normal mouse pejvakin had more peroxisomes than those expressing forms of mouse pejvakin with some of the mutations corresponding to those found in DFNB59 patients. Sound exposure increased the transcription of Pjvk and peroxisome numbers in the outer hair cells of Pjvk+/+ mice. To determine if reconstitution of hair cells with pejvakin could rescue the phenotype of Pjvk–/– mice, one ear was injected with pejvakin-encoding viruses that transduce only hair cells and the other ear was left untreated. ABR thresholds were improved, responses of outer hair cells to sound exposure were partially improved, and peroxisomal numbers after sound exposure were increased in the treated ear. Thus, sound triggers peroxisomal proliferation mediated by pejvakin to protect cells in the cochlea from oxidative stress.

S. Delmaghani, J. Defourny, A. Aghaie, M. Beurg, D. Dulon, N. Thelen, I. Perfettini, T. Zelles, M. Aller, A. Meyer, A. Emptoz, F. Giraudet, M. Leibovici, S. Dartevelle, G. Soubigou, M. Thiry, E. S. Vizi, S. Safieddine, J.-P. Hardelin, P. Avan, C. Petit, Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell 163, 894–906 (2015). [PubMed]

P. Mardones and C. Hetz, Peroxisomes get loud: A redox antidote to hearing loss. Cell 163, 790–791 (2015). [PubMed]