Investigating The Role Of Peroxisomes In Auditory Function In Mouse Cochlear Hair Cells

Hearing loss is one of the most common sensory disorders in the world,sensorineural hearing impairment is the most common form of hearing impairment,and at present,effective therapeutic drug or gene therapy methods for the treatment of sensorineural hearing impairment are lacking.Therefore,a more mechanistic understanding of sensorineural hearing impairment is required to find relevant targets that can be used to prevent and treat the impairment.Sensorineural hearing impairment is caused by a wide range of factors,including hair cell loss or dysfunction,spiral ganglion neurons(SGNs)degeneration,and stria vascularis(StV)atrophy.Nearly half of the cases of hereditary sensorineural hearing loss are associated with genetic mutations in hair cells.Therefore,understanding the functional maintenance and survival of hair cells is the key to prevent sensorineural hearing impairment.In several previous studies,dysfunction of multiple hair cell organelles was associated with hearing loss.Lysosomal disorder was shown to result in increased basal autophagy.leading to progressive hair cell degeneration and hearing loss.Endoplasmic reticulum(ER)stress could also lead to hair cell apoptosis and hearing loss,and the addition of salubrinal,an ER stress inhibitor,could delay hearing loss and preserve hair cells.Furthermore,mitochondrial dysfunction was also shown to increase oxidative stress and apoptosis of hair cells.As an organelle commonly reported to have similar functions to mitochondria,the role of peroxisomes in hair cells has not been extensively studies.At present,only a few literatures have reported that peroxisome may be involved in hearing protection.Pejvakin,encoded by Pjvk gene,plays a role in peroxisome proliferation,and Pjvk-/-mice were found to be susceptible to noise.In our previous study,we also reported the involvement of peroxisomes in regulating the mammalian target of rapamycin complex 1(mTORC1)signaling in the auditory system,A recent study showed that Pex3deficient mice(mice lacking Pex-3,which codes for peroxisomal biogenesis factor 3)suffered from hearing loss.Furthermore.peroxisome biogenesis disorders(PBDs)are associated with hearing loss in clinical cases of peroxisome abnormalities.However,a systematic investigation of peroxisomes’ role in cochlear hair cells is lacking,the purpose of this study is to explore the role and mechanism of peroxisome in cochlear hair cellsIn this study,we established two peroxisome-deficient mouse models(Atohl-Pex5-/-and Pax2-Pex5-/-)and found that peroxisomes in the hair cells of cochleae plays an important role in hearing.Furthermore,peroxisome deficiency-mediated negative effects on hearing did not involve mitochondrial dysfunction and oxidative damage.Although the mammalian target of rapamycin complex 1(mTORC1)signaling was shown to function through peroxisomes,no changes were observed in the mTORC1 signaling in Atoh1-Pex5-/-mice when compared to wild-type(WT)mice.However,the expression of large-conductance,voltage-,and Ca2+activated K+(BK)channels was less in Atoh1-Pex5-/-mice as compared to the WT mice,and the administration of activators of BK channels restored the auditory function in knockout mice,some of which approached the level of hearing in WT mice.These results suggest that peroxisomes in cochlear hair cells plays an important role in hearing by regulating BK channels.Hence,BK channels appear as the probable target for treating peroxisome-related hearing diseases such as PBDs.