The Effect Of Mitophagy On Aminoglycoside-induced Hearing Loss

Hearing impairment(deafness)is one of the most prevalent diseases in the world.With the increasing aging population,noise pollution,and ototoxic drug abuse,the number of people suffering from hearing impairment diseases is increasing year by year,and deafness has become a very serious socio-economic and political health problem worldwide.According to WHO recently report,around 63% of the population was belong to sensorineural deafness.Available studies have shown that the irreversible death of cochlear hair cells caused by noise and drugs is one of the main causes of sensorineural deafness.Kanamycin and neomycin are common aminoglycosides,of which cochlear hair cells are their main targets of action in the inner ear.Cell death is closely related to mitochondrial damage,and cells maintain mitochondrial homeostasis through the mitochondrial quality control system.Mitophagy can remove damaged mitochondria in time to maintain intracellular mitochondrial quality and homeostasis.Available evidence suggests that mitochondrial damage is one of the major factors in hair cell death caused by aminoglycosides,but the role of mitophagy in the process of aminoglycoside has not been reported.PINK1/PRKN-mediated mitophagy is the classical mitophagy pathway,and our study revealed that neomycin impeded PINK1/PRKN-mediated mitophagy.Neomycin slowed down the aggregation of PRKN on damaged mitochondria during mitophagy and the recognition of damaged mitochondria by autophagosomes.After observing changes in mitophagy flux using the mitophagy probe mt-m Keima,we found that neomycin treatment resulted in a significant reduction in the entry of damaged mitochondria to be degraded into lysosomes as well.Our further study showed that the expression of PINK1,a key factor of mitophagy,was significantly reduced after neomycin exposure,and that neomycin was responsible for the significant reduction of PINK1 expression by promoting the expression of the transcriptional regulator ATF3 and thus reducing the transcriptional activity of Pink1.Finally,we enhanced the level of mitophagy in hair cells by mitophagy agonists and showed that promoting mitophagy could protect against aminoglycoside-induced hearing loss.In conclusion,we investigated the occurrence of mitophagy and the specific molecular mechanism of mitophagy induced by neomycin for the first time in detail in the neomycin injury model and found that small-molecule drugs regulating mitophagy could be a potential therapeutic target for hearing loss caused by aminoglycosides.