Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.

Background: Consensus is lacking with regard to whether hearing loss is an independent risk factor for dementia. We therefore conducted a meta-analysis to clarify the relationship of hearing loss and dementia.Methods: Prospective cohort studies investigating the association between hearing loss and the incidence of dementia in a community-derived population were included by searching electronic databases that included PubMed, Embase, and Cochrane's Library. A random-effects model was adopted to combine the results.Results: Fourteen cohorts including 726,900 participants were analyzed. It was shown that hearing loss was independently associated with dementia [adjusted hazard ratio (HR): 1.59, 95% confidence interval (CI): 1.37 to 1.86, p < 0.001; I² = 86%]. Sensitivity analysis sequentially excluding any of the individual studies included showed similar results. Subgroup analysis according to the diagnostic methods for hearing loss, validation strategy for dementia, follow-up duration, and adjustment of apolipoprotein E genotype also showed consistent results (p-values for subgroup differences all > 0.05). Meta-analysis with five studies showed that hearing loss was also connected to higher risk of Alzheimer's disease (adjusted HR: 2.24, 95% CI: 1.32 to 3.79, p = 0.003; I² = 2%).Conclusions: Hearing loss may increase the risk of dementia in the adult population. Whether effective treatment for hearing loss could reduce the incidence of dementia should be explored in the future.

Aging, noise, and ototoxic drug-induced hair cell (HC) loss are the major causes of sensorineural hearing loss. Aminoglycoside antibiotics are commonly used in the clinic, but these often have ototoxic side effects due to the accumulation of oxygen-free radicals and the subsequent induction of HC apoptosis. Blebbistatin is a myosin II inhibitor that regulates microtubule assembly and myosin–actin interactions, and most research has focused on its ability to modulate cardiac or urinary bladder contractility. By regulating the cytoskeletal structure and reducing the accumulation of reactive oxygen species (ROS), blebbistatin can prevent apoptosis in many different types of cells. However, there are no reports on the effect of blebbistatin in HC apoptosis. In this study, we found that the presence of blebbistatin significantly inhibited neomycin-induced apoptosis in HC-like HEI-OC-1 cells. We also found that blebbistatin treatment significantly increased the mitochondrial membrane potential (MMP), decreased ROS accumulation, and inhibited pro-apoptotic gene expression in both HC-like HEI-OC-1 cells and explant-cultured cochlear HCs after neomycin exposure. Meanwhile, blebbistatin can protect the synaptic connections between HCs and cochlear spiral ganglion neurons. This study showed that blebbistatin could maintain mitochondrial function and reduce the ROS level and thus could maintain the viability of HCs after neomycin exposure and the neural function in the inner ear, suggesting that blebbistatin has potential clinic application in protecting against ototoxic drug-induced HC loss.

Atg7 is an indispensable factor that plays a role in canonical nonselective autophagy. Here we show that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage, somatic electromotility disturbances, and presynaptic ribbon degeneration over time, which led to the gradual wholesale loss of OHCs and subsequent early-onset profound hearing loss. Impaired autophagy disrupted OHC mitochondrial function and triggered the accumulation of dysfunctional mitochondria that would otherwise be eliminated in a timely manner. Atg7-independent autophagy/mitophagy processes could not compensate for Atg7 deficiency and failed to rescue the terminally differentiated, non-proliferating OHCs. Our results show that OHCs orchestrate intricate nonselective and selective autophagic/mitophagy pathways working in concert to maintain cellular homeostasis. Overall, our results demonstrate that Atg7-dependent autophagy plays a pivotal cytoprotective role in preserving OHCs and maintaining hearing function.

Background: Inner ear supporting cells (SCs) in the neonatal mouse cochlea are a potential source for hair cell (HC) regeneration, but several studies have shown that the regeneration ability of SCs decreases dramatically as mice age and that lost HCs cannot be regenerated in adult mice. To better understand how SCs might be better used to regenerate HCs, it is important to understand how the gene expression profile changes in SCs at different ages.Methods: Here, we usedSox2^GFP/+mice to isolate the Sox2+ SCs at postnatal day (P)3, P7, P14, and P30 via flow cytometry. Next, we used RNA-seq to determine the transcriptome expression profiles of P3, P7, P14, and P30 SCs. To further analyze the relationships between these age-related and differentially expressed genes in Sox2+ SCs, we performed gene ontology (GO) analysis.Results: Consistent with previous reports, we also found that the proliferation and HC regeneration ability of isolated Sox2+ SCs significantly decreased as mice aged. We identified numerous genes that are enriched and differentially expressed in Sox2+ SCs at four different postnatal ages, including cell cycle genes, signaling pathway genes, and transcription factors that might be involved in regulating the proliferation and HC differentiation ability of SCs. We thus present a set of genes that might regulate the proliferation and HC regeneration ability of SCs, and these might serve as potential new therapeutic targets for HC regeneration.Conclusions: In our research, we found several genes that might play an important role in regulating the proliferation and HC regeneration ability of SCs. These datasets are expected to serve as a resource to provide potential new therapeutic targets for regulating the ability of SCs to regenerate HCs in postnatal mammals.

Cochlear implantation has become the most effective treatment method for patients with profound and total hearing loss. However, its therapeutic efficacy is dependent on the number and normal physiological function of cochlear implant-targeted spiral ganglion neurons (SGNs). Electrical stimulation can be used as an effective cue to regulate the morphology and function of excitatory cells. Therefore, it is important to develop an efficient cochlear implant electroacoustic stimulation (EAS) system to study the behavior of SGNs. In this work, we present an electrical stimulation system constructed by combining a cochlear implant and a conductive Ti₃C₂T_x MXene-matrigel hydrogel. SGNs were cultured in the Ti₃C₂T_x MXene-matrigel hydrogel and exposed to electrical stimulation transduced by the cochlear implant. It was demonstrated that low-frequency stimulation promoted the growth cone development and neurite outgrowth of SGNs as well as signal transmission between cells. This work may have potential value for the clinical application of the Ti₃C₂T_x MXene hydrogel to optimize the postoperative listening effect of cochlear implantation and benefit people with sensorineural hearing loss.