Autophagy: A Novel Horizon for Hair Cell Protection

Liu, Chang; Zheng, Zhiwei; Wang, Pengjun; He, Shuangba; He, Yingzi

doi:https://doi.org/10.1155/2021/5511010

Neural Plasticity

On this page

Abstract Introduction Conclusion Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2021

View this Special Issue

Review Article | Open Access

Volume 2021 | Article ID 5511010 | https://doi.org/10.1155/2021/5511010

Autophagy: A Novel Horizon for Hair Cell Protection

Chang Liu,^1,2Zhiwei Zheng,^1,2Pengjun Wang,³Shuangba He,⁴and Yingzi He^1,2

Academic Editor: Jian Wang

Received10 Feb 2021

Accepted21 Jun 2021

Published30 Jun 2021

Abstract

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

1. Introduction

As a general sensory disorder in human society, hearing loss was a major concern worldwide. The causes of hearing loss are infections, noise, aging, and ototoxic drugs. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of several diseases [1–6]. During a variety of pathological and physiological states, the activation of autophagy seems beneficial, as it removes damaged organelles or defends microbial infection and is important in various diseases related to metabolism or neurodegeneration [7].

Autophagy suppresses necroptosis and PARP-mediated cell death under cellular stress conditions. Early studies demonstrated that autophagy might be a prosurvival factor in many pathological processes [8]. In retinal ganglion cells, it was found that autophagy suppresses cell apoptosis and promotes cell survival, while the deletion of autophagy significantly decreases cell survival during the degeneration of the optic nerve [9]. In the auditory system, several studies revealed the link between autophagy and hearing protection and proved that the upregulation of autophagy might contribute to the alleviation of morphological damage in the inner ear [6, 10]. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs), determined the effect of autophagy in hearing loss, and further discussed whether autophagy could serve as a potential measure in the protection of HCs.

2. Autophagy and Cochlear Development

Modulated by the growth factor signaling pathway, autophagy regulates cellular differentiation by providing energy and materials to the cells (such as immune cell [11]). Some studies proved the existence of autophagy in the inner ear of many species. For example, Atg4b^-/- null mice showed a defect in vestibular otoconia development, which might lead to the aberration of equilibrium [12]. Autophagy is involved in the neurogenesis in chicken’s auditory spiral ganglion [13]. Moreover, HCs might present autophagic morphological features after ototoxic insults [14]. These data indicated that autophagy is crucial at the early stage of inner ear development. In the early postnatal stage of mice, auditory ribbon synapses are formed and matured with the development of cochlear HC stereocilia [15–18]. According to previous studies, although ATG5-deficient auditory HCs (including OHCs and IHCs) show well-functional morphology and mechanotransduction at P5, progressive accumulation of polyubiquitinated protein, as well as degeneration, is observed at P14 [19], which might eventually cause hearing loss. Furthermore, the treatment of postnatal mice with autophagy inhibitors before the onset stage of hearing induces long-term auditory disorders. The disruptions of autophagy have deleterious effects on the development of cochlear ribbon synapses in mice [20]. Together, these results strongly suggested that autophagy plays a critical role in the formation of HC morphology at the early postnatal stage.

3. Autophagy and Hearing Loss

Sensorineural hearing loss (SNHL) includes noise-induced hearing loss (NIHL), age-related hearing loss (ARHL), inherited hearing loss, and ototoxic drug-induced hearing loss (ODIHL). SNHL occurs because of the irreversible damage to hair cells (HCs) and spiral ganglion neurons (SGNs), both of which have very limited regeneration ability in adult mouse cochlea [21–26]. Thus, how to protect the cochlear HC is a key scientific question in the hearing research field.

3.1. Autophagy and Aminoglycoside-Induced Hearing Loss

As widely used clinical drugs, aminoglycosides (AGs) are famous for the broad antibacterial spectrum [27]. However, the application is limited because of the severe side-effects (including the ototoxicity), which might induce sensorineural hearing loss permanently and affect the life quality of patients significantly [28]. AGs cause damage to the outer hair cells (OHCs) of the basal turn, and with continuing drug exposure, damage spreads to the other turns as well as inner hair cells (IHCs) [29].

In the tissues with the need of high energy, such as HCs [30], phosphatase and tensin homolog- (PTEN-) induced putative kinase 1 (PINK1) is highly expressed [31]. According to a previous study, the suppression of PINK1 and the loss of HEI-OC1 cells were increased, with or without gentamicin (GM) exposure [32]. In addition, the PINK1 knockdown (KD) cells showed less expression of LC3B but a higher degree of p53 and activated caspase 3, indicating that PINK1 alleviates the GM-induced ototoxicity by inducing autophagy and resisting the level of p53 in HCs [32].

In the brain and neuroendocrine system, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) is highly expressed, which is important in maintaining synaptic structures, stabilizing ubiquitin, and regulating proteasomal or lysosomal degradation [33]. In the auditory system, UCHL1 was found to be downregulated in the cochlea by gentamicin (GM) in a time-dependent manner, and in damage or pathological condition, UCHL1 deficiency was found to be associated with the autophagy pathway [34, 35]. According to this study, UCHL1 was downregulated after GM treatment, and after GM exposure, siRNA or the pharmacological inhibitor (LDN-91946) treatment exacerbated the damage to the cochlear explants and HEI-OC1 cells [36]. The silencing of the UCHL1 protein blocked autophagic flux and the inhibition of LAMP1 and LC3 colocalization. These findings suggested that by downregulating UCHL1, GM might serve as a negative regulator to the autophagosome and lysosome fusion [36].

Fatty acids extracted from avocado oil have several functions, including promoting collagen synthesis, reducing inflammation, and wound healing [37]. In the brain tissue of diabetic rats, the seed oil attenuates oxidative stress and prevents mitochondrial dysfunction [38]. A recent study showed the protective effect of avocado oil on auditory HCs. Also, the avocado oil extract (DKB122) was shown to protect the HCs from neomycin-induced damage via upregulating antioxidant pathways, inhibiting inflammatory gene expression, and activating autophagy [39]. The level of p62 protein in HEI-OC1 cells is decreased in a dose-dependent manner after DKB122 treatment. Furthermore, p62 binds to LC3 and incorporates into the autophagosome; strikingly, the downregulation of intracellular p62 suggested that DKB122 upregulates the autophagy in HEI-OC1 cells.

3.2. Autophagy and Cisplatin-Induced Hearing Loss

Cisplatin is an anticancer drug used in clinical treatment. Based on the broad-spectrum chemotherapeutic effects, cisplatin is widely utilized in various cancers, such as testicular cancer, breast cancer, and head/neck cancer [40, 41]. However, progressive hearing loss could also be caused by high doses of cisplatin [6, 42–46]. Previous studies have shown that the accumulation of reactive oxygen species (ROS) after cisplatin treatment is a critical factor inducing HC damage [47–49].

m⁶A is a fat mass and obesity-associated (FTO) demethylase that regulates mRNA metabolism by catalyzing demethylation of m⁶A [50], while meclofenamic acid (MA), an anti-inflammatory drug, serves as a selective inhibitor [51]. A previous study reported that MA2 (a more active form of MA) treatment significantly reduces the apoptosis level of HEI-OC1 cells after cisplatin exposure. However, the effects of MA2 on cisplatin-induced HEI-OC1 death might not involve the participation of m⁶A, because no significant increase of m⁶A was observed after MA2 treatment [49]. The data showed that the level of autophagy was upregulated after cisplatin exposure, while after treatment of HEI-OC1 cells with MA2, the cisplatin-induced cell apoptosis and autophagy activation were significantly decreased [49]. These results suggested that the correlation between autophagy and cisplatin-induced apoptosis is complicated, and excessive autophagy might promote HC apoptosis.

As a Pou family transcription factor [52], Pou4f3 is necessary for HC differentiation, especially for the functional transduction and synaptic specialization [53, 54]. The mutation of Pou4f3 leads to the loss of HCs in the cochlea and subsequently results in severe hearing loss [55]. A recent study demonstrated that Pou4f3 participated in cisplatin-induced autophagy. After cisplatin treatment or AAV2-Pou4f3 shRNA transfection, Pou4f3 expression was decreased markedly. However, the levels of Beclin-1 and LC3-II were upregulated, indicating that Pou4f3 mutation promotes cisplatin-induced autophagy [56]. In addition, as the autophagy activator, rapamycin promoted HC apoptosis, while 3-MA inhibited HC apoptosis. This Pou4f3 mutation promotes HC apoptosis in the cochlea via autophagy [56].

A regulator of cell death, STAT1, was also reported to be involved in cisplatin-induced HC death [57, 58]. A previous study used siRNA to knockdown STAT1 gene expression; consequently, the reduction of cisplatin-induced HC death was observed in vivo and in vitro [57]. In order to reveal the potential correlation between STAT1 and autophagy, other studies investigated the effect of STAT1 ablation on HC damage induced by cisplatin or GM. As shown in the study, comparing to the WT mice, both LC3-II conversion and Beclin-1 expression were increased in the explants from STAT1^-/- mice after cisplatin or GM treatment. However, 3-MA+cisplatin/GM treatment significantly reduced the level of surviving HCs in explants of STAT1^-/- mice, suggesting that autophagy is a potential protector in preventing cisplatin- and GM-induced HC death [59].

As a regulatory protein, glycogen synthase kinase 3β (GSK-3β) participates in a variety of physiological processes and the occurrence of several diseases [60–65]. Some studies also showed that as a downstream factor of AKT, GSK-3β is involved in the regulation of autophagy, while in the normal state GSK-3β suppresses the activation of autophagy. However, when abnormal external stimuli occur, the upstream kinase in the cells promotes the phosphorylation and leads to the inactivation of GSK-3β and blocks the inhibition on autophagy [66, 67]. In auditory research, gene knockout restored the inhibitory effect of GSK-3β, and the autophagy and cytoprotective effects in HEI-OC1 cells were enhanced successfully [68]. Furthermore, the GSK-3β-KO HEI-OC1 cells showed higher viability and higher autophagy rate after cisplatin treatment as compared to that of GSK-3β-WT HEI-OC1 cells. Moreover, cotreatment with 3-MA results in the reduction of autophagy accompanied by an upregulation of cell apoptosis [68]. These findings suggested that autophagy could be activated by downregulating the expression of GSK-3β, and autophagy exerts a protective effect against ototoxicity drugs.

As a member of the nucleotide-binding and oligomerization domain- (NOD-) like receptor (NLR) family, NLRX1 is important in regulating autophagy, ROS generation, and cell death in various kinds of cell types, responding to different stimuli [69–73]. In auditory research, it was found that NLRX1 was localized in the mitochondria of HEI-OC1 cells, and by activating the ROS/JNK signaling pathway and autophagy, NLRX1 sensitized the HEI-OC1 cells to cisplatin ototoxicity [74, 75]. According to the study, after treating HEI-OC1 cells with cisplatin, the increased expression of NLRX1 was synchronized with the activation of autophagy. However, by silencing the expression of NLRX1, the level of autophagy activation was reduced, and cell viability was increased [75]. Mechanistic studies revealed that by inhibiting ROS generation, autophagy activation and cell apoptosis could be successfully prevented in both HEI-OC1 cells and cochlear explants, providing a novel strategy against cisplatin-induced ototoxicity [75–78].

3.3. Autophagy and Noise-Induced Hearing Loss

Increased ROS production or decreased antioxidant activity causes oxidative damage, which is a key element causing noise-induced hearing loss (NIHL). However, ROS was also able to induce cellular defense processes, such as autophagy [79]. A recent study found that the level of oxidative stress in OHCs is noise-dose dependent and that the activation of autophagy exerts a protective effect against NIHL by alleviating the oxidative stress. As described previously, oxidative stress induced by temporary threshold shift (TTS) noise increases the level of LC3B in OHCs, and rapamycin treatment diminishes 4-HNE and 3-NT levels and decreases noise-induced HC loss. On the other hand, the reduction in LC3B via 3-MA or LC3B-siRNA increases the level of 3-NT and noise-induced cell death in OHCs [80].

Pejvakin, a peroxisome-associated protein from the gasdermin family, plays a critical role in sound-induced peroxisome proliferation [81]. Moreover, pejvakin participates in an early autophagic degradation of peroxisomes (pexophagy) in HCs after noise exposure [82]. According to the studies, pejvakin-mediated pexophagy prior to peroxisome proliferation protects the HCs against oxidative damage [83, 84]. As the lipid peroxidation in HCs was investigated through the assessment of the immunoreactivity of 4-HNE, an inverse correlation was established between pexophagy and 4-HNE, which suggested that pejvakin-mediated pexophagy plays a critical role in redox homeostasis and HC protection against noise-induced damage [82]. These results were also confirmed by the rescue experiments in Pjvk^-/- mice, as the viral transduction of Pjvk and LC3B cDNAs successfully restored the pexophagy and prevented the progress of oxidative stress [82]. Due to the similar clearance mechanisms owned by peroxisomes and mitochondria [85, 86], investigating whether mitochondrial autophagy has a protective effect against noise overexposure is essential.

Sleep deprivation (SD) also causes various inner ear diseases, such as hearing loss and tinnitus [87, 88]. The hypothalamic-pituitary-adrenal (HPA) axis is activated by successive SD, which subsequently leads to the upregulation of corticosterone [89], which in turn, activates the glucocorticoid receptors, resulting in the disruption of metabolic activity in the autophagy system [90]. The presence of corticosterone receptors in the auditory system has been demonstrated in many studies [91, 92], and it has been proved that high levels of corticosterone protect cochlear OHCs from various insults [93, 94]. Recently, the effects of SD on noise vulnerability were investigated with respect to the potential underlying mechanisms [95]. According to the study, the elevated expression of LC3B and autophagy activation is observed in the short-term SD+ acoustic trauma (AT) group, whereas repeated SD+AT group could not exert a similar effect. In addition, the SD+AT group exhibits high levels of corticosterone and severe OHC loss. This phenomenon could be attributed to the disruption of repeated SD to the homeostasis, resulting in the disorders of immunological malfunction [96, 97] and autophagy system disorder. However, the autophagy induced by short-term SD causes a protective effect on HCs in the apoptotic processes induced by oxidative stress. Thus, it is demonstrated that short-term SD exerts protective effects on HCs by regulating corticosterone and activating autophagy after noise exposure [95].

3.4. Age-Related Hearing Loss and Autophagy

As a predominant neurodegenerative disease, age-related hearing loss (AHL) is a common form of hearing loss [5, 98–102]. It is prevalent in adults aged ≥70 years, which results in social isolation, communication disorders, and a decline in physical function [103]. The SAMP8 strain is a classic model in studying the influence of aging on biological processes [104]. A previous study has revealed the mechanisms of ARHL, using SAMP8 mice, involved in the participation of oxidative stress, inflammation, and autophagic stress [105].

MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that control the stability of messenger RNA (mRNA). Recently, the existence of miRNAs in the cochlea has been proved, which suggested that miRNAs are critical in cochlear pathology [106, 107]. As a regulator controlling autophagy and cell death, miR-34a restrains autophagic flux by inhibiting autophagy protein ATG9a in HEI-OC1 cells [10, 108, 109]. Notably, the inhibitory effect of miR-34a to autophagy is mediated through multiple targets, such as SIRT1 and Bcl-2 [110–112]. As an NAD⁺-dependent histone deacetylase, SIRT1 is famous in the modulation of aging. The deacetylation of multiple autophagy-related proteins, including ATG7, ATG5, and ATG8 [113], or regulation of uncoupling protein 2 (UCP2) to stimulate mitophagy activates autophagy via SIRT1 [114]. According to a recent study, loss of HCs is observed in aged C57BL/6 mice, accompanied by the downregulation of autophagy and SIRT1 expression, and in HEI-OC1 cells, the decrease in SIRT1 leads to the reduction of LC3-II with an elevated level of p62. Moreover, silencing the expression of SIRT1 impaired the formation of the autophagosomes [115]. In addition, the long-term administration of resveratrol (SIRT1 activator) to the aging cochlea enhanced mitophagy, alleviated mitochondrial biogenesis, and improved the mitochondrial function [115]. Altogether, it suggested that the miR-34a/SIRT1 signaling pathway is a potential target for modulating autophagy, which is promising in delaying ARHL.

Inflammaging means a clinical condition in the elder with low-grade and chronic inflammation. Since it is related to several age-related diseases, it might increase the morbidity or mortality in the elderly. The long-term infection might alter the permeability and structure of the round window membrane [116], causing the permeation of lipopolysaccharide (LPS) into the inner ear [117]. When LPS enters the inner ear, it damages the HCs through multiple mechanisms, including inducing mitochondrial damage, accumulation of ROS, and activation of NF-κB, SAPK/JNK, caspases, or other apoptotic pathways [118–121]. FoxG1 is a critical transcription factor belonging to the forkhead family. It regulates the proliferation and differentiation of cells, and the mutations in the Foxg1 gene affect the development of axon and neuron [122]. During the development of the inner ear, FoxG1 is critical in maintaining the formation of HCs and the morphology of the cochlea [46]. FoxG1 also regulates the metabolism and biosynthesis of mitochondria [123–125], and hence, the unusual expression of FoxG1 results in opposing consequences to the function of mitochondria. Moreover, another study showed that the susceptibility of aging OC-1 cells to LPS-induced inflammation is regulated by FoxG1 via activated autophagy [5], thereby providing a potential target in AHL treatment.

3.5. Inherited Hearing Loss and Autophagy

The defection of mitochondrial tRNA in posttranscriptional modification is thought to be related to a variety of human hereditary diseases, including inherited hearing loss [126]. Recently, the molecular mechanism of deafness-related tRNAIle4295A>G mutations was deeply studied. It was found that abnormal tRNA metabolism may lead to mitochondrial translation disorders, respiratory deficiency, increased level of reactive oxygen species, and autophagy promotion [127]. However, whether the upregulation of autophagy in HCs is protective or not was not demonstrated in this study.

IGF-1 is a trophic factor belonging to the insulin family. It is involved in the development of the nervous system in adults, and hence, the mutations cause human syndromic deafness [128]. The correlation between IGF-1 and autophagy has been demonstrated in many studies. For example, activation of mTOR and IGF-1 downregulates autophagy in mammary epithelial cells [129]. On the other hand, in cultures of Purkinje neurons, IGF-1 promotes autophagy through the induction of autophagosome fusion with lysosomes [130]. However, in the auditory system, the role of IGF-1 in regulating autophagy does not seem crucial, as no significant difference was detected in the autophagic flux between IGF-1^+/+ mice and IGF-1^-/- mice [131]; however, the role of IGF-1 in regulating autophagy should not be excluded out. Hearing impairment is also caused by cochlear ischemia [132–134]. Reportedly, the patients with carotid arterial sclerosis might suffer severer NIHL [135].

Hearing impairment can also be induced by cochlear ischemia [132–134]. Reportedly, carotid arterial sclerosis exacerbates the effects of noise exposure. Arterial sclerosis might be a contributor to hearing loss in the elderly, especially in those exposed to noise [135, 136]. According to a recent study, autophagy exerts a protective effect in ischemia-induced hearing loss, as the activation of autophagy occurs simultaneously with the recovery of hearing after reperfusion [137]. However, additional studies are required to understand the underlying mechanism.

5. Future Aspect

5.1. Using Autophagy as an Antioxidative Therapy

The role of autophagy in the auditory system is that of an antioxidant to protect HCs and hearing [6, 80, 138]. The accumulation of intracellular free radicals and ROS is increased by oxidative stress after injuries, and once the protective ability of the antioxidant system is surpassed, HC death happens [139, 140]. Previously, antioxidative therapies mainly focused on decreasing the ROS release or enhancing the antioxidant capacity. However, the efficiency of the conventional antioxidants is obviously limited to the already damaged organelles [141]. As autophagy can remove both oxidized proteins and impaired mitochondria at the same time, it offers a novel measure for the protection of HCs by eliminating the already oxidized proteins and organelles. Thus, autophagy can not only remove ROS accumulation but also eliminate injured mitochondria, suggesting that autophagy is an ideal candidate for antioxidation therapy [142]. Several studies have confirmed that autophagy is a basic antioxidant measure. After exposure of HEI-OC-1 cells to neomycin, the activation of autophagy (by rapamycin) enhances the expression of antioxidant genes, while the inhibition of autophagy exerts an opposite effect [6]. The upregulation of autophagy level suppresses the oxidative stress, thus exerting a protective effect on the cells. Hence, the appropriate elevation of autophagy might prevent SNHL induced by multiple factors.

5.2. Epigenetic and Autophagy

As epigenetic modifications participate in various biological processes, including transcriptional regulation and cell differentiation [143, 144], the dysregulation of epigenetic modifications may lead to developmental disorders, as well as cancer [145]. Although epigenetic research was under intensive focus in other biological systems, the understanding of epigenetics in ototoxic drug/noise/aged-induced hearing loss is not yet clear. In addition to MIR-34 described above, MIR-96 is also a promising target involved in autophagy and hearing loss treatment. As the first miRNA mutation associated with human deafness, the mutation in MIR-96 results in nonsyndromic SNHL [146]. Although miRNA is an essential factor in mRNA regulation, the downstream genes of miR96 in the cochlea are yet to be identified. Recent studies on the tumor [147] and brain injury [148] suggested that ATG7 could be modulated by miR-96. ATG7 activates ATG12 and ATG8 that are the essential components in the formation of autophagosomes [149]. According to a previous study, the reduced expression of miR-96 may directly increase the level of ATG7, thereby elevating the autophagosome synthesis and autophagy hyperactivation and eventually resulting in neuronal degeneration and death [150]. However, the correlation between ATG7 and miR-96 in the auditory system remains to be elucidated.

6. Conclusion

Autophagy is involved in a variety of signaling pathways and plays a major role in the development and protection of HCs. Mitochondrion depolarization and ROS accumulation would happen when harmful stimulus exerted to HCs. If the damaged mitochondria cannot be cleared in time, the apoptosis pathway in HCs will be activated, leading to the death of HCs. However, with the activation of autophagy pathway, autophagosome could encapsulate the damaged mitochondria and fuse with lysosomes to form autophagosomes, thus degrading the damaged mitochondria and promoting the survival of HCs (Figure 1). However, autophagy seems to play a double-edged role in HC protection, some researchers believe that autophagy may aggravate HC damage, and others argue that autophagy can protect HCs from ototoxic factors, but the specific mechanism of autophagy is unclear. Along with the deepening of research, the mechanism of autophagy will be fully understood, and new treatments for hearing loss will be found in the future.

Conflicts of Interest

The authors declare no competing financial interests.

Authors’ Contributions

Chang Liu, Zhiwei Zheng, and Pengjun Wang contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 82071045 and 81870728) and Shanghai Rising-Star Program (19QA1401800).

References

N. Mizushima, B. Levine, A. M. Cuervo, and D. J. Klionsky, “Autophagy fights disease through cellular self-digestion,” Nature, vol. 451, no. 7182, pp. 1069–1075, 2008.
View at: Publisher Site | Google Scholar
E. Janda, C. Isidoro, C. Carresi, and V. Mollace, “Defective autophagy in Parkinson’s disease: role of oxidative stress,” Molecular Neurobiology, vol. 46, no. 3, pp. 639–661, 2012.
View at: Publisher Site | Google Scholar
Y. Ohsumi, “Historical landmarks of autophagy research,” Cell Research, vol. 24, no. 1, pp. 9–23, 2014.
View at: Publisher Site | Google Scholar
H. Zhou, X. Y. Qian, N. N. Xu et al., “Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice,” Cell Death & Disease, vol. 11, no. 10, p. 913, 2020.
View at: Publisher Site | Google Scholar
Z. H. He, S. Y. Zou, M. Li et al., “The nuclear transcription factor FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways,” Redox Biology, vol. 28, 2020.
View at: Publisher Site | Google Scholar
Z. H. He, L. N. Guo, Y. L. Shu et al., “Autophagy protects auditory hair cells against neomycin-induced damage,” Autophagy, vol. 13, no. 11, pp. 1884–1904, 2017.
View at: Publisher Site | Google Scholar
L. Yu, A. Alva, H. Su et al., “Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8,” Science, vol. 304, no. 5676, pp. 1500–1502, 2004.
View at: Publisher Site | Google Scholar
P. Boya, R. A. González-Polo, N. Casares et al., “Inhibition of macroautophagy triggers apoptosis,” Molecular and Cellular Biology, vol. 25, no. 3, pp. 1025–1040, 2005.
View at: Publisher Site | Google Scholar
N. Rodriguez-Muela, F. Germain, G. Marino, P. S. Fitze, and P. Boya, “Autophagy promotes survival of retinal ganglion cells after optic nerve axotomy in mice,” Cell Death and Differentiation, vol. 19, no. 1, pp. 162–169, 2012.
View at: Publisher Site | Google Scholar
J. Pang, H. Xiong, P. Lin et al., “Activation of miR-34a impairs autophagic flux and promotes cochlear cell death via repressing ATG9A : implications for age-related hearing loss,” Cell Death & Disease, vol. 8, no. 10, article e3079, 2017.
View at: Publisher Site | Google Scholar
N. Germic, A. Hosseini, S. Yousefi, A. Karaulov, and H. U. Simon, “Regulation of eosinophil functions by autophagy,” Seminars in Immunopathology, 2021.
View at: Publisher Site | Google Scholar
G. Mariño, A. F. Fernández, S. Cabrera et al., “Autophagy is essential for mouse sense of balance,” The Journal of Clinical Investigation, vol. 120, no. 7, pp. 2331–2344, 2010.
View at: Publisher Site | Google Scholar
M. R. Aburto, J. M. Hurle, I. Varela-Nieto, and M. Magarinos, “Autophagy during vertebrate development,” Cell, vol. 1, no. 3, pp. 428–448, 2012.
View at: Publisher Site | Google Scholar
M. P. Taylor and K. Kirkegaard, “Potential subversion of autophagosomal pathway by picornaviruses,” Autophagy, vol. 4, no. 3, pp. 286–289, 2008.
View at: Publisher Site | Google Scholar
C. Jones and P. Chen, “Chapter Eight Primary cilia in planar cell polarity regulation of the inner ear,” Current Topics in Developmental Biology, vol. 85, pp. 197–224, 2008.
View at: Publisher Site | Google Scholar
C. Petit and G. P. Richardson, “Linking genes underlying deafness to hair-bundle development and function,” Nature Neuroscience, vol. 12, no. 6, pp. 703–710, 2009.
View at: Publisher Site | Google Scholar
S. F. Maison, J. C. Adams, and M. C. Liberman, “Olivocochlear innervation in the mouse: immunocytochemical maps, crossed versus uncrossed contributions, and transmitter colocalization,” The Journal of Comparative Neurology, vol. 455, no. 3, pp. 406–416, 2003.
View at: Publisher Site | Google Scholar
H. M. Sobkowicz, J. E. Rose, G. E. Scott, and S. M. Slapnick, “Ribbon synapses in the developing intact and cultured organ of Corti in the mouse,” The Journal of Neuroscience, vol. 2, no. 7, pp. 942–957, 1982.
View at: Publisher Site | Google Scholar
C. Fujimoto, S. Iwasaki, S. Urata et al., “Autophagy is essential for hearing in mice,” Cell Death & Disease, vol. 8, no. 5, article e2780, 2017.
View at: Publisher Site | Google Scholar
W. Xiong, W. Wei, Y. Qi et al., “Autophagy is required for remodeling in postnatal developing ribbon synapses of cochlear inner hair cells,” Neuroscience, vol. 431, pp. 1–16, 2020.
View at: Publisher Site | Google Scholar
S. Zhang, Y. Zhang, Y. Dong et al., “Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea,” Cellular and Molecular Life Sciences, vol. 77, no. 7, pp. 1401–1419, 2020.
View at: Publisher Site | Google Scholar
Y. Zhang, S. Zhang, Z. Zhang et al., “Knockdown of Foxg1 in Sox9+ supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse utricle,” Aging, vol. 12, no. 20, pp. 19834–19851, 2020.
View at: Publisher Site | Google Scholar
S. S. Zhang, R. Y. Qiang, Y. Dong et al., “Hair cell regeneration from inner ear progenitors in the mammalian cochlea,” American Journal of Stem Cells, vol. 9, no. 3, pp. 25–35, 2020.
View at: Google Scholar
R. R. Guo, X. F. Ma, M. H. Liao et al., “Development and application of cochlear implant-based electric-acoustic stimulation of spiral ganglion neurons,” ACS Biomaterials Science & Engineering, vol. 5, no. 12, pp. 6735–6741, 2019.
View at: Publisher Site | Google Scholar
S. S. Zhang, D. D. Liu, Y. Dong et al., “Frizzled-9+supporting cells are progenitors for the generation of hair cells in the postnatal mouse cochlea,” Frontiers in Molecular Neuroscience, vol. 12, 2019.
View at: Publisher Site | Google Scholar
T. Wang, R. J. Chai, G. S. Kim et al., “Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle,” Nature Communications, vol. 6, no. 1, 2015.
View at: Publisher Site | Google Scholar
E. Durante-Mangoni, A. Grammatikos, R. Utili, and M. E. Falagas, “Do we still need the aminoglycosides?” International Journal of Antimicrobial Agents, vol. 33, no. 3, pp. 201–205, 2009.
View at: Publisher Site | Google Scholar
D. Baguley, D. McFerran, and D. Hall, “Tinnitus,” The Lancet, vol. 382, no. 9904, pp. 1600–1607, 2013.
View at: Publisher Site | Google Scholar
J. Xie, A. E. Talaska, and J. Schacht, “New developments in aminoglycoside therapy and ototoxicity,” Hearing Research, vol. 281, no. 1-2, pp. 28–37, 2011.
View at: Publisher Site | Google Scholar
Q. Yang, G. Sun, H. Yin et al., “PINK1 Protects Auditory Hair Cells and Spiral Ganglion Neurons from Cisplatin- induced Ototoxicity via Inducing Autophagy and Inhibiting JNK Signaling Pathway,” Free Radical Biology & Medicine, vol. 120, pp. 342–355, 2018.
View at: Publisher Site | Google Scholar
A. M. Pickrell and R. J. Youle, “The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson's Disease,” Neuron, vol. 85, no. 2, pp. 257–273, 2015.
View at: Publisher Site | Google Scholar
Q. Yang, Y. Zhou, H. Yin et al., “PINK1 protects against gentamicin-induced sensory hair cell damage: possible relation to induction of autophagy and inhibition of p 53 signal pathway,” Frontiers in Molecular Neuroscience, vol. 11, p. 403, 2018.
View at: Publisher Site | Google Scholar
G. Ristic, W. L. Tsou, and S. V. Todi, “An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes,” Frontiers in Molecular Neuroscience, vol. 7, p. 72, 2014.
View at: Publisher Site | Google Scholar
F. E. Magraoui, C. Reidick, H. E. Meyer, and H. W. Platta, “Autophagy-related deubiquitinating enzymes involved in health and disease,” Cell, vol. 4, no. 4, pp. 596–621, 2015.
View at: Publisher Site | Google Scholar
S. Costes, T. Gurlo, J. F. Rivera, and P. C. Butler, “UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in β-cells,” Autophagy, vol. 10, no. 6, pp. 1004–1014, 2014.
View at: Publisher Site | Google Scholar
Y. J. Kim, K. Kim, Y. Y. Lee, O. S. Choo, J. H. Jang, and Y. H. Choung, “Downregulated UCHL1 accelerates gentamicin-induced auditory cell death via autophagy,” Molecular Neurobiology, vol. 56, no. 11, pp. 7433–7447, 2019.
View at: Publisher Site | Google Scholar
B. S. Nayak, S. S. Raju, and A. V. Chalapathi Rao, “Wound healing activity of Persea americana (avocado) fruit: a preclinical study on rats,” Journal of Wound Care, vol. 17, no. 3, pp. 123–125, 2008.
View at: Publisher Site | Google Scholar
O. Ortiz-Avila, M. Esquivel-Martinez, B. E. Olmos-Orizaba, A. Saavedra-Molina, A. R. Rodriguez-Orozco, and C. Cortes-Rojo, “Avocado oil improves mitochondrial function and decreases oxidative stress in brain of diabetic rats,” Journal Diabetes Research, vol. 2015, article 485759, 9 pages, 2015.
View at: Publisher Site | Google Scholar
T. N. M. Pham, S. Y. Jeong, D. H. Kim et al., “Protective mechanisms of avocado oil extract against ototoxicity,” Nutrients, vol. 12, no. 4, p. 947, 2020.
View at: Publisher Site | Google Scholar
D. V. T. Catenacci, N. C. Tebbutt, I. Davidenko et al., “Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial,” The Lancet Oncology, vol. 18, no. 11, pp. 1467–1482, 2017.
View at: Publisher Site | Google Scholar
M. L. Telli, K. M. Timms, J. Reid et al., “Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer,” Clinical Cancer Research, vol. 22, no. 15, pp. 3764–3773, 2016.
View at: Publisher Site | Google Scholar
S. Gao, C. Cheng, M. H. Wang et al., “Blebbistatin inhibits neomycin-induced apoptosis in hair cell-like HEI-OC-1 cells and in cochlear hair cells,” Frontiers in Cellular Neuroscience, vol. 13, 2020.
View at: Publisher Site | Google Scholar
Y. Q. Zhang, W. Li, Z. H. He et al., “Pre-treatment with fasudil prevents neomycin-induced hair cell damage by reducing the accumulation of reactive oxygen species,” Frontiers in Molecular Neuroscience, vol. 12, 2019.
View at: Publisher Site | Google Scholar
L. Liu, Y. Chen, J. Qi et al., “Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea,” Cell Death & Disease, vol. 7, no. 3, p. e2136, 2016.
View at: Publisher Site | Google Scholar
Z. H. Zhong, X. L. Fu, H. Li et al., “Citicoline protects auditory hair cells against neomycin-induced damage,” Frontiers in Cell and Development Biology, vol. 8, 2020.
View at: Publisher Site | Google Scholar
Z. H. He, Q. J. Fang, H. Li et al., “The role of FOXG1 in the postnatal development and survival of mouse cochlear hair cells,” Neuropharmacology, vol. 144, pp. 43–57, 2019.
View at: Publisher Site | Google Scholar
J. Choi, S. H. Kim, Y. C. Rah et al., “Effects of caffeic acid on cisplatin-induced hair cell damage in HEI-OC1 auditory cells,” International Journal of Pediatric Otorhinolaryngology, vol. 78, no. 12, pp. 2198–2204, 2014.
View at: Publisher Site | Google Scholar
W. W. Liu, X. C. Xu, Z. M. Fan et al., “Wnt signaling activates TP53-induced glycolysis and apoptosis regulator and protects against cisplatin-induced spiral ganglion neuron damage in the mouse cochlea,” Antioxidants & Redox Signaling, vol. 30, no. 11, pp. 1389–1410, 2019.
View at: Publisher Site | Google Scholar
H. Li, Y. D. Song, Z. H. He et al., “Meclofenamic acid reduces reactive oxygen species accumulation and apoptosis, inhibits excessive autophagy, and protects hair cell-like HEI-OC1 cells from cisplatin-induced damage,” Frontiers in Cellular Neuroscience, vol. 12, 2018.
View at: Publisher Site | Google Scholar
X. Wang, Z. Lu, A. Gomez et al., “N⁶-methyladenosine-dependent regulation of messenger RNA stability,” Nature, vol. 505, no. 7481, pp. 117–120, 2014.
View at: Publisher Site | Google Scholar
Y. Huang, J. Yan, Q. Li et al., “Meclofenamic acid selectively inhibits FTO demethylation of m⁶A over ALKBH5,” Nucleic Acids Research, vol. 43, no. 1, pp. 373–384, 2015.
View at: Publisher Site | Google Scholar
B. Andersen and M. G. Rosenfeld, “POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease,” Endocrine Reviews, vol. 22, no. 1, pp. 2–35, 2001.
View at: Publisher Site | Google Scholar
H. J. Kim, H. H. Won, K. J. Park et al., “SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15),” PLoS One, vol. 8, no. 11, article e79063, 2013.
View at: Publisher Site | Google Scholar
M. Xiang, W. Q. Gao, T. Hasson, and J. J. Shin, “Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells,” Development, vol. 125, no. 20, pp. 3935–3946, 1998.
View at: Publisher Site | Google Scholar
L. Erkman, R. J. McEvilly, L. Luo et al., “Role of transcription factors a Brn-3.1 and Brn-3.2 in auditory and visual system development,” Nature, vol. 381, no. 6583, pp. 603–606, 1996.
View at: Publisher Site | Google Scholar
F. Xu, W. Yan, and Y. Cheng, “Pou4f3 gene mutation promotes autophagy and apoptosis of cochlear hair cells in cisplatin-induced deafness mice,” Archives of Biochemistry and Biophysics, vol. 680, article 108224, 2020.
View at: Publisher Site | Google Scholar
T. Kaur, D. Mukherjea, K. Sheehan, S. Jajoo, L. P. Rybak, and V. Ramkumar, “Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation,” Cell Death & Disease, vol. 2, no. 7, article e180, 2011.
View at: Publisher Site | Google Scholar
N. C. Schmitt, E. W. Rubel, and N. M. Nathanson, “Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate,” The Journal of Neuroscience, vol. 29, no. 12, pp. 3843–3851, 2009.
View at: Publisher Site | Google Scholar
S. Levano and D. Bodmer, “Loss of STAT1 protects hair cells from ototoxicity through modulation of STAT3, c-Jun, Akt, and autophagy factors,” Cell Death & Disease, vol. 6, no. 12, article e2019, 2015.
View at: Publisher Site | Google Scholar
F. Takahashi-Yanaga, “Activator or inhibitor? GSK-3 as a new drug target,” Biochemical Pharmacology, vol. 86, no. 2, pp. 191–199, 2013.
View at: Publisher Site | Google Scholar
D. Wu and W. Pan, “GSK3: a multifaceted kinase in Wnt signaling,” Trends in Biochemical Sciences, vol. 35, no. 3, pp. 161–168, 2010.
View at: Publisher Site | Google Scholar
J. Y. Qi, L. Y. Zhang, F. Z. Tan et al., “Espin distribution as revealed by super-resolution microscopy of stereocilia,” American Journal of Translational Research, vol. 12, no. 1, pp. 130–141, 2020.
View at: Google Scholar
J. Y. Qi, Y. Liu, C. F. Chu et al., “A cytoskeleton structure revealed by super-resolution fluorescence imaging in inner ear hair cells,” Cell Discovery, vol. 5, no. 1, 2019.
View at: Publisher Site | Google Scholar
A. Li, D. You, W. Y. Li et al., “Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2,” Drug Delivery, vol. 25, no. 1, pp. 1033–1043, 2018.
View at: Publisher Site | Google Scholar
X. Y. Yu, W. W. Liu, Z. M. Fan et al., “c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI- OC1 cells in vitro,” Scientific Reports, vol. 7, no. 1, 2017.
View at: Publisher Site | Google Scholar
I. Azoulay-Alfaguter, R. Elya, L. Avrahami, A. Katz, and H. Eldar-Finkelman, “Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cell growth,” Oncogene, vol. 34, no. 35, pp. 4613–4623, 2015.
View at: Publisher Site | Google Scholar
J. Kubisch, D. Türei, L. Földvári-Nagy et al., “Complex regulation of autophagy in cancer - integrated approaches to discover the networks that hold a double-edged sword,” Seminars in Cancer Biology, vol. 23, no. 4, pp. 252–261, 2013.
View at: Publisher Site | Google Scholar
T. Liu, S. Zong, P. Luo et al., “Enhancing autophagy by down-regulating GSK-3β alleviates cisplatin-induced ototoxicity in vivo and in vitro,” Toxicology Letters, vol. 313, pp. 11–18, 2019.
View at: Publisher Site | Google Scholar
A. A. Abdul-Sater, N. Saïd-Sadier, V. M. Lam et al., “Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1,” The Journal of Biological Chemistry, vol. 285, no. 53, pp. 41637–41645, 2010.
View at: Publisher Site | Google Scholar
Y. Lei, H. Wen, Y. Yu et al., “The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy,” Immunity, vol. 36, no. 6, pp. 933–946, 2012.
View at: Publisher Site | Google Scholar
Y. Lei, H. Wen, and J. P. Ting, “The NLR protein, NLRX1, and its partner, TUFM, reduce type I interferon, and enhance autophagy,” Autophagy, vol. 9, no. 3, pp. 432-433, 2013.
View at: Publisher Site | Google Scholar
E. Imbeault, T. M. Mahvelati, R. Braun, P. Gris, and D. Gris, “Nlrx1 regulates neuronal cell death,” Molecular Brain, vol. 7, no. 1, 2014.
View at: Publisher Site | Google Scholar
S. Coutermarsh-Ott, A. Simmons, V. Capria et al., “NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling,” Oncotarget, vol. 7, no. 22, pp. 33096–33110, 2016.
View at: Publisher Site | Google Scholar
H. Yin, G. Sun, Q. Yang et al., “NLRX1 accelerates cisplatin-induced ototoxity in HEI-OC1 cells via promoting generation of ROS and activation of JNK signaling pathway,” Scientific Reports, vol. 7, no. 1, article 44311, 2017.
View at: Publisher Site | Google Scholar
H. Yin, Q. Yang, Z. Cao et al., “Activation of NLRX1-mediated autophagy accelerates the ototoxic potential of cisplatin in auditory cells,” Toxicology and Applied Pharmacology, vol. 343, pp. 16–28, 2018.
View at: Publisher Site | Google Scholar
Z. H. He, S. Sun, M. Waqas et al., “Reduced TRMU expression increases the sensitivity of hair-cell-like HEI-OC-1 cells to neomycin damage in vitro,” Scientific Reports, vol. 6, no. 1, 2016.
View at: Publisher Site | Google Scholar
M. Guan, Q. J. Fang, Z. H. He et al., “Inhibition of ARC decreases the survival of HEI-OC-1 cells after neomycin damage in vitro,” Oncotarget, vol. 7, no. 41, pp. 66647–66659, 2016.
View at: Publisher Site | Google Scholar
S. Sun, M. Z. Sun, Y. P. Zhang et al., “In vivo overexpression of X-linked inhibitor of apoptosis protein protects against neomycin-induced hair cell loss in the apical turn of the cochlea during the ototoxic-sensitive period,” Frontiers in Cellular Neuroscience, vol. 8, 2014.
View at: Publisher Site | Google Scholar
P. J. Vernon and D. Tang, “Eat-me: autophagy, phagocytosis, and reactive oxygen species signaling,” Antioxidants & Redox Signaling, vol. 18, no. 6, pp. 677–691, 2013.
View at: Publisher Site | Google Scholar
H. Yuan, X. Wang, K. Hill et al., “Autophagy attenuates noise-induced hearing loss by reducing oxidative stress,” Antioxidants & Redox Signaling, vol. 22, no. 15, pp. 1308–1324, 2015.
View at: Publisher Site | Google Scholar
S. Delmaghani, J. Defourny, A. Aghaie et al., “Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes,” Cell, vol. 163, no. 4, pp. 894–906, 2015.
View at: Publisher Site | Google Scholar
J. Defourny, A. Aghaie, I. Perfettini, P. Avan, S. Delmaghani, and C. Petit, “Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 16, pp. 8010–8017, 2019.
View at: Publisher Site | Google Scholar
J. J. Smith and J. D. Aitchison, “Peroxisomes take shape,” Nature Reviews. Molecular Cell Biology, vol. 14, no. 12, pp. 803–817, 2013.
View at: Publisher Site | Google Scholar
M. Schrader, N. A. Bonekamp, and M. Islinger, “Fission and proliferation of peroxisomes,” Biochimica et Biophysica Acta, vol. 1822, no. 9, pp. 1343–1357, 2012.
View at: Publisher Site | Google Scholar
A. L. Anding and E. H. Baehrecke, “Cleaning house: selective autophagy of organelles,” Developmental Cell, vol. 41, no. 1, pp. 10–22, 2017.
View at: Publisher Site | Google Scholar
C. Lismont, M. Nordgren, P. P. Van Veldhoven, and M. Fransen, “Redox interplay between mitochondria and peroxisomes,” Frontiers in Cell and Development Biology, vol. 3, 2015.
View at: Publisher Site | Google Scholar
J. M. Bhatt, N. Bhattacharyya, and H. W. Lin, “Relationships between tinnitus and the prevalence of anxiety and depression,” Laryngoscope, vol. 127, no. 2, pp. 466–469, 2017.
View at: Publisher Site | Google Scholar
T. Pan, R. S. Tyler, H. Ji, C. Coelho, and S. A. Gogel, “Differences among patients that make their tinnitus worse or better,” American Journal of Audiology, vol. 24, no. 4, pp. 469–476, 2015.
View at: Publisher Site | Google Scholar
R. E. Gonzalez-Castañeda, A. Y. Galvez-Contreras, C. J. Martínez-Quezada et al., “Sex-related effects of sleep deprivation on depressive- and anxiety-like behaviors in mice,” Experimental Animals, vol. 65, no. 1, pp. 97–107, 2016.
View at: Publisher Site | Google Scholar
P. Bonaldo and M. Sandri, “Cellular and molecular mechanisms of muscle atrophy,” Disease Models & Mechanisms, vol. 6, no. 1, pp. 25–39, 2013.
View at: Publisher Site | Google Scholar
K. E. Rarey, L. M. Curtis, and W. J. F. ten Cate, “Tissue specific levels of glucocorticoid receptor within the rat inner ear,” Hearing Research, vol. 64, no. 2, pp. 205–210, 1993.
View at: Publisher Site | Google Scholar
Y. Tahera, I. Meltser, P. Johansson, A. C. Hansson, and B. Canlon, “Glucocorticoid receptor and nuclear factor-κB interactions in restraint stress-mediated protection against acoustic trauma,” Endocrinology, vol. 147, no. 9, pp. 4430–4437, 2006.
View at: Publisher Site | Google Scholar
K. Takemura, M. Komeda, M. Yagi et al., “Direct inner ear infusion of dexamethasone attenuates noise-induced trauma in guinea pig,” Hearing Research, vol. 196, no. 1-2, pp. 58–68, 2004.
View at: Publisher Site | Google Scholar
I. Meltser, Y. Tahera, and B. Canlon, “Glucocorticoid receptor and mitogen-activated protein kinase activity after restraint stress and acoustic trauma,” Journal of Neurotrauma, vol. 26, no. 10, pp. 1835–1845, 2009.
View at: Publisher Site | Google Scholar
P. Li, D. Bing, S. Wang et al., “Sleep deprivation modifies noise-induced cochlear injury related to the stress hormone and autophagy in female mice,” Frontiers in Neuroscience, vol. 13, p. 1297, 2019.
View at: Publisher Site | Google Scholar
C. Y. Chao, J. S. Wu, Y. C. Yang et al., “Sleep duration is a potential risk factor for newly diagnosed type 2 diabetes mellitus,” Metabolism, vol. 60, no. 6, pp. 799–804, 2011.
View at: Publisher Site | Google Scholar
M. R. Irwin, “Why sleep is important for health: a psychoneuroimmunology perspective,” Annual Review of Psychology, vol. 66, no. 1, pp. 143–172, 2015.
View at: Publisher Site | Google Scholar
M. Cheslock and O. De Jesus, Presbycusis, Stat Pearls, Treasure Island (FL), 2020.
X. L. Fu, X. Y. Sun, L. Q. Zhang et al., “Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss,” The Journal of Clinical Investigation, vol. 128, no. 11, pp. 4938–4955, 2018.
View at: Publisher Site | Google Scholar
Y. Y. Ding, W. Meng, W. J. Kong, Z. H. He, and R. J. Chai, “The role of FoxG1 in the inner ear,” Frontiers in Cell and Development Biology, vol. 8, 2020.
View at: Publisher Site | Google Scholar
Y. Liu, J. Y. Qi, X. Chen et al., “Critical role of spectrin in hearing development and deafness,” Science Advances, vol. 5, no. 4, p. eaav7803, 2019.
View at: Publisher Site | Google Scholar
C. Cheng, Y. F. Wang, L. Guo et al., “Age-related transcriptome changes in Sox2+supporting cells in the mouse cochlea,” Stem Cell Research & Therapy, vol. 10, no. 1, 2019.
View at: Publisher Site | Google Scholar
N. C. Homans, R. M. Metselaar, J. G. Dingemanse et al., “Prevalence of age-related hearing loss, including sex differences, in older adults in a large cohort study,” The Laryngoscope, vol. 127, no. 3, pp. 725–730, 2017.
View at: Publisher Site | Google Scholar
T. Takeda, M. Hosokawa, S. Takeshita et al., “A new murine model of accelerated senescence,” Mechanisms of Ageing and Development, vol. 17, no. 2, pp. 183–194, 1981.
View at: Publisher Site | Google Scholar
J. Menardo, Y. Tang, S. Ladrech et al., “Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse cochlea,” Antioxidants & Redox Signaling, vol. 16, no. 3, pp. 263–274, 2012.
View at: Publisher Site | Google Scholar
H. Xiong, J. Pang, H. Yang et al., “Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss,” Neurobiology of Aging, vol. 36, no. 4, pp. 1692–1701, 2015.
View at: Publisher Site | Google Scholar
Q. Zhang, H. Liu, J. McGee, E. J. Walsh, G. A. Soukup, and D. Z. He, “Identifying MicroRNAs involved in degeneration of the organ of Corti during age-related hearing loss,” PLoS One, vol. 8, no. 4, article e62786, 2013.
View at: Publisher Site | Google Scholar
J. Yang, D. Chen, Y. He et al., “MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9,” Age, vol. 35, no. 1, pp. 11–22, 2013.
View at: Publisher Site | Google Scholar
N. Liu, M. Landreh, K. Cao et al., “The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila,” Nature, vol. 482, no. 7386, pp. 519–523, 2012.
View at: Publisher Site | Google Scholar
Y. Yang, H. W. Cheng, Y. Qiu et al., “MicroRNA-34a plays a key role in cardiac repair and regeneration following myocardial infarction,” Circulation Research, vol. 117, no. 5, pp. 450–459, 2015.
View at: Publisher Site | Google Scholar
R. Huang, Y. Xu, W. Wan et al., “Deacetylation of nuclear LC3 drives autophagy initiation under starvation,” Molecular Cell, vol. 57, no. 3, pp. 456–466, 2015.
View at: Publisher Site | Google Scholar
R. Huang and W. Liu, “Identifying an essential role of nuclear LC3 for autophagy,” Autophagy, vol. 11, no. 5, pp. 852-853, 2015.
View at: Publisher Site | Google Scholar
M. Morita, S. P. Gravel, V. Chénard et al., “mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation,” Cell Metabolism, vol. 18, no. 5, pp. 698–711, 2013.
View at: Publisher Site | Google Scholar
E. F. Fang, M. Scheibye-Knudsen, L. E. Brace et al., “Defective Mitophagy in XPA via PARP-1 Hyperactivation and NAD⁺/SIRT1 Reduction,” Cell, vol. 157, no. 4, pp. 882–896, 2014.
View at: Publisher Site | Google Scholar
H. Xiong, S. Chen, L. Lai et al., “Modulation of miR-34a/SIRT1 signaling protects cochlear hair cells against oxidative stress and delays age-related hearing loss through coordinated regulation of mitophagy and mitochondrial biogenesis,” Neurobiology of Aging, vol. 79, pp. 30–42, 2019.
View at: Publisher Site | Google Scholar
Y. J. Yoon and S. Hellstrom, “Ultrastructural characteristics of the round window membrane during pneumococcal otitis media in rat,” Journal of Korean Medical Science, vol. 17, no. 2, pp. 230–235, 2002.
View at: Publisher Site | Google Scholar
H. Kawauchi, T. F. DeMaria, and D. J. Lim, “Endotoxin permeability through the round window,” Acta Oto-Laryngologica. Supplementum, vol. 457, pp. 100–115, 1989.
View at: Publisher Site | Google Scholar
J. M. Platnich, H. Chung, A. Lau et al., “Shiga toxin/lipopolysaccharide activates caspase-4 and gasdermin D to trigger mitochondrial reactive oxygen species upstream of the NLRP3 inflammasome,” Cell Reports, vol. 25, no. 6, pp. 1525–1536.e7, 2018.
View at: Publisher Site | Google Scholar
W. Abdulmahdi, D. Patel, M. M. Rabadi et al., “HMGB1 redox during sepsis,” Redox Biology, vol. 13, pp. 600–607, 2017.
View at: Publisher Site | Google Scholar
S. da Silveira Cruz-Machado, C. E. Carvalho-Sousa, E. K. Tamura et al., “TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway,” Journal of Pineal Research, vol. 49, no. 2, pp. 183–192, 2010.
View at: Publisher Site | Google Scholar
M. A. Khan, A. Farahvash, D. N. Douda et al., “JNK activation turns on LPS- and gram-negative bacteria-induced NADPH oxidase-dependent suicidal NETosis,” Scientific Reports, vol. 7, no. 1, p. 3409, 2017.
View at: Publisher Site | Google Scholar
C. H. Hwang, A. Simeone, E. Lai, and D. K. Wu, “Foxg1 is required for proper separation and formation of sensory cristae during inner ear development,” Developmental Dynamics, vol. 238, no. 11, pp. 2725–2734, 2009.
View at: Publisher Site | Google Scholar
M. Brancaccio, C. Pivetta, M. Granzotto, C. Filippis, and A. Mallamaci, “Emx2 and Foxg1 inhibit gliogenesis and promote neuronogenesis,” Stem Cells, vol. 28, no. 7, pp. 1206–1218, 2010.
View at: Publisher Site | Google Scholar
S. G. Dastidar, P. M. Landrieu, and S. R. D'Mello, “FoxG1 promotes the survival of postmitotic neurons,” The Journal of Neuroscience, vol. 31, no. 2, pp. 402–413, 2011.
View at: Publisher Site | Google Scholar
L. Pancrazi, G. di Benedetto, L. Colombaioni et al., “Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 45, pp. 13910–13915, 2015.
View at: Publisher Site | Google Scholar
M. T. Bohnsack and K. E. Sloan, “The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease,” Cellular and Molecular Life Sciences, vol. 75, no. 2, pp. 241–260, 2018.
View at: Publisher Site | Google Scholar
F. Meng, M. Zhou, Y. Xiao et al., “A deafness-associated tRNA mutation caused pleiotropic effects on the m¹G37 modification, processing, stability and aminoacylation of tRNA^Ile and mitochondrial translation,” Nucleic Acids Research, vol. 49, no. 2, pp. 1075–1093, 2021.
View at: Publisher Site | Google Scholar
S. Murillo-Cuesta, L. Rodríguez-de la Rosa, R. Cediel, L. Lassaletta, and I. Varela-Nieto, “The role of insulin-like growth factor-I in the physiopathology of hearing,” Frontiers in Molecular Neuroscience, vol. 4, p. 11, 2011.
View at: Publisher Site | Google Scholar
A. Sobolewska, M. Gajewska, J. Zarzynska, B. Gajkowska, and T. Motyl, “IGF-I, EGF, and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathway,” European Journal of Cell Biology, vol. 88, no. 2, pp. 117–130, 2009.
View at: Publisher Site | Google Scholar
M. Bains, M. L. Florez-McClure, and K. A. Heidenreich, “Insulin-like growth factor-I prevents the accumulation of autophagic vesicles and cell death in purkinje neurons by increasing the rate of autophagosome-to- lysosome fusion and degradation,” The Journal of Biological Chemistry, vol. 284, no. 30, pp. 20398–20407, 2009.
View at: Publisher Site | Google Scholar
R. de Iriarte Rodríguez, S. Pulido, L. Rodríguez-de la Rosa, M. Magariños, and I. Varela-Nieto, “Age-regulated function of autophagy in the mouse inner ear,” Hearing Research, vol. 330, no. Part A, pp. 39–50, 2015.
View at: Publisher Site | Google Scholar
C. Kim, J. H. Sohn, M. U. Jang et al., “Ischemia as a potential etiologic factor in idiopathic unilateral sudden sensorineural hearing loss: analysis of posterior circulation arteries,” Hearing Research, vol. 331, pp. 144–151, 2016.
View at: Publisher Site | Google Scholar
C. D. Lin, I. H. Wei, M. H. Tsai et al., “Changes in guinea pig cochlea after transient cochlear ischemia,” Neuroreport, vol. 21, no. 15, pp. 968–975, 2010.
View at: Publisher Site | Google Scholar
T. Yoshida, N. Hakuba, I. Morizane et al., “Hematopoietic stem cells prevent hair cell death after transient cochlear ischemia through paracrine effects,” Neuroscience, vol. 145, no. 3, pp. 923–930, 2007.
View at: Publisher Site | Google Scholar
M. Yoshioka, Y. Uchida, S. Sugiura et al., “The impact of arterial sclerosis on hearing with and without occupational noise exposure: a population-based aging study in males,” Auris Nasus Larynx, vol. 37, no. 5, pp. 558–564, 2010.
View at: Publisher Site | Google Scholar
B. Mazurek, H. Haupt, P. Georgiewa, B. F. Klapp, and A. Reisshauer, “A model of peripherally developing hearing loss and tinnitus based on the role of hypoxia and ischemia,” Medical Hypotheses, vol. 67, no. 4, pp. 892–899, 2006.
View at: Publisher Site | Google Scholar
H. Yang, J. Pang, H. Xiong et al., “The protective effect of autophagy on ischemia/reperfusion-induced hearing loss: implications for sudden hearing loss,” Neuroreport, vol. 28, no. 17, pp. 1157–1163, 2017.
View at: Publisher Site | Google Scholar
B. Fang and H. Xiao, “Rapamycin alleviates cisplatin-induced ototoxicity in vivo,” Biochemical and Biophysical Research Communications, vol. 448, no. 4, pp. 443–447, 2014.
View at: Publisher Site | Google Scholar
T. Finkel and N. J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, vol. 408, no. 6809, pp. 239–247, 2000.
View at: Publisher Site | Google Scholar
U. Lechowicz, A. Pollak, D. Raj-Koziak et al., “Tinnitus in patients with hearing loss due to mitochondrial DNA pathogenic variants,” European Archives of Oto-Rhino-Laryngology, vol. 275, no. 8, pp. 1979–1985, 2018.
View at: Publisher Site | Google Scholar
H. Sies, “Oxidative stress: a concept in redox biology and medicine,” Redox Biology, vol. 4, pp. 180–183, 2015.
View at: Publisher Site | Google Scholar
S. Giordano, V. Darley-Usmar, and J. Zhang, “Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease,” Redox Biology, vol. 2, pp. 82–90, 2014.
View at: Publisher Site | Google Scholar
M. J. Provenzano and F. E. Domann, “A role for epigenetics in hearing: establishment and maintenance of auditory specific gene expression patterns,” Hearing Research, vol. 233, no. 1-2, pp. 1–13, 2007.
View at: Publisher Site | Google Scholar
W. Reik, “Stability and flexibility of epigenetic gene regulation in mammalian development,” Nature, vol. 447, no. 7143, pp. 425–432, 2007.
View at: Publisher Site | Google Scholar
W. S. Layman and J. Zuo, “Epigenetic regulation in the inner ear and its potential roles in development, protection, and regeneration,” Frontiers in Cellular Neuroscience, vol. 8, p. 446, 2015.
View at: Publisher Site | Google Scholar
Á. Mencía, S. Modamio-Høybjør, N. Redshaw et al., “Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss,” Nature Genetics, vol. 41, no. 5, pp. 609–613, 2009.
View at: Publisher Site | Google Scholar
Z. W. Zhang, Y. Wu, S. Yuan et al., “Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage,” Brain Research, vol. 1701, pp. 112–125, 2018.
View at: Publisher Site | Google Scholar
J. Gan, Q. Cai, Y. Qu et al., “miR-96 attenuates status epilepticus-induced brain injury by directly targeting Atg7 and Atg16L1,” Scientific Reports, vol. 7, no. 1, article 10270, 2017.
View at: Publisher Site | Google Scholar
S. B. Hong, B. W. Kim, K. E. Lee et al., “Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8,” Nature Structural & Molecular Biology, vol. 18, no. 12, pp. 1323–1330, 2011.
View at: Publisher Site | Google Scholar
U. Bandyopadhyay, M. Nagy, W. A. Fenton, and A. L. Horwich, “Absence of lipofuscin in motor neurons of SOD1-linked ALS mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 30, pp. 11055–11060, 2014.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2021 Chang Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1339

Downloads

882

Citations

Neural Plasticity

Reestablishing Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells for Hearing Loss 2021

Autophagy: A Novel Horizon for Hair Cell Protection

Abstract

1. Introduction

2. Autophagy and Cochlear Development

3. Autophagy and Hearing Loss

3.1. Autophagy and Aminoglycoside-Induced Hearing Loss

3.2. Autophagy and Cisplatin-Induced Hearing Loss

3.3. Autophagy and Noise-Induced Hearing Loss

3.4. Age-Related Hearing Loss and Autophagy

3.5. Inherited Hearing Loss and Autophagy

4. Other Factors Related to Autophagy in the Inner Ear

5. Future Aspect

5.1. Using Autophagy as an Antioxidative Therapy

5.2. Epigenetic and Autophagy

6. Conclusion

Conflicts of Interest

Authors’ Contributions

Acknowledgments

References

Copyright