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

Xiong, Hao; Chen, Suijun; Lai, Lan; Yang, Haidi; Xu, Yue; Pang, Jiaqi; Su, Zhi; Lin, Hanqing; Zheng, Yiqing

doi:10.1016/j.neurobiolaging.2019.03.013

Cited by 86 publications

(51 citation statements)

References 46 publications

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“…Our previous studies demonstrated that SIRT1 has a protective role in IVDD 31,32 . Furthermore, several studies revealed that SIRT1 plays a key role in mitophagy and apoptosis in a variety of aging-related diseases via SIRT1-Parkin-Mitohphagy pathway [33][34][35][36][37] . In present study, we showed that circERCC2 regulated the expression of SIRT1 by sponging miR-182-5p.…”

Section: Discussionmentioning

confidence: 99%

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

et al. 2019

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The molecular mechanism of intervertebral disc degeneration (IVDD) remains unclear. This study aimed to investigate the role of circular RNAs (circRNAs) in the pathogenesis of IVDD. We sued nucleus pulposus (NP) tissues of patients, tert-butyl hydroperoxide (TBHP) stimulated NP cells (NPCs), and IVDD rat model to explore the interaction between circERCC2 and miR-182-5p/SIRT1 axis. The results showed that downregulation of circERCC2 increased the level of miR-182-5p and decreased the level of SIRT1 in degenerative NP tissues in vivo as well as in TBHP-stimulated NPCs in vitro. Treatment of SIRT1-si activated apoptosis and inhibited mitophagy. Moreover, miR-182-5p-si could regulate the mitophagy and the apoptosis of NPCs by targeting SIRT1. The effects of circERCC2 on NPCs and IVDD rat model were mediated by miR-182-5p/SIRT1 axis. In conclusion, this study provides the first evidence that circERCC2 could ameliorate IVDD through miR-182-5p/SIRT1 axis by activating mitophagy and inhibiting apoptosis, and suggests that circERCC2 is a potentially effective therapeutic target for IVDD.

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Section: Discussionmentioning

confidence: 99%

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

et al. 2019

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“…Indeed, Sirt1 activation by resveratrol treatment prevents outer hair cell loss and rescues the reduced synaptic ribbon counts in inner hair cells upon aging. 30,31 Future studies exploring the CSB-Sirt1-NAD axis in the context of hearing loss are warranted as the role of Sirt1 on cochlear function is still a subject of debate. 32 NR is generally recognized as safe for use in dietary supplements and well-tolerated up to 1000 g daily in humans for 6 weeks.…”

Section: Discussionmentioning

confidence: 99%

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

et al. 2020

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Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (CSA −/− and CSB m/m ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD + , a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD + levels are reduced in the cochlea of CSB m/m mice and that short-term treatment (10 days) with the NAD + precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSB m/m mice. Similar, but more modest effects were observed in CSA −/− mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA −/− and CSB m/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD (H) binding pocket which regulates its activity. Intriguingly, NAD + supplementation rescues reduced synaptic ribbon formation in both CSA −/− and CSB m/m mutant cochleae. These findings provide valuable insight into the mechanism of CS-and ARHL-associated hearing loss, and suggest a possible intervention.npj Aging and Mechanisms of Disease (2020) 6:1 ; https://doi.

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“…Citicoline has been recently shown to increase SIRT1 protein expression, and this is strongly related to its neuroprotective activities ( Hurtado et al, 2013 ). A previous study showed that increased SIRT1 protects against cisplatin-induced damage to HCs ( Xiong et al, 2019 ). Therefore, we will further study whether the protective effect of citicoline on neomycin-induced HC damage works through SIRT1 activation.…”

Section: Discussionmentioning

confidence: 99%

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

Zhong

et al. 2020

Front. Cell Dev. Biol.

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Aminoglycoside-induced hair cell (HC) loss is one of the most important causes of hearing loss. After entering the inner ear, aminoglycosides induce the production of high levels of reactive oxygen species (ROS) that subsequently activate apoptosis in HCs. Citicoline, a nucleoside derivative, plays a therapeutic role in central nervous system injury and in neurodegenerative disease models, including addictive disorders, stroke, head trauma, and cognitive impairment in the elderly, and has been widely used in the clinic as an FDA approved drug. However, its effect on auditory HCs remains unknown. Here, we used HC-like HEI-OC-1 cells and whole organ explant cultured mouse cochleae to explore the effect of citicoline on aminoglycoside-induced HC damage. Consistent with previous reports, both ROS levels and apoptosis were significantly increased in neomycin-induced cochlear HCs and HEI-OC-1 cells compared to undamaged controls. Interestingly, we found that co-treatment with citicoline significantly protected against neomycin-induced HC loss in both HEI-OC-1 cells and whole organ explant cultured cochleae. Furthermore, we demonstrated that citicoline could significantly reduce neomycin-induced mitochondrial dysfunction and inhibit neomycin-induced ROS accumulation and subsequent apoptosis. Thus, we conclude that citicoline can protect against neomycin-induced HC loss by inhibiting ROS aggregation and thus preventing apoptosis in HCs, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect HCs.

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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

Cited by 86 publications

References 46 publications

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage

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