Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

Fu, Xiaolong; Sun, Xiaoyang; Zhang, Linqing; Jin, Yecheng; Chai, Renjie; Yang, Lili; Zhang, Aizhen; Liu, Xiangguo; Bai, Xia; Li, Jianfeng; Wang, Haibo; Gao, Jiangang

doi:10.1172/jci98058

Cited by 62 publications

(66 citation statements)

References 60 publications

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“…The rats in the simulated ageing groups accumulated more MDA than those in the corresponding control groups, and GSH content and SOD activity demonstrated opposite change trends. Many previous studies have indicated that oxidative stress is closely related to the occurrence and development of central presbycusis, consistent with the results of our study [53][54][55]. ROS destroy cell function, destroy normal tissues and cells and affect normal osmotic pressure, further leading to metabolic disorders of important organs and eventually to overall ageing [56][57][58].…”

Section: Discussionsupporting

confidence: 92%

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

Chen

Sun

et al. 2020

The FEBS Journal

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Central presbycusis is caused by degradation of the auditory centre during ageing. Its main characteristics are difficulties in understanding language and localizing sound. Presbycusis is an increasingly critical public health problem, but the underlying molecular mechanism has not been fully elucidated. Ferroptosis is a form of regulated cell death caused by iron-and reactive oxygen species-induced lipid peroxidation. Ferroptosis is related to many pathological processes, but whether it participates in the degeneration of the auditory system remains unclear. To investigate this, we measured iron levels in a simulated ageing model established by the addition of D-galactose (D-gal). We found, for the first time, that iron accumulated within cells and that the ultrastructural features of ferroptosis appeared in the auditory cortex with ageing. These changes were accompanied by upregulation of iron regulatory protein 2 (IRP-2), which led to an increase in transferrin receptor 1 (TfR-1), thus increasing iron entry into cells and potentially leading to ferroptosis. In addition, the malondialdehyde (MDA) content and the occurrence of mitochondrial DNA common deletions (CDs) increased, neuron degeneration appeared, and glutathione (GSH) and superoxide dismutase (SOD) activity decreased. Furthermore, we found that treatment with the iron chelator deferoxamine (DFO) and knockdown of IRP-2 both relieved ferroptosis during the simulated ageing process, thus achieving a partial protective effect to delay ageing. In summary, we describe here the first discovery that age-related iron deposition and ferroptosis may be associated with auditory cortex neurodegeneration. Relieving ferroptosis might thus be a new intervention strategy for age-related hearing loss.

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Section: Discussionsupporting

confidence: 92%

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

Chen

Sun

et al. 2020

The FEBS Journal

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“…Blocking was performed using 5% normal donkey serum and 5% BSA in PBS to prevent nonspecific binding of the secondary antibody. Following blocking, the sections were incubated with primary antibodies: mouse anti-bIII Tubulin antibody (Sigma Aldrich, and diluted 1:1000), rabbit polyclonal to Superoxide Dismutase 1-SOD1 antibody (ab13498, diluted 1:1000) or mouse monoclonal anti-3-Nitrotyrosine antibody (ab110282, 1 lg/mL) 27 and incubated for 24 hours at 48C. Secondary antibody incubation was carried out for 1 hour with a 1:1000 dilution of the appropriate secondary antibodies.…”

Section: Pattern Ergmentioning

confidence: 99%

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Stankowska

Dibas

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Determine the toxicity, bioavailability in the retina, and neuroprotective effects of a hybrid antioxidant-nitric oxide donor compound SA-2 against oxidative stress-induced retinal ganglion cell (RGC) death in neurodegenerative animal models. METHODS. Optic nerve crush (ONC) and ischemia reperfusion (I/R) injury models were used in 12-week-old C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mice were treated intravitreally with either vehicle or SA-2. Retinal thickness was measured by spectral-domain optical coherence tomography (SD-OCT). The electroretinogram and pattern ERG (PERG) were used to assess retinal function. RGC survival was determined by counting RBPMS-positive RGCs and immunohistochemical analysis of superoxide dismutase 1 (SOD1) levels was carried out in the retina sections. Concentrations of SA-2 in the retina and choroid were determined using HPLC and MS. In addition, the direct effect of SA-2 treatment on RGC survival was assessed in ex vivo rat retinal explants under hypoxic (0.5% O 2) conditions. RESULTS. Compound SA-2 did not induce any appreciable change in retinal thickness, or in a-or b-wave amplitude in naive animals. SA-2 was found to be bioavailable in both the retina and choroid after a single intravitreal injection (2% wt/vol). An increase in SOD1 levels in the retina of mice subjected to ONC and SA-2 treatment, suggests an enhancement in antioxidant activity. SA-2 provided significant (P < 0.05) RGC protection in all three of the tested RGC injury models in rodents. PERG amplitudes were significantly higher in both I/R and ONC mouse eyes following SA-2 treatment (P 0.001) in comparison with the vehicle and control groups. CONCLUSIONS. Compound SA-2 was effective in preventing RGC death and loss of function in three different rodent models of acute RGC injury: ONC, I/R, and hypoxia.

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“…ARHL, or presbycusis, is a progressive decline in hearing function that is the most prevalent type of SNHL in the elderly [17,18,19,20]. It is characterized by higher hearing thresholds, beginning at high frequencies and spreading toward low frequencies, accompanied by the loss of HCs and SGNs from the basal to apical turn [21,22,23,24,25,26]. The mechanism underlying ARHL is considered to be multifactorial, involving environmental and hereditary factors, but remains unclear.…”

Section: Hearing Loss and Mitochondrial Dysfunctionmentioning

confidence: 99%

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

Zhang

Gong

2021

Neural Plasticity

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Mitochondrial dysfunction has been suggested to be a risk factor for sensorineural hearing loss (SNHL) induced by aging, noise, ototoxic drugs, and gene. Reactive oxygen species (ROS) are mainly derived from mitochondria, and oxidative stress induced by ROS contributes to cochlear damage as well as mitochondrial DNA mutations, which may enhance the sensitivity and severity of hearing loss and disrupt ion homeostasis (e.g., Ca2+ homeostasis). The formation and accumulation of ROS further undermine mitochondrial components and ultimately lead to apoptosis and necrosis. SIRT3–5, located in mitochondria, belong to the family of sirtuins, which are highly conserved deacetylases dependent on nicotinamide adenine dinucleotide (NAD+). These deacetylases regulate diverse cellular biochemical activities. Recent studies have revealed that mitochondrial sirtuins, especially SIRT3, modulate ROS levels in hearing loss pathologies. Although the precise functions of SIRT4 and SIRT5 in the cochlea remain unclear, the molecular mechanisms in other tissues indicate a potential protective effect against hearing loss. In this review, we summarize the current knowledge regarding the role of mitochondrial dysfunction in hearing loss, discuss possible functional links between mitochondrial sirtuins and SNHL, and propose a perspective that SIRT3–5 have a positive effect on SNHL.

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Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

Cited by 62 publications

References 60 publications

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex

Hybrid Compound SA-2 is Neuroprotective in Animal Models of Retinal Ganglion Cell Death

Mitochondrial Dysfunction and Sirtuins: Important Targets in Hearing Loss

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