Dataset Information

Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage via the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway.

ABSTRACT: Mitochondrial oxidative stress is involved in hair cell damage caused by noise-induced hearing loss (NIHL). Sirtuin-3 (SIRT3) plays an important role in hair cell survival by regulating mitochondrial function; however, the role of SIRT3 in NIHL is unknown. In this study, we used 3-TYP to inhibit SIRT3 and found that this inhibition aggravated oxidative damage in the hair cells of mice with NIHL. Moreover, 3-TYP reduced the enzymatic activity and deacetylation levels of superoxide dismutase 2 (SOD2). Subsequently, we administered adeno-associated virus-SIRT3 to the posterior semicircular canals and found that SIRT3 overexpression significantly attenuated hair cell injury and that this protective effect of SIRT3 could be blocked by 2-methoxyestradiol, a SOD2 inhibitor. These findings suggest that insufficient SIRT3/SOD2 signaling leads to mitochondrial oxidative damage resulting in hair cell injury in NIHL. Thus, ameliorating noise-induced mitochondrial redox imbalance by intervening in the SIRT3/SOD2 signaling pathway may be a new therapeutic target for hair cell injury.

SUBMITTER: Liang W

PROVIDER: S-EPMC8637754 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage <i>via</i> the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway.

Liang Wenqi W Zhao Chunli C Chen Zhongrui Z Yang Zijing Z Liu Ke K Gong Shusheng S

Frontiers in cell and developmental biology 20211118

Mitochondrial oxidative stress is involved in hair cell damage caused by noise-induced hearing loss (NIHL). Sirtuin-3 (SIRT3) plays an important role in hair cell survival by regulating mitochondrial function; however, the role of SIRT3 in NIHL is unknown. In this study, we used 3-TYP to inhibit SIRT3 and found that this inhibition aggravated oxidative damage in the hair cells of mice with NIHL. Moreover, 3-TYP reduced the enzymatic activity and deacetylation levels of superoxide dismutase 2 (SO ...[more]

PMID: 34869361

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Project description: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.Abbreviations: AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A1; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.

Dataset Information

Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage via the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway.

Publications

Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage <i>via</i> the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway.

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