Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage.
Yuhua ZhangQiaojun FangHongfeng WangJieyu QiShan SunMenghui LiaoYunhao WuYangnan HuPei JiangCheng ChengXiaoyun QianMingliang TangWei CaoShang XiangChen ZhangJianming YangXia GaoZheng YingRen-Jie ChaiPublished in: Autophagy (2022)
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.
Keyphrases
- cell death
- nlrp inflammasome
- reactive oxygen species
- oxidative stress
- cell cycle arrest
- hearing loss
- induced apoptosis
- randomized controlled trial
- pseudomonas aeruginosa
- diabetic rats
- transcription factor
- stem cells
- quality control
- bone marrow
- signaling pathway
- cell proliferation
- drug induced
- combination therapy
- genome wide
- mesenchymal stem cells
- functional connectivity
- long non coding rna
- smoking cessation
- big data
- endoplasmic reticulum stress
- artificial intelligence
- resting state
- fluorescent probe
- single molecule