title: Reduced TRMU expression increases the sensitivity of hair-cell-like HEI-OC-1 cells to neomycin damage in vitro.
abstract: Aminoglycosides are ototoxic to the cochlear hair cells, and mitochondrial dysfunction is one of the major mechanisms behind ototoxic drug-induced hair cell death. TRMU (tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase) is a mitochondrial protein that participates in mitochondrial tRNA modifications, but the role of TRMU in aminoglycoside-induced ototoxicity remains to be elucidated. In this study, we took advantage of the HEI-OC-1 cell line to investigate the role of TRMU in aminoglycoside-induced cell death. We found that TRMU is expressed in both hair cells and HEI-OC-1 cells, and its expression is significantly decreased after 24 h neomycin treatment. We then downregulated TRMU expression with siRNA and found that cell death and apoptosis were significantly increased after neomycin injury. Furthermore, when we down-regulated TRMU expression, we observed significantly increased mitochondrial dysfunction and increased levels of reactive oxygen species (ROS) after neomycin injury, suggesting that TRMU regulates mitochondrial function and ROS levels. Lastly, the antioxidant N-acetylcysteine rescued the mitochondrial dysfunction and cell apoptosis that was induced by TRMU downregulation, suggesting that ROS accumulation contributed to the increased aminoglycosides sensitivity of HEI-OC-1 cells after TRMU downregulation. This study provides evidence that TRMU might be a new therapeutic target for the prevention of aminoglycoside-induced hair cell death.
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Zuhong
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Waqas
authors.affiliation: Department of Otolaryngology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Fuping
authors.initials: F
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Medical School, Southeast University, Nanjing 210096, China.
authors.forename: Mingshu
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institutes of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.|Institutes of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioelectronics, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|MOE Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing 210096, China.|Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
authors.forename: Renjie
authors.initials: R
authors.lastname: Chai
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009355:Neomycin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012359:tRNA Methyltransferases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D012359:tRNA Methyltransferases; C485897:tRNA (5-methylaminomethyl-2-thiouridylate)-methyltransferase 1, mouse; D009355:Neomycin; D000111:Acetylcysteine