title: Bmi1 regulates auditory hair cell survival by maintaining redox balance.
abstract: Reactive oxygen species (ROS) accumulation are involved in noise- and ototoxic drug-induced hair cell loss, which is the major cause of hearing loss. Bmi1 is a member of the Polycomb protein family and has been reported to regulate mitochondrial function and ROS level in thymocytes and neurons. In this study, we reported the expression of Bmi1 in mouse cochlea and investigated the role of Bmi1 in hair cell survival. Bmi1 expressed in hair cells and supporting cells in mouse cochlea. Bmi1(-/-) mice displayed severe hearing loss and patched outer hair cell loss from postnatal day 22. Ototoxic drug-induced hair cells loss dramatically increased in Bmi1(-/-) mice compared with that in wild-type controls both in vivo and in vitro, indicating Bmi1(-/-) hair cells were significantly more sensitive to ototoxic drug-induced damage. Cleaved caspase-3 and TUNEL staining demonstrated that apoptosis was involved in the increased hair cell loss of Bmi1(-/-) mice. Aminophenyl fluorescein and MitoSOX Red staining showed the level of free radicals and mitochondrial ROS increased in Bmi1(-/-) hair cells due to the aggravated disequilibrium of antioxidant-prooxidant balance. Furthermore, the antioxidant N-acetylcysteine rescued Bmi1(-/-) hair cells from neomycin injury both in vitro and in vivo, suggesting that ROS accumulation was mainly responsible for the increased aminoglycosides sensitivity in Bmi1(-/-) hair cells. Our findings demonstrate that Bmi1 has an important role in hair cell survival by controlling redox balance and ROS level, thus suggesting that Bmi1 may work as a new therapeutic target for the prevention of hair cell death.
authors.affiliation: 1] Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China [2] Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
authors.forename: L
authors.identifier: 0000000233942278
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
authors.forename: W
authors.initials: W
authors.lastname: Ni
authors.affiliation: 1] Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China [2] Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China [3] Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China [2] Central Laboratory, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing 210096, China.
authors.forename: D
authors.initials: D
authors.lastname: Miao
authors.affiliation: Co-innovation Center of Neuroregeneration, Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China.
authors.forename: R
authors.initials: R
authors.lastname: Chai
authors.affiliation: 1] Department of Otorhinolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, China [2] Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China [3] State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D034381:Hearing Loss / Q000139:chemically induced / Q000473:pathology; D007760:Labyrinth Supporting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009355:Neomycin / Q000009:adverse effects; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; C489421:Bmi1 protein, mouse; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D063150:Polycomb Repressive Complex 1; D009355:Neomycin