title: Autophagic flux, a possible mechanism for delayed gentamicin-induced ototoxicity.
abstract: Aminoglycoside antibiotics including gentamicin (GM) induce delayed ototoxic effects such as hearing loss after long-term use, unlike the early-onset ototoxicity caused by cisplatin. The purpose of the study was to identify the mechanism of the delayed GM-induced ototoxicity by exploring the role of autophagy in vitro and in vivo. Treating HEI-OC1 auditory cells with GM led to a time-dependent increase of the autophagosome marker LC3-II, which was accompanied by cell death. In contrast, cisplatin and penicillin caused a rapid increase and had no effect on LC3-II levels, respectively. LC3-II-expressing autophagosomes co-localized with the labeled GM. GM-treated autophagosomes expressed reduced levels of Rab7, which is necessary for the fusion of autophagosomes with lysosomes. When the autophagic flux enhancer rapamycin was applied to GM-treated cells, Rab7 and the lysosomal enzyme cathepsin D were upregulated, and increased cell survival was observed. In animal studies, the intraperitoneal injection of GM worsened hearing thresholds and induced the accumulation of LC3 in the organ of Corti. This hearing impairment was attenuated by rapamycin. These findings suggest that the delayed onset-ototoxicity of GM may be closely related to the accumulation of autophagosomes via impaired autophagy. This GM-induced auditory cell death could be inhibited by enhancing autophagic flux.
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Dali Bai Autonomous Prefecture People's Hospital, Renminnan road 35, Dali, Yunnan 671000, China.
authors.forename: Chunjie
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Rural and Biosystems Engineering, Chonnam National University, Gwangju 61186, Republic of Korea.
authors.forename: Jangho
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, BK21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.
authors.forename: Beomyong
authors.initials: B
authors.lastname: Shin
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.|Department of Medical Sciences, Ajou University Graduate School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.
authors.forename: Oak-Sung
authors.initials: OS
authors.lastname: Choo
authors.affiliation: Department of Biomedical Sciences, BK21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.|Department of Biomedical Sciences, BK21 Plus Research Center for Biomedical Sciences, Ajou University Graduate School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.|Department of Medical Sciences, Ajou University Graduate School of Medicine, San 5 Woncheon-dong, Yeongtong-gu, Suwon 16499, Republic of Korea.
authors.forename: Yun-Hoon
authors.initials: YH
authors.lastname: Choung
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D004423:Ear / Q000473:pathology*; D005839:Gentamicins / Q000009:adverse effects*; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects; D008954:Models, Biological; D020011:Protective Agents / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D005839:Gentamicins; D020011:Protective Agents; D020123:Sirolimus