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.

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

“…Recent reports have shown that aminoglycoside antibiotics induce autophagy when injected i.p. in rats (46). However, the basal levels of autophagy were very low in the cochleae, since little LC3II was detected.…”

Synergistic Ototoxicity of Gentamicin and Low-Dose Irradiation: Molecular Basis and Clinical Significance

“…Recent studies showed that gentamicin-mediated ototoxicity was closely associated with impairment of autophagy. Gentamicin was demonstrated to impair the fusion of autophagosome and lysosome, which led to a time-dependent increase of autophagosome marker LC3b-II, and subsequently an increase of cell death [Kim et al, 2017]. Independent studies also showed that activation of autophagy was able to attenuate gentamicin-induced ototoxicity and nephrotoxicity [Cui et al, 2015;He et al, 2017].…”

“…A recent study suggested that gentamicin-mediated ototoxicity was associated with impairment of autophagic flux [Kim et al, 2017]. To study if the same mechanism applied to synergistic ototoxicity from gentamicin and low-dose irradiation, we monitored the protein level changes of LC3b-I and II (components of the autophagosome) and SQSTM1/p62 protein (a substrate of autophagy) in cells exposed to gentamicin, radiation, or both.…”

Protective Mechanisms of Avocado Oil Extract Against Ototoxicity

“…Blocking autophagy flux by AG results in the accumulation of autophagosome bodies, resulting in ear toxicity. By contrast, enhancement of autophagic flux is believed to improve AG-induced [54] and cisplatin-induced [55] auditory cell death. The antioxidant aspect of autophagy also acts as an important defense mechanism for other types of acquired hearing loss, such as noise-induced and age-related hearing loss.…”