Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.

Autor:	Wu P; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.; Department of Biological Structure, University of Washington, Seattle, WA 98195, United States., Becker FB; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.; Department of Otolaryngology-HNS, University of Washington, Seattle, WA 98195, United States., Ogelman R; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.; Department of Biological Structure, University of Washington, Seattle, WA 98195, United States., Camci ED; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.; Department of Otolaryngology-HNS, University of Washington, Seattle, WA 98195, United States., Linbo TH; Department of Biological Structure, University of Washington, Seattle, WA 98195, United States.; Department of Otolaryngology-HNS, University of Washington, Seattle, WA 98195, United States., Simon JA; Clinical Research, Human Biology, and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States., Rubel EW; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States., Raible DW; Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA 98195, United States.; Department of Biological Structure, University of Washington, Seattle, WA 98195, United States.; Department of Otolaryngology-HNS, University of Washington, Seattle, WA 98195, United States.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 12. Date of Electronic Publication: 2024 Jul 12.
DOI:	10.1101/2024.05.30.596537
Abstrakt:	Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics such as neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 hour of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 hours for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.
Databáze:	MEDLINE
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