title: A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity.
abstract: Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the previously developed bioorthogonal noncanonical amino acid tagging method, we used click chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a Food and Drug Administration-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity.
authors: Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Shimon P
authors: SP
authors: Francis
authors: Joshua
authors: J
authors: Katz
authors: Kathryn D
authors: KD
authors: Fanning
authors: Kimberly A
authors: KA
authors: Harris
authors: Brian D
authors: BD
authors: Nicholas
authors: Michael
authors: M
authors: Lacy
authors: James
authors: J
authors: Pagana
authors: Paul F
authors: PF
authors: Agris
authors: Jung-Bum
authors: JB
authors: Shin
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives; D000480:Alkynes; D000617:Aminoglycosides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002452:Cell Count; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism*; D004427:Ear Diseases / Q000139:chemically induced*; D004789:Enzyme Activation / Q000187:drug effects; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009924:Organ Culture Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000378:metabolism / Q000633:toxicity*; D012335:RNA, Ribosomal / Q000378:metabolism; D000077157:Sorafenib
chemical_list: D000480:Alkynes; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D012335:RNA, Ribosomal; C506098:azidohomoalanine; C551041:homopropargylglycine; D009536:Niacinamide; D000077157:Sorafenib; D048031:JNK Mitogen-Activated Protein Kinases; D000409:Alanine; D005998:Glycine