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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,20]]},"abstract":"<jats:p>Exposure to loud noise triggers sensory organ damage and degeneration that, in turn, leads to hearing loss. Despite the troublesome impact of noise-induced hearing loss (NIHL) in individuals and societies, treatment strategies that protect and restore hearing are few and insufficient. As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required. Biological zinc is mostly bound to proteins, where it plays major structural or catalytic roles; however, there is also a pool of unbound, mobile (labile) zinc. Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role. In the brain, labile zinc fine-tunes neurotransmission and sensory processing. However, injury-induced dysregulation of labile zinc signaling contributes to neurodegeneration. Here, we tested whether zinc dysregulation occurs and contributes to NIHL in mice. We found that ZnT3, the vesicular zinc transporter responsible for loading zinc into vesicles, is expressed in cochlear hair cells and the spiral limbus, with labile zinc also present in the same areas. Soon after noise trauma, ZnT3 and zinc levels are significantly increased, and their subcellular localization is vastly altered. Disruption of zinc signaling, either via ZnT3 deletion or pharmacological zinc chelation, mitigated NIHL, as evidenced by enhanced auditory brainstem responses, distortion product otoacoustic emissions, and number of hair cell synapses. These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.<\/jats:p>","DOI":"10.1073\/pnas.2310561121","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T14:06:40Z","timestamp":1707919600000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery"],"prefix":"10.1073","volume":"121","author":[{"given":"Brandon","family":"Bizup","sequence":"first","affiliation":[{"name":"Pittsburgh Hearing Research Center, Department of Otolaryngology, University of Pittsburgh","place":["Pittsburgh"]},{"name":"Department of Neurobiology, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"Brutsaert","sequence":"additional","affiliation":[{"name":"Pittsburgh Hearing Research Center, Department of Otolaryngology, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9619-4190","authenticated-orcid":false,"given":"Christopher L.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Pittsburgh Hearing Research Center, Department of Otolaryngology, University of Pittsburgh","place":["Pittsburgh"]},{"name":"Department of Neurobiology, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3132-4409","authenticated-orcid":false,"given":"Amantha","family":"Thathiah","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanos","family":"Tzounopoulos","sequence":"additional","affiliation":[{"name":"Pittsburgh Hearing Research Center, Department of Otolaryngology, University of Pittsburgh","place":["Pittsburgh"]},{"name":"Department of Neurobiology, University of Pittsburgh","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,14]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2016.11.013"},{"key":"e_1_3_5_2_2","unstructured":"National Institute on Deafness and Other Communication Disorders Quick Statistics (2021). https:\/\/www.nidcd.nih.gov\/health\/statistics\/quick-statistics-hearing. 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