{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:25:19Z","timestamp":1787117119470,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca\n                      <jats:sup>2\u207a<\/jats:sup>\n                      uptake, but its involvement in cisplatin-induced ototoxicity remains poorly understood. We investigated MCU expression and its association with cisplatin-induced injury in mouse cochlear basilar membranes and HEI-OC1 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>MCU protein abundance and localization were assessed by Western blotting and immunofluorescence. MCU expression was genetically reduced by lentiviral knockdown, and Ru360 was used as a pharmacological intervention. Apoptosis-related proteins and transcriptomic changes were evaluated. An acute cisplatin-induced ototoxicity model was established in C57BL\/6 mice and assessed using auditory brainstem response (ABR) measurements and outer hair cell counts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Cisplatin increased MCU expression and reduced SERCA2 expression; the cisplatin-induced increase in MCU was partially reversed by BAPTA-AM and the endoplasmic reticulum stress inhibitor 4-PBA. MCU knockdown did not affect basal cell viability but attenuated cisplatin-induced reductions in viability, TUNEL positivity, and cleaved caspase-3. It was also associated with increased SERCA2 and decreased IP3R, GRP75, and VDAC1 expression. RNA sequencing identified differentially expressed genes enriched in autophagy-related processes and mTOR signaling. MCU knockdown was associated with increased PI3K\/AKT\/mTOR signaling and changes in Beclin1, LC3B-II, and p62. Ru360 cotreatment partially reproduced the protective phenotype\n                      <jats:italic>in vitro<\/jats:italic>\n                      and was associated with attenuated ABR threshold elevation at selected frequencies and reduced outer hair cell loss\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings support an association between MCU-related signaling, PI3K\/AKT\/mTOR pathway activation, altered autophagy-related markers, and reduced cisplatin-induced cochlear injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1913816","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:39:27Z","timestamp":1787114367000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MCU knockdown attenuates cisplatin-induced damage of auditory cells: potential involvement of PI3K\/AKT\/mTOR signaling and autophagy-related processes"],"prefix":"10.3389","volume":"17","author":[{"given":"Yue","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]},{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong Second Provincial General Hospital","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, People\u2019s Hospital, Peking University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]},{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]},{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongjun","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]},{"name":"Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.jacbts.2024.01.007","article-title":"Mitochondrial Ca2+ uniporter-dependent energetic dysfunction drives hypertrophy in heart failure","volume":"9","author":"Alves-Figueiredo","year":"2024","journal-title":"JACC Basic Transl. 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