{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:12:46Z","timestamp":1782886366615,"version":"3.54.5"},"reference-count":66,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>The hair bundle of cochlear hair cells comprises specialized microvilli, the stereocilia, which fulfil the role of mechanotransduction. Genetic defects and environmental noise challenge the maintenance of hair bundle structure, critically contributing to age\u2010related hearing loss. Stereocilia fusion is a major component of the hair bundle pathology in mature hair cells, but its role in hearing loss and its molecular basis are poorly understood. Here, we utilized super\u2010resolution expansion microscopy to examine the molecular anatomy of outer hair cell stereocilia fusion in mouse models of age\u2010related hearing loss, heightened endoplasmic reticulum stress and prolonged noise exposure. Prominent stereocilia fusion in our model of heightened endoplasmic reticulum stress, <jats:italic>Manf (Mesencephalic astrocyte\u2010derived neurotrophic factor)\u2010<\/jats:italic>inactivated mice in a background with <jats:italic>Cadherin 23\u00a0<\/jats:italic>missense mutation, impaired mechanotransduction and calcium balance in stereocilia. This was indicated by reduced FM1\u201043 dye uptake through the mechanotransduction channels, reduced neuroplastin\/PMCA2 expression and increased expression of the calcium buffer oncomodulin inside stereocilia. Sparse BAIAP2L2 and myosin 7a expression was retained in the fused stereocilia but mislocalized away from their functional sites at the tips. These hair bundle abnormalities preceded cell soma degeneration, suggesting a sequela from stereociliary molecular perturbations to cell death signalling. In the age\u2010related hearing loss and noise\u2010exposure models, stereocilia fusion was more restricted within the bundles, yet both models exhibited oncomodulin upregulation at the fusion sites, implying perturbed calcium homeostasis. We conclude that stereocilia fusion is linked with the failure to maintain cellular proteostasis and with disturbances in stereociliary calcium balance.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16178-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Stereocilia fusion is a hair cell pathology causing hearing loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Inactivation of <jats:italic>Manf<\/jats:italic>, a component of the endoplasmic reticulum proteostasis machinery, has a cell\u2010intrinsic mode of action in triggering outer hair cell stereocilia fusion and the death of these cells.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The genetic background with <jats:italic>Cadherin 23\u00a0<\/jats:italic>missense mutation contributes to the high susceptibility of outer hair cells to stereocilia fusion, evidenced in <jats:italic>Manf<\/jats:italic>\u2010inactivated mice and in the mouse models of early\u2010onset hearing loss and noise exposure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Endoplasmic reticulum stress feeds to outer hair cell stereocilia bundle pathology and impairs the molecular anatomy of calcium regulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The maintenance of the outer hair cell stereocilia bundle cohesion is challenged by intrinsic and extrinsic stressors, and understanding the underlying mechanisms will probably benefit the development of interventions to promote hearing health.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286318","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T17:02:00Z","timestamp":1721667720000},"page":"3995-4025","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Stereocilia fusion pathology in the cochlear outer hair cells at the nanoscale level"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9630-2366","authenticated-orcid":false,"given":"Kuu","family":"Ik\u00e4heimo","sequence":"first","affiliation":[{"name":"Molecular and Integrative Biosciences Research Programme University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4473-2180","authenticated-orcid":false,"given":"Saija","family":"Leinonen","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Biosciences Research Programme University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7596-6680","authenticated-orcid":false,"given":"Tuuli","family":"Lankinen","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Biosciences Research Programme University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5674-8830","authenticated-orcid":false,"given":"Maria","family":"Lindahl","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HILIFE Unit University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart","family":"Saarma","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HILIFE Unit University of Helsinki  Helsinki 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