{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:49:51Z","timestamp":1792622991265,"version":"4.5.0"},"reference-count":86,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institutes of Health (NIH)\/National Institute on Aging (NIA)","doi-asserted-by":"publisher","award":["R21DC014357"],"award-info":[{"award-number":["R21DC014357"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1\/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1\/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic\u2013pituitary\u2013adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.<\/jats:p>","DOI":"10.3390\/antiox12061225","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T01:38:41Z","timestamp":1686101921000},"page":"1225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1\/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5418-8991","authenticated-orcid":false,"given":"Winston J. T.","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand"},{"name":"Department of Surgery (Otolaryngology), Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Santos-Sacchi","sequence":"additional","affiliation":[{"name":"Department of Surgery (Otolaryngology), Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Tonello","sequence":"additional","affiliation":[{"name":"School of Medicine, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-3669","authenticated-orcid":false,"given":"Anil","family":"Shanker","sequence":"additional","affiliation":[{"name":"School of Medicine, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla V.","family":"Ivanova","sequence":"additional","affiliation":[{"name":"School of Graduate Studies and Research, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/S0140-6736(21)00516-X","article-title":"Hearing loss prevalence and years lived with disability, 1990\u20132019: Findings from the Global Burden of Disease Study 2019","volume":"397","author":"Haile","year":"2021","journal-title":"Lancet"},{"key":"ref_2","unstructured":"WHO (2021). 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