{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:37:07Z","timestamp":1790271427176,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1A2B2005022 and 2019M3E5D1A02068573"],"award-info":[{"award-number":["2018R1A2B2005022 and 2019M3E5D1A02068573"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007631","name":"Chungnam National University Hospital","doi-asserted-by":"publisher","award":["2017-CF-030"],"award-info":[{"award-number":["2017-CF-030"]}],"id":[{"id":"10.13039\/501100007631","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related hearing loss (ARHL) is an irreversible, progressive neurodegenerative disorder and is presently untreatable. Previous studies using animal models have suggested mitochondrial damage and programmed cell death to be involved with ARHL. Thus, we further investigated the pathophysiologic role of mitochondria and necroptosis in aged C57BL\/6J male mice. Aged mice (20 months old) exhibited a significant loss of hearing, number of hair cells, neuronal fibers, and synaptic ribbons compared to young mice. Ultrastructural analysis of aged cochleae revealed damaged mitochondria with absent or disorganized cristae. Aged mice also showed significant decrease in cochlear blood flow, and exhibited increase in gene expression of proinflammatory cytokines (IL-1\u03b2, IL-6, and TNF-\u03b1), receptor-interacting serine\/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL). Immunofluorescence (IF) assays of cytochrome C oxidase I (COX1) confirmed mitochondrial dysfunction in aged cochleae, which correlated with the degree of mitochondrial morphological damage. IF assays also revealed localization and increased expression of RIPK3 in sensorineural tissues that underwent significant necroptosis (inner and outer hair cells and stria vascularis). Together, our data shows that the aging cochlea exhibits damaged mitochondria, enhanced synthesis of proinflammatory cytokines, and provides new evidence of necroptosis in the aging cochlea in in vivo.<\/jats:p>","DOI":"10.3390\/ijms21072505","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T06:10:28Z","timestamp":1586153428000},"page":"2505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Mitochondrial Damage and Necroptosis in Aging Cochlea"],"prefix":"10.3390","volume":"21","author":[{"given":"Ah-Ra","family":"Lyu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Convergence Research Center, Chungnam National University Hospital, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Jae","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Ae","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Hun","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-304X","authenticated-orcid":false,"given":"Yang Hoon","family":"Huh","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Center, Korea Basic Science Institute, Cheongju 28119, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Reum","family":"Je","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Center, Korea Basic Science Institute, Cheongju 28119, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-9585","authenticated-orcid":false,"given":"Min Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-3791","authenticated-orcid":false,"given":"Yong-Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea"},{"name":"Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a033217","DOI":"10.1101\/cshperspect.a033217","article-title":"Age-related hearing loss","volume":"9","author":"Bowl","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.heares.2013.01.021","article-title":"Current concepts in age-related hearing loss: Epidemiology and mechanistic pathways","volume":"303","author":"Yamasoba","year":"2013","journal-title":"Hear. Res."},{"key":"ref_3","first-page":"77","article-title":"Epidemiology of age related hearing loss: A review","volume":"13","author":"Quaranta","year":"2015","journal-title":"Hear. Res."},{"key":"ref_4","unstructured":"World Health Organization (WHO) (2018). Addressing the Rising Prevalence of Hearing Loss, WHO."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"582849","DOI":"10.1155\/2014\/582849","article-title":"Oxidative stresses and mitochondrial dysfunction in age-related hearing loss","volume":"2014","author":"Fujimoto","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3109\/00206098009070071","article-title":"Genotypic differences in behavioral, physiological and anatomical expressions of age-related hearing loss in the laboratory mouse","volume":"19","author":"Henry","year":"1980","journal-title":"Audiol. Off. Organ Int. Soc. Audiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s101620010075","article-title":"Spiral ligament pathology: A major aspect of age-related cochlear degeneration in C57BL\/6 mice","volume":"2","author":"Hequembourg","year":"2001","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1288\/00005537-197901000-00001","article-title":"Development and degeneration of hearing in the C57\/b16 mouse: Relation of electrophysiologic responses from the round window and cochlear nucleus to cochlear anatomy and behavioral responses","volume":"89","author":"Mikaelian","year":"1979","journal-title":"Laryngoscope"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.joto.2016.03.003","article-title":"Anti-apoptotic treatment in mouse models of age-related hearing loss","volume":"11","author":"Han","year":"2016","journal-title":"J. Otol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"19432","DOI":"10.1073\/pnas.0908786106","article-title":"Age-related hearing loss in C57BL\/6J mice is mediated by Bak-dependent mitochondrial apoptosis","volume":"106","author":"Someya","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.cell.2010.10.002","article-title":"Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction","volume":"143","author":"Someya","year":"2010","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fujimoto, C., and Yamasoba, T. (2019). Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review. Antioxidants (Basel), 8.","DOI":"10.3390\/antiox8040109"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1111\/febs.13324","article-title":"Age-related changes in mitochondrial antioxidant enzyme Trx2 and TXNIP-Trx2-ASK1 signal pathways in the auditory cortex of a mimetic aging rat model: Changes to Trx2 in the auditory cortex","volume":"282","author":"Sun","year":"2015","journal-title":"FEBS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"730","DOI":"10.18632\/aging.100927","article-title":"N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in gamma-glutamyl transferase 1 deficient mice","volume":"8","author":"Ding","year":"2016","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1038\/s41598-018-23436-w","article-title":"Loss of IDH2 Accelerates Age-related Hearing Loss in Male Mice","volume":"8","author":"White","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.mad.2010.04.006","article-title":"Mitochondrial oxidative damage and apoptosis in age-related hearing loss","volume":"131","author":"Someya","year":"2010","journal-title":"Mech. Ageing Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2905","DOI":"10.1038\/cddis.2017.286","article-title":"Necroptosis in neurodegenerative diseases: A potential therapeutic target","volume":"8","author":"Zhang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.heares.2016.11.013","article-title":"Cellular mechanisms of noise-induced hearing loss","volume":"349","author":"Kurabi","year":"2017","journal-title":"Hear. Res."},{"key":"ref_19","first-page":"e0195230","article-title":"Effects of dexamethasone on intracochlear inflammation and residual hearing after cochleostomy: A comparison of administration routes","volume":"13","author":"Lyu","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12646","DOI":"10.1038\/s41598-019-49133-w","article-title":"Cochlear Glucocorticoid Receptor and Serum Corticosterone Expression in a Rodent Model of Noise-induced Hearing Loss: Comparison of Timing of Dexamethasone Administration","volume":"9","author":"Lee","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Shin, S.A., Lyu, A.-R., Jeong, S.-H., Kim, T.H., Park, M.J., and Park, Y.-H. (2019). Acoustic Trauma Modulates Cochlear Blood Flow and Vasoactive Factors in a Rodent Model of Noise-Induced Hearing Loss. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215316"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7601232","DOI":"10.1155\/2018\/7601232","article-title":"Susceptibility of Diabetic Mice to Noise Trauma","volume":"2018","author":"Han","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C T method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zeng, L., Yang, Y., Hu, Y., Sun, Y., Du, Z., Xie, Z., Zhou, T., and Kong, W. (2014). Age-related decrease in the mitochondrial sirtuin deacetylase Sirt3 expression associated with ROS accumulation in the auditory cortex of the mimetic aging rat model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088019"},{"key":"ref_25","first-page":"93","article-title":"Mitochondrial diabetes and deafness: Possible dysfunction of strial marginal cells of the inner ear","volume":"40","author":"Olmos","year":"2011","journal-title":"J. Otolaryngol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.mito.2004.07.040","article-title":"Mitochondrial dysfunction in hearing loss","volume":"4","author":"Kopke","year":"2004","journal-title":"Mitochondrion"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.mcn.2012.07.004","article-title":"Mouse models of age-related mitochondrial neurosensory hearing loss","volume":"55","author":"Han","year":"2013","journal-title":"Mol. Cell Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/iub.86","article-title":"Cytochrome c oxidase biogenesis: New levels of regulation","volume":"60","author":"Fontanesi","year":"2008","journal-title":"IUBMB Life"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Park, M.J., Aja, S., Li, Q., Degano, A.L., Penati, J., Zhuo, J., Roe, C.R., and Ronnett, G.V. (2014). Anaplerotic triheptanoin diet enhances mitochondrial substrate use to remodel the metabolome and improve lifespan, motor function, and sociability in MeCP2-null mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109527"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1007\/s11064-017-2249-1","article-title":"The Contribution of Necroptosis in Neurodegenerative Diseases","volume":"42","author":"Shao","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/s41419-018-0872-7","article-title":"Mechanism and disease implications of necroptosis and neuronal inflammation","volume":"9","author":"Oliveira","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1101\/gad.312561.118","article-title":"Necroptosis in development and diseases","volume":"32","author":"Shan","year":"2018","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.heares.2011.11.007","article-title":"Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice","volume":"283","author":"Kane","year":"2012","journal-title":"Hear. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0378-5955(99)00003-9","article-title":"Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses","volume":"130","author":"Zheng","year":"1999","journal-title":"Hear. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.brainres.2009.02.012","article-title":"Inheritance patterns of progressive hearing loss in laboratory strains of mice","volume":"1277","author":"Johnson","year":"2009","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3109\/00016489109138418","article-title":"Age-related loss of auditory sensitivity in two mouse genotypes","volume":"111","author":"Li","year":"1991","journal-title":"Acta Otolaryngol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0378-5955(97)00155-X","article-title":"A major gene affecting age-related hearing loss in C57BL\/6J mice","volume":"114","author":"Johnson","year":"1997","journal-title":"Hear. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1016\/j.neurobiolaging.2009.09.009","article-title":"F1 (CBA\u00d7 C57) mice show superior hearing in old age relative to their parental strains: Hybrid vigor or a new animal model for \u201cGolden Ears\u201d?","volume":"32","author":"Frisina","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.molmed.2017.02.005","article-title":"Mitochondrial Sirtuins and Molecular Mechanisms of Aging","volume":"23","author":"Santos","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.18632\/aging.100800","article-title":"Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmah-null mice affect hearing loss","volume":"7","author":"Kwon","year":"2015","journal-title":"Aging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.exger.2015.07.003","article-title":"Impaired unfolded protein response in the degeneration of cochlea cells in a mouse model of age-related hearing loss","volume":"70","author":"Wang","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Suzukawa, K., Tomlin, J., Pak, K., Chavez, E., Kurabi, A., Baird, A., Wasserman, S.I., and Ryan, A.F. (2014). A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102739"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1073\/pnas.1222285110","article-title":"Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise","volume":"110","author":"Yan","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"325702","DOI":"10.1155\/2013\/325702","article-title":"Age-related hearing loss in Mn-SOD heterozygous knockout mice","volume":"2013","author":"Kinoshita","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1016\/j.neurobiolaging.2012.02.007","article-title":"Efferent synapses return to inner hair cells in the aging cochlea","volume":"33","author":"Lauer","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S0891-5849(02)01439-9","article-title":"Effect of SOD1 overexpression on age- and noise-related hearing loss","volume":"34","author":"Coling","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0378-5955(99)00070-2","article-title":"Effects of a hair cell transcription factor, Brn-3.1, gene deletion on homozygous and heterozygous mouse cochleas in adulthood and aging","volume":"134","author":"Keithley","year":"1999","journal-title":"Hear. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/0197-4580(89)90039-0","article-title":"Ultrastructural features of neurons in the C57BL\/6J mouse anteroventral cochlear nucleus: Young mice versus old mice with chronic presbycusis","volume":"10","author":"Briner","year":"1989","journal-title":"Neurobiol. Aging"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Choi, M.J., Kang, H., Lee, Y.Y., Choo, O., Jang, J.H., Park, S., Moon, J., Choi, S.J., and Choung, Y. (2019). Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis. Cells, 8.","DOI":"10.3390\/cells8050409"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1159\/000489241","article-title":"Current Mechanistic Concepts in Ischemia and Reperfusion Injury","volume":"46","author":"Wu","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1523\/JNEUROSCI.1384-18.2019","article-title":"Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity","volume":"39","author":"Ruhl","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e1262","DOI":"10.1038\/cddis.2014.177","article-title":"Receptor-interacting protein kinases modulate noise-induced sensory hair cell death","volume":"5","author":"Zheng","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.neulet.2014.06.042","article-title":"The role of RIP3 mediated necroptosis in ouabain-induced spiral ganglion neurons injuries","volume":"578","author":"Wang","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.ijporl.2012.05.016","article-title":"Protective effect of NecroX, a novel necroptosis inhibitor, on gentamicin-induced ototoxicity","volume":"76","author":"Park","year":"2012","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3389\/fimmu.2018.00223","article-title":"Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super-Resolution Immunohistochemistry","volume":"9","author":"Liu","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/MAO.0000000000000879","article-title":"Anti CD163+, Iba1+, and CD68+ Cells in the Adult Human Inner Ear: Normal Distribution of an Unappreciated Class of Macrophages\/Microglia and Implications for Inflammatory Otopathology in Humans","volume":"37","author":"Nadol","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.immuni.2019.03.012","article-title":"Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity","volume":"50","author":"Mantovani","year":"2019","journal-title":"Immunity"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3389\/fphys.2014.00323","article-title":"Necroptosis: Is there a role for mitochondria?","volume":"5","author":"Marshall","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"16247","DOI":"10.1074\/jbc.M112.435545","article-title":"Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling","volume":"288","author":"Chen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"24742","DOI":"10.3390\/ijms141224742","article-title":"Necrostatin-1 attenuates ischemia injury induced cell death in rat tubular cell line NRK-52E through decreased Drp1 expression","volume":"14","author":"Zhang","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.celrep.2013.10.034","article-title":"Widespread mitochondrial depletion via mitophagy does not compromise necroptosis","volume":"5","author":"Tait","year":"2013","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:15:21Z","timestamp":1760174121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,3]]},"references-count":61,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072505"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072505","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,3]]}}}