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Approaches to Mitigate Mitochondrial Dysfunction in Sensorineural Hearing Loss

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Abstract

Mitochondria are highly dynamic multifaceted organelles with various functions including cellular energy metabolism, reactive oxygen species (ROS) generation, calcium homeostasis, and apoptosis. Because of these diverse functions, mitochondria are key regulators of cell survival and death, and their dysfunction is implicated in numerous diseases, particularly neurodegenerative disorders such as Alzheimer’s Disease, Parkinson's Disease, and Huntington’s Disease. One of the most common neurodegenerative disorders is sensorineural hearing loss (SNHL). SNHL primarily originates from the degenerative changes in the cochlea, which is the auditory portion of the inner ear. Many cochlear cells contain an abundance of mitochondria and are metabolically highly active, rendering them susceptible to mitochondrial dysfunction. Indeed, the causal role of mitochondrial dysfunction in SNHL progression is well established, and therefore, targeted for treatment. In this review, we aim to compile the emerging findings in the literature indicating the role of mitochondrial dysfunction in the progression of sensorineural hearing loss and highlight potential therapeutics targeting mitochondrial dysfunction for hearing loss treatment.

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References

  1. Afifi, P. O., and H. H. Elsanadiky. Audiological findings in children with ataxia-telangiectasia (A-T) syndrome. Int. J. Pediatr. Otorhinolaryngol. 92:94–98, 2017

    Article  Google Scholar 

  2. Amati-Bonneau, P., et al. OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann. Neurol. 58:958–963, 2005

    Article  CAS  Google Scholar 

  3. Bhatta, P., et al. Capsaicin protects against cisplatin ototoxicity by changing the STAT3/STAT1 ratio and activating cannabinoid (CB2) receptors in the cochlea. Sci. Rep. 2019. https://doi.org/10.1038/s41598-019-40425-9

    Article  Google Scholar 

  4. Bielefeld, E. C., et al. Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration. Acta Otolaryngol. 127:914–919, 2007

    Article  CAS  Google Scholar 

  5. Brown, K. D., et al. Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss. Cell Metab. 20:1059–1068, 2014

    Article  CAS  Google Scholar 

  6. Cabelof, D. C., et al. Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. Mutat. Res. 500:135–145, 2002

    Article  CAS  Google Scholar 

  7. Campbell, K. C., et al. Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India. Int. J. Audiol. 2021. https://doi.org/10.1080/14992027.2021.1983215

    Article  Google Scholar 

  8. Chen, H., A. Chomyn, and D. C. Chan. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J. Biol. Chem. 280:26185–26192, 2005

    Article  CAS  Google Scholar 

  9. Chen, B., et al. Increased mitochondrial DNA damage and decreased base excision repair in the auditory cortex of D-galactose-induced aging rats. Mol. Biol. Rep. 38:3635–3642, 2011

    Article  CAS  Google Scholar 

  10. Cho, S. I., E.-R. Jo, and H. Song. Urolithin A attenuates auditory cell senescence by activating mitophagy. Sci. Rep. 12:7704, 2022

    Article  CAS  Google Scholar 

  11. Chocron, E. S., E. Munkácsy, and A. M. Pickering. Cause or casualty: the role of mitochondrial DNA in aging and age-associated disease. Biochim. Biophys. Acta Mol. Basis Dis. 1865:285, 2019

    Article  CAS  Google Scholar 

  12. Das, R., and O. Chakrabarti. Mitochondrial hyperfusion: a friend or a foe. Biochem. Soc. Trans. 48:631–644, 2020

    Article  CAS  Google Scholar 

  13. De La Luz, M., and A. Sordo. Mitochondrial dysfunction and hearing loss. In: Handbook of Mitochondrial Dysfunction, edited by S. I. Ahmad. Boca Raton: CRC Press, 2019, pp. 163–170

    Google Scholar 

  14. Ding, E., et al. Analysis of polymorphisms associated with base excision repair in patients susceptible and resistant to noise-induced hearing loss. Dis. Mark. 2019. https://doi.org/10.1155/2019/9327106

    Article  Google Scholar 

  15. Dong, T., et al. Opa1 prevents apoptosis and cisplatin-induced ototoxicity in murine cochleae. Front. Cell Dev. Biol. 2021. https://doi.org/10.3389/fcell.2021.744838

    Article  Google Scholar 

  16. Doosti, A., et al. Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers. Noise Health. 16:223–227, 2014

    Article  Google Scholar 

  17. Fang, E. F., et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 157:882–896, 2014

    Article  CAS  Google Scholar 

  18. Fang, E. F., et al. NAD + replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24:566–581, 2016

    Article  CAS  Google Scholar 

  19. Fang, E. F., et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17:308, 2016

    Article  CAS  Google Scholar 

  20. Fernandez-Marcos, P. J., and J. Auwerx. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93:884S, 2011

    Article  CAS  Google Scholar 

  21. Fetoni, A. R., et al. Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs. Acta Otorhinolaryngol. Ital. 29:70, 2009

    CAS  Google Scholar 

  22. Fetoni, A. R., R. Piacentini, A. Fiorita, G. Paludetti, and D. Troiani. Water-soluble Coenzyme Q10 formulation (Q-ter) promotes outer hair cell survival in a guinea pig model of noise induced hearing loss (NIHL). Brain Res. 1257:108–116, 2009

    Article  CAS  Google Scholar 

  23. Finck, B. N., and D. P. Kelly. Peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation. 115:2540–2548, 2007

    Article  Google Scholar 

  24. Fujimoto, C., and T. Yamasoba. Oxidative stresses and mitochondrial dysfunction in age-related hearing loss. Oxid. Med. Cell. Longev. 2014:1–6, 2014

    Article  CAS  Google Scholar 

  25. Geisler, J. G. 2,4 Dinitrophenol as medicine. Cells. 8:280, 2019

    Article  CAS  Google Scholar 

  26. Han, B., et al. Correlation between mitochondrial DNA 4977bp deletion and presbycusis: a system review and meta-analysis. Medicine (United States). 98:e16302, 2019

    CAS  Google Scholar 

  27. Hancock, J. T., R. Desikan, and S. J. Neill. Role of reactive oxygen species in cell signalling pathways. Biochem. Soc. Trans. 29:345–350, 2001

    Article  CAS  Google Scholar 

  28. He, Z., et al. Autophagy protects auditory hair cells against neomycin-induced damage. Autophagy. 13:1884–1904, 2017

    Article  CAS  Google Scholar 

  29. Huang, T., R. Santarelli, and A. Starr. Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals. Brain Res. 1300:97–104, 2009

    Article  CAS  Google Scholar 

  30. Intano, G. W., E. J. Cho, C. A. McMahan, and C. A. Walter. Age-related base excision repair activity in mouse brain and liver nuclear extracts. J. Gerontol. A. Biol. Sci. Med. Sci. 58:205–211, 2003

    Article  Google Scholar 

  31. Kalinec, G. M., et al. Extracellular vesicles from auditory cells as nanocarriers for anti-inflammatory drugs and pro-resolving mediators. Front. Cell. Neurosci. 13:530, 2019

    Article  CAS  Google Scholar 

  32. Kamogashira, T., C. Fujimoto, and T. Yamasoba. Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss. Biomed. Res. Int. 2015:1–7, 2015

    Article  Google Scholar 

  33. Kamogashira, T., K. Hayashi, C. Fujimoto, S. Iwasaki, and T. Yamasoba. Functionally and morphologically damaged mitochondria observed in auditory cells under senescence-inducing stress. npj Aging Mech Dis. 2017. https://doi.org/10.1038/s41514-017-0002-2

    Article  Google Scholar 

  34. Kauppila, J. H. K., et al. Base-excision repair deficiency alone or combined with increased oxidative stress does not increase mtDNA point mutations in mice. Nucleic Acids Res. 46:6642, 2018

    Article  CAS  Google Scholar 

  35. Kil, J., C. Pierce, H. Tran, R. Gu, and E. D. Lynch. Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase. Hear. Res. 226:44–51, 2007

    Article  CAS  Google Scholar 

  36. Kim, S. J., C. Park, J. N. Lee, and R. Park. Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction. Toxicol. Appl. Pharmacol. 353:43–54, 2018

    Article  CAS  Google Scholar 

  37. Kim, J. H., et al. Protective effect of berberine chloride against cisplatin-induced ototoxicity. Genes Genomics. 44:1–7, 2022

    Article  Google Scholar 

  38. Koide, Y., et al. Association between uncoupling protein 2 gene Ala55val polymorphism and sudden sensorineural hearing loss. J. Int. Adv. Otol. 14:166–169, 2018

    Article  Google Scholar 

  39. Kopke, R., et al. Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial. Hear. Res. 323:40–50, 2015

    Article  CAS  Google Scholar 

  40. Kraus, F., and M. T. Ryan. The constriction and scission machineries involved in mitochondrial fission. J. Cell Sci. 130:2953–2960, 2017

    CAS  Google Scholar 

  41. Krokan, H. E., and M. Bjørås. Base excision repair. Cold Spring Harb. Perspect. Biol. 5:1–22, 2013

    Article  Google Scholar 

  42. Lazarou, M., et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 524:309–314, 2015

    Article  CAS  Google Scholar 

  43. Lee, Y., H. Y. Lee, R. A. Hanna, and A. B. Gustafsson. Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 301:H1924, 2011

    Article  CAS  Google Scholar 

  44. Lee, Y. K., H. G. Youn, H. J. Wang, and G. Yoon. Decreased mitochondrial OGG1 expression is linked to mitochondrial defects and delayed hepatoma cell growth. Mol. Cells. 35:489–497, 2013

    Article  CAS  Google Scholar 

  45. Lin, H., et al. Inhibition of DRP-1-dependent mitophagy promotes cochlea hair cell senescence and exacerbates age-related hearing loss. Front. Cell. Neurosci. 13:550, 2019

    Article  CAS  Google Scholar 

  46. Lisan, Q., et al. Prevalence of hearing loss and hearing aid use among adults in France in the CONSTANCES Study. JAMA Netw. Open. 5:e2217633–e2217633, 2022

    Article  Google Scholar 

  47. Liu, Y.-H., et al. Involvement of the SIRT1/PGC-1α signaling pathway in noise-induced hidden hearing loss. Front. Physiol. 13:798395, 2022

    Article  Google Scholar 

  48. Manche, S. K., M. Jangala, P. Putta, R. M. Koralla, and J. Akka. Association of oxidative stress gene polymorphisms with presbycusis. Gene. 593:277–283, 2016

    Article  CAS  Google Scholar 

  49. Matsuda, N., et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189:211–221, 2010

    Article  CAS  Google Scholar 

  50. Mokhtari, V., P. Afsharian, M. Shahhoseini, S. M. Kalantar, and A. Moini. A Review on various uses of N-acetyl cysteine. Cell J. 19:11–17, 2017

    Google Scholar 

  51. Moussa, Z., Z. M. A. Judeh, and S. A. Ahmed. Nonenzymatic exogenous and endogenous antioxidants. Free Radic. Med. Biol. 2019. https://doi.org/10.5772/INTECHOPEN.87778

    Article  Google Scholar 

  52. Muderris, T., et al. Efficiency of resveratrol in the prevention and treatment of age-related hearing loss. Exp. Ther. Med. 2022. https://doi.org/10.3892/etm.2021.10962

    Article  Google Scholar 

  53. Nascimento-dos-Santos, G., et al. Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina. Biochim. Biophys. Acta Mol. Basis Dis. 1866:165686, 2020

    Article  CAS  Google Scholar 

  54. Oh, J., C. K. Youn, Y. Jun, E. R. Jo, and S. I. Cho. Reduced mitophagy in the cochlea of aged C57BL/6J mice. Exp. Gerontol. 137:110946, 2020

    Article  CAS  Google Scholar 

  55. Okur, M. N., et al. Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling. Aging Cell. 2020. https://doi.org/10.1111/acel.13268

    Article  Google Scholar 

  56. Okur, M. N., et al. Short-term NAD + supplementation prevents hearing loss in mouse models of Cockayne syndrome. npj Aging Mech Dis. 2020. https://doi.org/10.1038/s41514-019-0040-z

    Article  Google Scholar 

  57. Okur, M. N., et al. TITLE: Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice. bioRxiv. 2022. https://doi.org/10.1101/2022.08.25.505332

    Article  Google Scholar 

  58. Paciello, F., et al. Pioglitazone represents an effective therapeutic target in preventing oxidative/inflammatory cochlear damage induced by noise exposure. Front. Pharmacol. 2018. https://doi.org/10.3389/fphar.2018.01103

    Article  Google Scholar 

  59. Perkins, G., et al. Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing loss in mice. J. Neurosci. 40:8556–8572, 2020

    Article  CAS  Google Scholar 

  60. Pierelli, G., et al. Uncoupling protein 2: a key player and a potential therapeutic target in vascular diseases. Oxid. Med. Cell. Longev. 2017:1–11, 2017

    Article  Google Scholar 

  61. Popov, L. D. Mitochondrial biogenesis: An update. J. Cell. Mol. Med. 24:4892, 2020

    Article  CAS  Google Scholar 

  62. Prakash, A., and S. Doublié. Base excision repair in the mitochondria. J. Cell. Biochem. 116:1490–1499, 2015

    Article  CAS  Google Scholar 

  63. Puschner, B., and J. Schacht. Energy metabolism in cochlear outer hair cells in vitro. Hear. Res. 114:102–106, 1997

    Article  CAS  Google Scholar 

  64. Salehi, P., et al. In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss. bioRxiv. 2022. https://doi.org/10.1101/2022.01.26.477836

    Article  Google Scholar 

  65. Scheibye-Knudsen, M., et al. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J. Exp. Med. 209:855–869, 2012

    Article  CAS  Google Scholar 

  66. Schreiber, S. N., et al. The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. Proc. Natl. Acad. Sci. USA. 101:6472–6477, 2004

    Article  CAS  Google Scholar 

  67. Seidman, M., S. Babu, W. Tang, E. Naem, and W. S. Quirk. Effects of resveratrol on acoustic trauma. Otolaryngol. Head. Neck Surg. 129:463–470, 2003

    Article  Google Scholar 

  68. Setz, C., et al. Induction of mitophagy in the HEI-OC1 auditory cell line and activation of the Atg12/LC3 pathway in the organ of Corti. Hear. Res. 361:52–65, 2018

    Article  CAS  Google Scholar 

  69. Sharma, G., et al. Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss. bioRxiv. 2021. https://doi.org/10.1101/2021.01.11.426268

    Article  Google Scholar 

  70. Shinomiya, H., et al. Hearing dysfunction in Xpa-deficient mice. Front. Aging Neurosci. 9:19, 2017

    Article  Google Scholar 

  71. Tao, H., Y. Zhang, X. Zeng, G. I. Shulman, and S. Jin. Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat. Med. 20:1263–1269, 2014

    Article  CAS  Google Scholar 

  72. Tropitzsch, A., et al. Poly (ADP-Ribose) Polymerase-1 (PARP1) deficiency and pharmacological inhibition by pirenzepine protects from cisplatin-induced ototoxicity without affecting antitumor efficacy. Front. Cell. Neurosci. 2019. https://doi.org/10.3389/fncel.2019.00406

    Article  Google Scholar 

  73. Ventura-Clapier, R., A. Garnier, and V. Veksler. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α. Cardiovasc. Res. 79:208–217, 2008

    Article  CAS  Google Scholar 

  74. Virbasius, J. V., and R. C. Scarpulla. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: A potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl. Acad. Sci. USA. 91:1309–1313, 1994

    Article  CAS  Google Scholar 

  75. Vyssokikh, M. Y., et al. Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program. Proc. Natl. Acad. Sci. USA. 117:6491–6501, 2020

    Article  CAS  Google Scholar 

  76. Wang, Y., et al. Effects of D-methionine in mice with noise-induced hearing loss mice. J. Int. Med. Res. 47:3874, 2019

    Article  CAS  Google Scholar 

  77. Weijian, Z., et al. PGC-1α overexpression promotes mitochondrial biogenesis to protect auditory cells against cisplatin-induced cytotoxicity. J. Bio-X Res. 2:81–86, 2019

    Google Scholar 

  78. Wilson, B. T., et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet. Med. 18:483–493, 2015

    Article  Google Scholar 

  79. Winterbourn, C. C., and M. B. Hampton. Thiol chemistry and specificity in redox signaling. Free Radic. Biol. Med. 45:549–561, 2008

    Article  CAS  Google Scholar 

  80. Xiong, H., et al. SIRT1 expression in the cochlea and auditory cortex of a mouse model of age-related hearing loss. Exp. Gerontol. 51:8–14, 2014

    Article  CAS  Google Scholar 

  81. Yamaguchi, T., M. Yoneyama, Y. Onaka, A. Imaizumi, and K. Ogita. Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: a comparative and mechanistic study. J. Pharmacol. Sci. 134:225–233, 2017

    Article  CAS  Google Scholar 

  82. Yang, Q., et al. PINK1 protects against gentamicin-induced sensory hair cell damage: possible relation to induction of autophagy and inhibition of p53 signal pathway. Front. Mol. Neurosci. 2018. https://doi.org/10.3389/fnmol.2018.00403

    Article  Google Scholar 

  83. Youn, C. K., Y. Jun, E. R. Jo, and S. I. Cho. Age-related hearing loss in C57BL/6J Mice is associated with mitophagy impairment in the central auditory system. Int. J. Mol. Sci. 21:1–14, 2020

    Article  Google Scholar 

  84. Yumusakhuylu, A. C., et al. Protective role of resveratrol against cisplatin induced ototoxicity in guinea pigs. Int. J. Pediatr. Otorhinolaryngol. 76:404–408, 2012

    Article  Google Scholar 

  85. Zhang, L. N., et al. Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice. Diabetes. 62:1297–1307, 2013

    Article  CAS  Google Scholar 

  86. Zhang, Y., et al. Decreased poly(ADP-ribose) polymerase 1 expression attenuates glucose oxidase-induced damage in rat cochlear marginal strial cells. Mol. Neurobiol. 53:5971–5984, 2016

    Article  CAS  Google Scholar 

  87. Zhang, Y., et al. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage. Autophagy. 2022. https://doi.org/10.1080/15548627.2022.2062872

    Article  Google Scholar 

  88. Zhao, X. Y., et al. The effect of overexpression of PGC-1α on the mtDNA4834 common deletion in a rat cochlear marginal cell senescence model. Hear. Res. 296:13–24, 2013

    Article  CAS  Google Scholar 

  89. Zhao, Z., et al. ROS-responsive nanoparticle as a berberine carrier for OHC-targeted therapy of noise-induced hearing loss. ACS Appl. Mater. Interfaces. 13:7102–7114, 2021

    Article  CAS  Google Scholar 

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Okur, M.N., Djalilian, H.R. Approaches to Mitigate Mitochondrial Dysfunction in Sensorineural Hearing Loss. Ann Biomed Eng 50, 1762–1770 (2022). https://doi.org/10.1007/s10439-022-03103-y

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