№4-6(7) 2024

DOI 10.37219/2528-8253-2024-4-6-9

Dieieva YuV, Dovhych SV

Molecular mechanisms of apoptosis in sensorineural hearing loss: the role of BID, BAD, BAK, BCL-x genes

Dieieva Julia V.
Bogomolets National Medical University, Kyiv, Ukraine
Head of the department of Otorhinolaryngology
MD, PhD, professor
E-mail: deyeva@bigmir.net
ORCID ID: https://orcid.org/0000-0003-0552-1254
https://www.scopus.com/authid/detail.uri?authorId=55359076200
Dovgich Sergey
Bogomolets National Medical University, Kyiv, Ukraine
Associate Professor of the Department of Otorhinolaryngology
PhD
E-mail: sergeydovgi4@gmail.com
ORCID: https://orcid.org/0009-0002-5983-6323

MOLECULAR MECHANISMS OF APOPTOSIS IN SENSORINEURAL HEARING LOSS: THE ROLE OF BID, BAD, BAK, BCL-X GENES

Dieieva YuV, Dovhych SV

Bogomolets National Medical University

Email: sergeydovgi4@gmail.com

Abstract

Background: Sensorineural hearing loss (SNHL) is a common pathology affecting over 1.5 billion people worldwide. Understanding the molecular mechanisms of apoptosis, particularly the role of BID, BAD, BAK, and BCL-x genes, is critical for developing effective treatment methods.

Objective: To analyze current data on the effects of oxidative stress on the expression of BID, BAD, BAK, and BCL-x genes in the context of sensorineural hearing loss development.

Materials and Methods: A systematic literature review was conducted using PubMed, Scopus, Web of Science, and Google Scholar databases for the period 2020-2025. The analysis included clinical, experimental, and review articles investigating the role of apoptosis genes in SNHL. A meta-analysis of the studied genes’ expression data was performed.

Results: Increased expression of proapoptotic genes BID, BAD, and BAK (FC >1.5) and decreased expression of the antiapoptotic gene BCL-x (FC ≈ 0.73) were found in patients with SNHL. Oxidative stress was identified as a key factor in activating apoptosis in hair cells. Combined therapy with antioxidants and apoptosis inhibitors showed potential in preserving up to 30% of functional auditory cells in early stages of SNHL.

Conclusions: The study confirms the key role of BID, BAD, BAK, and BCL-x genes in SNHL pathogenesis and substantiates the promise of developing therapeutic strategies aimed at modulating these genes’ expression and reducing oxidative stress.

Keywords: sensorineural hearing loss, apoptosis, oxidative stress, BID, BAD, BAK, BCL-x, apoptosis gene expression.

References

  1. Barriuso D, Alvarez-Frutos L, Gonzalez-Gutierrez L, Motiño O, Kroemer G, Palacios-Ramirez R, Senovilla L. Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence.Int J Mol Sci. 2023 Mar 28;24(7):6374. doi: 10.3390/ ijms24076374.
  2. Bas J, Nguyen T, Gillet G. Involvement of Bcl-xL in Neuronal Function and Development. Int J Mol Sci. 2021 Mar 21;22(6):3202. doi: 10.3390/ ijms22063202.
  3. Bos T, Ratti JA, Harada H. Targeting stress-response pathways and therapeutic resistance in head and neck cancer. Front Oral Health. 2021 Jun 23:2:676643. doi: 10.3389/froh.2021.676643.
  4. Chen B, Xu H, Mi Y, Jiang W, Guo D, Zhang J, Zhao Y, Tang W. Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice. Am J Physiol Cell Physiol. 2020 Sep 1;319(3):C569-C578. doi: 10.1152/ajpcell.00483. 2019.
  5. Cheng AG, Cunningham LL, Rubel EW. Mechanisms of hair cell death and protection. Curr Opin Otolaryngol Head Neck Surg. 2005 Dec;13(6): 343-8.
  6. Gill NB, Dowker-Key PD, Hedrick M, Bettaieb A. Unveiling the Role of Oxidative Stress in Cochlear Hair Cell Death: Prospective Phytochemical Therapeutics against Sensorineural Hearing Loss. Int J Mol Sci. 2024 Apr 12;25(8):4272. doi: 10. 3390/ijms25084272.
  7. Huang Q, Xiong H, Yang H, Ou Y, Zhang Z, Chen S, Ye Y, Zheng Y. Differential Expression of Bcl-2 in the Cochlea and Auditory Cortex of a Mouse Model of Age-Related Hearing Loss. Audiol Neurootol. 2016;21(5):326-332. doi: 10.1159/ 000450937. 
  8. Kamogashira T, Fujimoto C, Yamasoba T. Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss. Biomed Res Int. 2015:2015:617207. doi: 10.1155/2015/617207.
  9. Kim YJ, Choo OS, Lee JS, Jang JH, Woo HG, Choung YH. BCL2 Interacting Protein 3-like/NIX-mediated Mitophagy Plays an Important Role in the Process of Age-related Hearing Loss. Neuroscience. 2021 Feb 10:455:39-51. doi: 10.1016/j. neuroscience.2020.12.005.
  10. Li P, Li S, Wang L, Li H, Wang Y, Liu H, Wang X, Zhu X, Liu Z, Ye F, Zhang Y. Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome. Front Cell Dev Biol. 2023 Feb 20:11:1119773. doi: 10. 3389/fcell.2023.1119773.
  11. Morrill S, He DZZ. Apoptosis in inner ear sensory hair cells. J Otol. 2017 Dec;12(4):151-164. doi: 10.1016/j.joto.2017.08.001.
  12. Muderris T, Yar Sağlam AS, Unsal D, Mülazimoğlu S, Sevil E, Kayhan H. Efficiency of resveratrol in the prevention and treatment of age-related hearing loss. Exp Ther Med. 2022 Jan;23(1):40. doi: 10.3892/etm.2021.10962.
  13. Nassauer L, Staecker H, Huang P, Renslo B, Goblet M, Harre J, Warnecke A, Schott JW, Morgan M, Galla M, Schambach A. Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL. Mol Ther Nucleic Acids. 2024 Feb 19;35(1):102157. doi: 10.1016/j.omtn.2024.102157.
  14. Nunez DA, Guo RC. Acquired sensorineural hearing loss, oxidative stress, and microRNAs. Neural Regen Res. 2025 Sep 1;20(9):2513-2519. doi: 10.4103/NRR.NRR-D-24-00579.
  15. Safabakhsh S, Wijesinghe P, Nunez M and Nunez DA. The role of hypoxia-associated miRNAs in acquired sensorineural hearing loss. Front Cell Neurosci. 2022 Aug 5:16:916696. doi: 10.3389/fncel.2022.916696.
  16. Tan WJT, Song L. Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss. Hear Res. 2023 Jul:434:108783. doi: 10.1016/j.heares.2023.108783.
  17. Teraoka M, Hato N, Inufusa H, You F. Role of Oxidative Stress in Sensorineural Hearing Loss. Int J Mol Sci. 2024 Apr 9;25(8):4146. doi: 10.3390/ijms25084146.
  18. Voss AK, Strasser A. The essentials of developmental apoptosis. 2020 Feb 26:9:F1000 Faculty Rev-148. doi: 10.12688/f1000research.21571.1.
  19. Xie L, Zhou Q, Chen X, Du X, Liu Z, Fei B, Hou J, Dai Y, She W. Elucidation of the Hdac2/Sp1/miR-204-5p/Bcl-2 axis as a modulator of cochlear apoptosis via in vivo/in vitro models of acute hearing loss. Mol Ther Nucleic Acids. 2021 Jan 20:23:1093-1109. doi: 10.1016/j.omtn.2021.01.017.
  20. Yu Y, Yang J, Luan F, Gu G, Zhao R, Wang Q, Dong Z, Tang J, Wang W, Sun J, Lv P, Zhang H and Wang C. Sensorineural Hearing Loss and Mitochondrial Apoptosis of Cochlear Spiral Ganglion Neurons in Fibroblast Growth Factor 13 Knockout Mice. Front Cell Neurosci. 2021 Jun 16:15:658586. doi: 10.3389/fncel.2021.658586.