Sestrin 2 deficiency exacerbates noise-induced cochlear injury through inhibiting ULK1/Parkin-mediated mitophagy

  • Antioxid Redox Signal. 2022 Jun 16. doi: 10.1089/ars.2021.0283.
Yalan Li  1  2 ,  Shengsheng Li  3 ,  Liyuan Wu  4  5 ,  Tingting Wu  4  6 ,  Mengxiao Li  4  7 ,  Deliang Du  4  8 ,  Yalin Chen  4  9 ,  Caiji Wang  4  10 ,  Xuanyi Li  11 ,  Shili Zhang  4  12 ,  Zeqi Zhao  13 ,  Liting Zheng  4  14 ,  Mengbing Chen  4  15 ,  Menghua Li  4  16 ,  Ting Li  17 ,  Xi Shi  4  18 ,  Yuehua Qiao  4  19  20
Affiliations
  • 1. Xuzhou Medical University, 38044, Institute of Audiology and Balance Science, Xuzhou, China.
  • 2. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 3. Jiangsu University, 12676, Department of Neurosurgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China; [email protected].
  • 4. Xuzhou Medical University, 38044, Institute of Audiology and Balance Science, Xuzhou, Jiangsu, China.
  • 5. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 6. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 7. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 8. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 9. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 10. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 11. Xuzhou Medical University, 38044, Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; [email protected].
  • 12. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 13. Xuzhou Medical University, 38044, Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; [email protected].
  • 14. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 15. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 16. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 17. Xuzhou Medical University, 38044, School of Life Sciences Xuzhou Medical University, Xuzhou, Jiangsu, China; [email protected].
  • 18. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China; [email protected].
  • 19. Xuzhou Medical University, 38044, The Artificial Auditory Laboratory of Jiangsu Province, Xuzhou, Jiangsu, China.
  • 20. Xuzhou Medical University, 38044, Department of Otorhinolaryngology-Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; [email protected].
PMID: 35708118 DOI: 10.1089/ars.2021.0283
Abstract

Aims: Noise damage to auditory hair cells is associated with oxidative stress and mitochondrial dysfunction. This study was aimed to investigate the possible effect of sestrin 2 (SESN2), an endogenous antioxidant protein, on noise-induced hearing loss (NIHL) and the underlying mechanisms.

Results: We identified SESN2 as a protective factor against oxidative stress in NIHL via activation of Parkin-mediated Mitophagy. Consistently, SESN2 expression was increased and Mitophagy was induced during the early stage after a temporary threshold shift (TTS) due to noise exposure or H2O2 stimulation; conversely, SESN2 deficiency blocked Mitophagy and exacerbated acoustic trauma. Mechanistically, SESN2 interacted with Unc-51-like protein kinase 1 (ULK1), promoting ULK1 pro-tein level stabilization by interfering with its proteasomal degradation. This stabili-zation is essential for Mitophagy initiation, since restoring ULK1 expression in SESN2-silenced cells rescued Mitophagy defects. Innovation & Conclusion: Our results provide novel insights regarding SESN2 as a therapeutic target against noise-induced cochlear injury, possibly through improved Mitophagy.

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