Sestrin2 plays a protective role in age-related hearing loss by inhibiting NLRP3-inflammasome activity

IF 5.3 3区医学 Q2 CELL BIOLOGY Mechanisms of Ageing and Development Pub Date : 2024-07-15 DOI:10.1016/j.mad.2024.111964

Liting Zheng , Menghua Li , Yalan Li , Liyuan Wu , Konduru Naveena , Mengzhu Zheng , Zhanqun Yang , Yong Pan , Yunshi Zhang , Shujin Chen , Yuehua Qiao , Yice Xu , Long Chen , Xi Shi

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Abstract

Age-related hearing loss (ARHL) is an auditory disease characterized by gradual loss of high-frequency hearing sensitivity. Excessive reactive oxygen species trigger NLRP3-inflammasome activation that may be crucial for ARHL pathogenesis. The antioxidant factor Sestrin2 (SESN2) has been reported to be involved in the remission of oxidative stress and ARHL. However, the mechanism by which SESN2 protects auditory cells in the aging mouse cochlea remains unknown. Here, we observed that ectopic overexpression of SESN2 delayed ARHL, whereas SESN2 knockdown accelerated it. Importantly, we elucidated that SESN2 exerts a hearing-protective effect by inhibiting the production of NLRP3 by acting as a mitophagy agonist. Our study proposes a new theoretical basis for SESN2 prevention of ARHL and provides a novel therapeutic strategy for maintaining SESN2 activity in the aging cochlea.

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Sestrin2 通过抑制 NLRP3-炎症小体的活性，在老年性听力损失中发挥保护作用。

老年性听力损失（ARHL）是一种听觉疾病，其特点是高频听力敏感性逐渐丧失。过量的活性氧会引发 NLRP3-炎症小体活化，这可能是 ARHL 发病的关键因素。据报道，抗氧化因子 Sestrin2（SESN2）参与了氧化应激和 ARHL 的缓解过程。然而，SESN2保护老化小鼠耳蜗中听觉细胞的机制仍不清楚。在这里，我们观察到异位过表达 SESN2 会延缓 ARHL 的发生，而敲除 SESN2 则会加速 ARHL 的发生。重要的是，我们阐明了 SESN2 通过作为有丝分裂激动剂抑制 NLRP3 的产生，从而起到保护听力的作用。我们的研究为 SESN2 预防 ARHL 提出了新的理论依据，并为维持 SESN2 在老化耳蜗中的活性提供了新的治疗策略。

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来源期刊

Mechanisms of Ageing and Development 医学-老年医学

CiteScore

11.10

自引率

1.90%

发文量

审稿时长

32 days

期刊介绍： Mechanisms of Ageing and Development is a multidisciplinary journal aimed at revealing the molecular, biochemical and biological mechanisms that underlie the processes of aging and development in various species as well as of age-associated diseases. Emphasis is placed on investigations that delineate the contribution of macromolecular damage and cytotoxicity, genetic programs, epigenetics and genetic instability, mitochondrial function, alterations of metabolism and innovative anti-aging approaches. For all of the mentioned studies it is necessary to address the underlying mechanisms. Mechanisms of Ageing and Development publishes original research, review and mini-review articles. The journal also publishes Special Issues that focus on emerging research areas. Special issues may include all types of articles following peered review. Proposals should be sent directly to the Editor-in-Chief.