Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss
Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss
复制标题
抑制 DRP-1 依赖性线粒体自噬促进耳蜗毛细胞衰老并加剧与年龄相关的听力损失
DOI：
10.3389/fncel.2019.00550
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发表时间：
2019-12-17
影响因子：
5.3
通讯作者：
Zheng, Yiqing
中科院分区：
文献类型：
--
作者：
Lin, Hanqing;Xiong, Hao;Zheng, Yiqing
背景：线粒体功能障碍被认为是导致年龄相关性听力损失（AHL）的原因。线粒体功能的调节需要线粒体质量控制，包括线粒体自噬和动力学。 Dynamin 相关蛋白 1 (DRP-1) 被认为在这种调节中发挥着核心作用。然而，DRP-1 在 AHL 中的潜在机制仍不清楚。在这里，我们检查了 DRP-1 依赖性线粒体自噬的下降是否有助于 AHL 的发展。方法：我们使用过氧化氢 (H2O2) 诱导细胞和耳蜗衰老，并通过衰老相关的 β-半乳糖苷酶染色评估衰老水平。我们通过荧光成像和 LC3II 和 P62 的蛋白质印迹评估了线粒体自噬水平。通过 ATP 测定、mtDNA 测定和 JC-1 评估线粒体功能。结果：我们发现衰老细胞和老年小鼠中 DRP-1 的表达和线粒体自噬水平均下降。当暴露于 H2O2 时，HEI-OC1 细胞中 DRP-1 的过度表达会引发线粒体自噬并保留线粒体功能，而 DRP-1 沉默的细胞则表现出相反的情况。此外，Mdivi-1 对 DRP-1 的抑制会阻止线粒体自噬并加剧老年 C57BL/6 小鼠的听力损失。结论：这些结果表明，DRP-1 启动线粒体自噬，消除线粒体功能障碍，并可能预防氧化应激诱导的衰老。这些结果为 AHL 提供了潜在的治疗靶点。
Background: Mitochondrial dysfunction is considered to contribute to the development of age-related hearing loss (AHL). The regulation of mitochondrial function requires mitochondrial quality control, which includes mitophagy and dynamics. Dynamin-related Protein 1 (DRP-1) is believed to play a central role in this regulation. However, the underlying mechanism of DRP-1 in AHL remains unclear. Here, we examined whether the decline of DRP-1-dependent mitophagy contributes to the development of AHL. Methods: We induced cellular and cochlear senescence using hydrogen peroxide (H2O2) and evaluated the level of senescence through senescence-associated β-galactosidase staining. We evaluated mitophagy levels via fluorescence imaging and Western Blotting of LC3II and P62. Mitochondrial function was assessed by ATP assay, mtDNA assay, and JC-1. Results: We found that both the expression of DRP-1 and the mitophagy level decreased in senescent cells and aged mice. DRP-1 overexpression in HEI-OC1 cells initiated mitophagy and preserved mitochondrial function when exposed to H2O2, while cells with DRP-1 silencing displayed otherwise. Moreover, inhibition of DRP-1 by Mdivi-1 blocked mitophagy and exacerbated hearing loss in aged C57BL/6 mice. Conclusion: These results indicated that DRP-1 initiated mitophagy, eliminated mitochondrial dysfunction, and may protect against oxidative stress-induced senescence. These results provide a potential therapeutic target for AHL.