miR-34a/SIRT1信号调控线粒体生成与线粒体自噬在老年性聋发病中的作用及机制研究

The mechanisms underlying age-related hearing loss (AHL) remains largely unknown and there is no therapeutic target so far. Our previous study has revealed miR-34a/SIRT1 signaling is involved in the pathogenesis of AHL, but the detailed mechanism is unclear. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The imbalance between these opposing processes impairs the function of mitochondria and is the pathophysiological basis of a variety of neurodegenerative diseases. Whether the imbalance between mitochondrial biogenesis and mitophagy contributes to AHL onset remains largely elusive. Recently, we found oxidative stress inhibited mitophagy and promoted to HEI-OC1 cell death. Application of miR-34a inhibitor or SIRT1 activator improved mitochondrial biogenesis and mitophagy and attenuated HEI-OC1 cell death induced by oxidative stress. Moreover, the imbalance between mitochondrial biogenesis and mitophagy was also observed in the cochlea of aging C57BL/6 mice. Interestingly, pharmacological activation or overexpression of SIRT1 delayed the onset of AHL in C57BL/6 mice. The aim of this study is to elucidate the role and mechanisms of modulation of mitochondrial biogenesis and mitophagy by miR-34a/SIRT1 signaling in the pathogenesis of AHL. Hopefully we could provide novel therapeutic targets for the prevention and treatment of AHL.

老年性聋（AHL）发病机制复杂，尚无明确治疗靶点。我们前期工作已证实miR-34a/SIRT1信号参与AHL的发病，但具体机制尚未阐明。线粒体生成与线粒体自噬共同参与线粒体稳态的维持，两者动态平衡的失调可导致线粒体功能受损，是多种神经退行性疾病的病理生理学基础，但其是否参与AHL的发病尚不清楚。我们新近研究发现氧化应激抑制线粒体自噬水平，促进HEI-OC1毛细胞死亡；应用miR-34a抑制剂或SIRT1激活剂可改善线粒体生成与线粒体自噬水平，减少HEI-OC1毛细胞的氧化应激损伤。同时我们也发现在老年C57BL/6小鼠耳蜗存在线粒体生成与线粒体自噬平衡失调现象；SIRT1激活剂或者过表达SIRT1均可延缓C57BL/6小鼠的AHL发展。本项目将进一步揭示miR-34a/SIRT1信号调控线粒体生成与线粒体自噬参与AHL发病的作用和机制，为防治AHL提供新的分子靶点。

老年性聋（AHL）的发病机制尚未阐明。本课题旨在探讨miR-34a/SIRT1信号通过影响线粒体稳态介导毛细胞死亡及AHL的具体机制。首先，我们发现在HEI-OC1毛细胞中，H2O2诱导的氧化应激可以激活细胞线粒体自噬，同时抑制线粒体生成，最终损害细胞线粒体功能，导致细胞死亡。通过药物抑制miR-34a/SIRT1信号通路可以增强线粒体自噬及线粒体生成水平，缓解毛细胞的氧化应激损伤。在C57BL/6小鼠中我们发现线粒体自噬及线粒体生成水平随年龄上调，食物中添加SIRT1激活剂白藜芦醇可以平衡线粒体自噬及线粒体生成水平，减少毛细胞及螺旋神经节的缺失，延缓AHL的发生。与野生型小鼠相比，SIRT1过表达小鼠更迟出现听力下降（Neurobiology of Aging, 2019a）。我们还发现miR-34a的下游靶分子ATG9a通过与自噬关键因子TFEB结合并促进其入核。miR-34a激活通过抑制ATG9a/TFEB通路影响自噬流。长时程补充雷帕霉素可以部分恢复外毛细胞TFEB的入核及自噬流、减少外毛细胞的死亡及内毛细胞带状突触的丢失，并可延缓C57BL/6小鼠的AHL（Neuroscience, 2022）。此外，我们还明确线粒体自噬异常是促进AHL发病的重要因素（Frontiers in Cellular Neuroscience, 2019）；SIRT1激活剂白藜芦醇延缓AHL的作用主要通过改善毛细胞自噬水平来实现（Neurobiology of Aging, 2019b）；总之，我们的研究证实miR-34a/SIRT1信号通路可通过调节毛细胞线粒体功能和自噬水平影响细胞功能，在年龄相关性毛细胞死亡及AHL的发病中发挥重要作用，靶向miR-34a/SIRT1信号通路有可能成为治疗AHL的重要手段。