年龄相关性听力损失中线粒体氧化还原-自噬-线粒体自噬检查点的治疗时机

文献信息

中文摘要

背景： 年龄相关性听力损失（ARHL）常见、致残，且目前主要依靠补偿性设备而非机制修饰疗法进行管理。当前转化管线的主要弱点不是缺乏候选通路，而是缺乏一个将耳蜗表型、线粒体损伤状态和干预强度联系起来的时机框架。因此，这篇修订后的综述聚焦于一个分阶段的线粒体氧化还原质量控制模型。我们认为，当高能量耳蜗区室——外毛细胞和内毛细胞、螺旋神经节神经元以及外侧壁/血管纹——越过一个阈值，使得线粒体活性氧（ROS）、线粒体DNA和转移RNA完整性受损、溶酶体功能不足以及不完全的线粒体自噬相互强化时，ARHL就会出现。强调三个检查点，因为它们在机制上可操作且在实验上可测量：NAD+-SIRT3依赖的线粒体去乙酰化和抗氧化稳定化、NRF2依赖的氧化还原和解毒缓冲，以及PINK1-Parkin依赖的选择性线粒体自噬。我们还扩展了侧壁视角，强调血管纹和螺旋韧带氧化还原不稳定可降低耳蜗内电位储备并改变表观感觉神经表型。提出了一个实用的治疗顺序：通过NAD+-SIRT3和NRF2进行早期底物强化；中期恢复自噬-溶酶体能力；仅当通量（而不仅仅是标志物积累）被证明受限时，才增强选择性线粒体自噬。最后，我们定义了一个生物标志物和检测框架，将耳蜗组织终点与血液或外淋巴替代物区分开来，并将小鼠机制验证与人类试验分层分开。这种方法阐明了哪些证据足以用于预防研究、哪些仍然缺失，以及未来的ARHL试验如何与机制和时机保持一致。

英文摘要

Age-related hearing loss (ARHL) is common, disabling, and still managed largely with compensatory devices rather than mechanism-modifying therapy. The major weakness in the current translational pipeline is not the absence of candidate pathways, but the lack of a timing framework that links cochlear phenotype, mitochondrial injury state, and intervention intensity. This revised Review therefore focuses on a staged mitochondrial redox-quality-control model. We argue that ARHL emerges when high-energy cochlear compartments-outer and inner hair cells, spiral ganglion neurons, and the lateral wall/stria vascularis-cross a threshold at which mitochondrial reactive oxygen species (ROS), impaired mitochondrial DNA and transfer RNA integrity, lysosomal insufficiency, and incomplete mitophagy reinforce each other. Three checkpoints are emphasized because they are mechanistically actionable and experimentally measurable: NAD+-SIRT3-dependent mitochondrial deacetylation and antioxidant stabilization, NRF2-dependent redox and detoxification buffering, and PINK1-Parkin-dependent selective mitophagy. We also expand the sidewall perspective, highlighting that strial and spiral ligament redox instability can reduce endocochlear-potential reserve and modify the apparent sensory-neural phenotype. A practical therapeutic sequence is proposed: early substrate reinforcement through NAD+-SIRT3 and NRF2; mid-stage restoration of autophagy-lysosome competence; and selective mitophagy enhancement only when flux, not merely marker accumulation, is demonstrably limiting. Finally, we define a biomarker and detection framework that distinguishes cochlear tissue endpoints from blood or perilymph proxies and separates mouse proof-of-mechanism from human trial stratification. This approach clarifies which evidence is sufficient for prevention studies, which remains missing, and how future ARHL trials can be aligned with mechanism and timing.