Department of Premedical Science, Chosun University College of Medicine, Gwangju 61452, Korea.
Department of Anatomy, Chosun University College of Medicine, Gwangju 61452, Korea.
Int J Mol Sci. 2020 Sep 29;21(19):7202. doi: 10.3390/ijms21197202.
Aging is associated with functional and morphological changes in the sensory organs, including the auditory system. Mitophagy, a process that regulates the turnover of dysfunctional mitochondria, is impaired with aging. This study aimed to investigate the effect of aging on mitophagy in the central auditory system using an age-related hearing loss mouse model. C57BL/6J mice were divided into the following four groups based on age: 1-, 6-, 12-, and 18-month groups. The hearing ability was evaluated by measuring the auditory brainstem response (ABR) thresholds. The mitochondrial DNA damage level and the expression of mitophagy-related genes, and proteins were investigated by real-time polymerase chain reaction and Western blot analyses. The colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus was analyzed by immunofluorescence analysis. The expression of genes involved in mitophagy, such as , , and in the mouse auditory cortex and inferior colliculus, was investigated by immunohistochemical staining. The ABR threshold increased with aging. In addition to the mitochondrial DNA integrity, the mRNA levels of , , , and , as well as the protein levels of , , , , LC3B, mitochondrial oxidative phosphorylation (OXPHOS) subunits I-IV in the mouse auditory cortex significantly decreased with aging. The immunofluorescence analysis revealed that the colocalization of mitophagosomes and lysosomes in the mouse auditory cortex and inferior colliculus decreased with aging. The immunohistochemical analysis revealed that the expression of , , and decreased in the mouse auditory cortex and inferior colliculus with aging. These findings indicate that aging-associated impaired mitophagy may contribute to the cellular changes observed in an aged central auditory system, which result in age-related hearing loss. Thus, the induction of mitophagy can be a potential therapeutic strategy for age-related hearing loss.
衰老是与感觉器官（包括听觉系统）的功能和形态变化相关的。自噬是调节功能失调线粒体更新的过程，随着年龄的增长而受损。本研究旨在使用与年龄相关的听力损失小鼠模型研究衰老对中枢听觉系统自噬的影响。C57BL/6J 小鼠根据年龄分为以下四组：1 个月、6 个月、12 个月和 18 个月组。通过测量听觉脑干反应（ABR）阈值评估听力能力。通过实时聚合酶链反应和 Western blot 分析研究线粒体 DNA 损伤水平和自噬相关基因和蛋白的表达。通过免疫荧光分析分析小鼠听觉皮层和下丘脑中自噬体和溶酶体的共定位。通过免疫组织化学染色研究小鼠听觉皮层和下丘脑中参与自噬的基因，如 、 、 和 的表达。ABR 阈值随年龄增长而增加。除了线粒体 DNA 完整性外，随着年龄的增长，小鼠听觉皮层中 、 、 、 和 的 mRNA 水平以及 、 、 、LC3B、线粒体氧化磷酸化（OXPHOS）亚基 I-IV 的蛋白水平均显著降低。免疫荧光分析显示，随着年龄的增长，小鼠听觉皮层和下丘脑中自噬体和溶酶体的共定位减少。免疫组织化学分析显示，随着年龄的增长，小鼠听觉皮层和下丘脑中的 、 、 和 的表达减少。这些发现表明，与衰老相关的自噬受损可能导致衰老中枢听觉系统中观察到的细胞变化，从而导致与年龄相关的听力损失。因此，诱导自噬可能是治疗与年龄相关的听力损失的潜在策略。
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