Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex
Relieving ferroptosis may partially reverse neurodegeneration of the auditory cortex
复制标题
缓解铁死亡可能部分逆转听觉皮层的神经退行性变
DOI：
10.1111/febs.15266
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发表时间：
2020-03-17
期刊：
影响因子：
5.4
通讯作者：
Kong, Wei-Jia
中科院分区：
文献类型：
--
作者：
Chen, Xi;Li, Dan;Kong, Wei-Jia
中枢性老年性耳聋是由听觉中枢在衰老过程中的退化引起的。其主要特点是理解语言困难和声音定位困难。老年性耳聋是一个日益严重的公共卫生问题，但其潜在的分子机制尚未完全阐明。铁下垂是一种由铁和活性氧诱导的脂质过氧化引起的细胞死亡。铁下垂与许多病理过程有关，但它是否参与听觉系统的变性尚不清楚。为了研究这一点，我们在一个通过添加d-半乳糖（d-gal）建立的模拟衰老模型中测量了铁水平。我们首次发现，随着年龄的增长，铁在细胞内积累，铁下垂的超微结构特征出现在听觉皮层。这些变化伴随着铁调节蛋白2 （IRP-2）的上调，导致转铁蛋白受体1 （TfR-1）的增加，从而增加铁进入细胞并可能导致铁凋亡。线粒体DNA共同缺失（CDs）发生率升高，神经元退行性变，谷胱甘肽（GSH）和超氧化物歧化酶（SOD）活性降低。此外，我们发现铁螯合剂去铁胺（DFO）治疗和IRP-2的下调都缓解了模拟衰老过程中的铁下沉，从而实现了部分延缓衰老的保护作用。总之，我们在此描述了首次发现与年龄相关的铁沉积和铁下垂可能与听觉皮层神经退行性变有关。因此，缓解铁下垂可能是一种新的干预策略，用于年龄相关性听力损失。
Central presbycusis is caused by degradation of the auditory centre during ageing. Its main characteristics are difficulties in understanding language and localizing sound. Presbycusis is an increasingly critical public health problem, but the underlying molecular mechanism has not been fully elucidated. Ferroptosis is a form of regulated cell death caused by iron- and reactive oxygen species-induced lipid peroxidation. Ferroptosis is related to many pathological processes, but whether it participates in the degeneration of the auditory system remains unclear. To investigate this, we measured iron levels in a simulated ageing model established by the addition ofd-galactose (d-gal). We found, for the first time, that iron accumulated within cells and that the ultrastructural features of ferroptosis appeared in the auditory cortex with ageing. These changes were accompanied by upregulation of iron regulatory protein 2 (IRP-2), which led to an increase in transferrin receptor 1 (TfR-1), thus increasing iron entry into cells and potentially leading to ferroptosis. In addition, the malondialdehyde (MDA) content and the occurrence of mitochondrial DNA common deletions (CDs) increased, neuron degeneration appeared, and glutathione (GSH) and superoxide dismutase (SOD) activity decreased. Furthermore, we found that treatment with the iron chelator deferoxamine (DFO) and knockdown of IRP-2 both relieved ferroptosis during the simulated ageing process, thus achieving a partial protective effect to delay ageing. In summary, we describe here the first discovery that age-related iron deposition and ferroptosis may be associated with auditory cortex neurodegeneration. Relieving ferroptosis might thus be a new intervention strategy for age-related hearing loss.