TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response
复制标题
TDP-43 诱导线粒体损伤并激活线粒体未折叠蛋白反应
DOI：
10.1371/journal.pgen.1007947
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发表时间：
2019-05-01
期刊：
影响因子：
4.5
通讯作者：
Wu, Jane Y.
中科院分区：
文献类型：
--
作者：
Wang, Peng;Deng, Jianwen;Wu, Jane Y.
TDP-43基因突变或调控异常与TDP-43蛋白病有关，TDP-43蛋白病是一系列神经退行性疾病，包括额颞叶变性(FTLD)和肌萎缩侧索硬化症(ALS)。然而，潜在的分子和细胞缺陷仍不清楚。在这里，我们报告了一项系统的研究，将患者大脑样本的分析与TDP-43蛋白病的细胞和动物模型相结合。对患者样本的电子显微镜(EM)分析显示，显著的线粒体损伤，包括异常的脊和脊的丢失；在TDP-43蛋白病的细胞和动物模型中，这些超微结构的变化一直被观察到。在这些模型中，TDP-43表达增加导致线粒体功能障碍，包括线粒体膜电位降低和活性氧(ROS)生成增加。TDP-43表达抑制线粒体复合体I活性，减少线粒体ATP合成。重要的是，TDP-43在细胞和动物模型中都激活了线粒体未折叠蛋白反应(UPRmt)。下调线粒体蛋白水解酶LonP1可增加线粒体TDP-43水平，加重TDP-43诱导的线粒体损伤和神经变性。综上所述，我们的结果表明，TDP-43诱导的线粒体损伤是TDP-43蛋白病变的一个关键方面。我们的工作不仅揭示了LonP1在调节线粒体TDP-43水平上的未知作用，而且也加深了我们对TDP-43蛋白病发病机制的理解。我们的研究表明，阻断或逆转线粒体损伤可能为这些毁灭性疾病提供一种潜在的治疗方法。
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.