Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlying TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.

中文翻译：

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TDP-43蛋白病变和神经变性中的线粒体异常。

TAR DNA结合蛋白43（TDP-43）的遗传突变导致肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）。重要的是，以神经元和神经胶质细胞中TDP-43的异常磷酸化，泛素化，裂解或核耗竭为特征的TDP-43蛋白病是各种主要的神经退行性疾病（包括ALS，FTD和阿尔茨海默氏病（AD））的常见病理特征。 。尽管TDP-43蛋白病的病理机制仍然难以捉摸，但病理相关的TDP-43反复显示在线粒体内或外，并在功能上参与线粒体形态，运输和功能的调节，提示线粒体为可能是TDP-43蛋白病的靶标。在这篇评论中，我们首先描述有关TDP-43与线粒体结合的当前知识。然后，我们详细审查了受病理TDP-43干扰的多个线粒体途径，包括线粒体裂变和融合动力学，线粒体运输，生物能学和线粒体质量控制。最后，我们简要讨论TDP-43蛋白病和线粒体异常的研究如何为神经退行性治疗提供新途径。