Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine and New Drug Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China.
Transl Neurodegener. 2020 Oct 30;9(1):40. doi: 10.1186/s40035-020-00219-w.
Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body. Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases. As mitochondria age in cells, they gradually become inefficient and potentially toxic. Acute injury can trigger the permeability of mitochondrial membranes, which can lead to apoptosis or necrosis. Transactive response DNA-binding protein 43 kDa (TDP-43) is a protein widely present in cells. It can bind to RNA, regulate a variety of RNA processes, and play a role in the formation of multi-protein/RNA complexes. Thus, the normal physiological functions of TDP-43 are particularly important for cell survival. Normal TDP-43 is located in various subcellular structures including mitochondria, mitochondrial-associated membrane, RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding, mitochondrial protein translation, and mRNA transport and translation. Importantly, TDP-43 is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, which are characterized by abnormal phosphorylation, ubiquitination, lysis or nuclear depletion of TDP-43 in neurons and glial cells. Although the pathogenesis of TDP-43 proteinopathy remains unknown, the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology, transport, and function suggest that mitochondria are associated with TDP-43-related diseases. Autophagy is a basic physiological process that maintains the homeostasis of cells, including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm; therefore, it is considered protective against neurodegenerative diseases. However, the combination of abnormal TDP-43 aggregation, mitochondrial dysfunction, and insufficient autophagy can lead to a variety of aging-related pathologies. In this review, we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria. Finally, we discuss a novel approach for neurodegenerative treatment based on the knowledge.
线粒体是细胞活动的能量中心，参与体内生理功能和代谢平衡及内稳态的维持。线粒体功能的改变与多种退行性和急性疾病有关。随着细胞中线粒体的衰老，它们逐渐变得低效并可能有毒。急性损伤会触发线粒体膜的通透性，这可能导致细胞凋亡或坏死。转激活反应 DNA 结合蛋白 43kDa（TDP-43）是一种广泛存在于细胞中的蛋白质。它可以与 RNA 结合，调节多种 RNA 过程，并在形成多蛋白/RNA 复合物中发挥作用。因此，TDP-43 的正常生理功能对细胞存活尤为重要。正常的 TDP-43 位于包括线粒体、线粒体相关膜、RNA 颗粒和应激颗粒在内的各种亚细胞结构中，以调节内质网-线粒体结合、线粒体蛋白翻译以及 mRNA 运输和翻译。重要的是，TDP-43 与多种神经退行性疾病有关，包括肌萎缩侧索硬化症、额颞叶痴呆和阿尔茨海默病，这些疾病的特征是神经元和神经胶质细胞中 TDP-43 的异常磷酸化、泛素化、裂解或核缺失。尽管 TDP-43 蛋白病的发病机制尚不清楚，但存在于线粒体内外的病理性 TDP-43 以及 TDP-43 在调节线粒体形态、运输和功能方面的功能参与表明，线粒体与 TDP-43 相关疾病有关。自噬是一种维持细胞内稳态的基本生理过程，包括靶向清除细胞质中异常聚集的蛋白质和受损的细胞器；因此，它被认为对神经退行性疾病具有保护作用。然而，异常 TDP-43 聚集、线粒体功能障碍和自噬不足的结合会导致多种与衰老相关的病理。在这篇综述中，我们描述了目前关于线粒体与 TDP-43 的关联以及自噬在清除异常聚集的 TDP-43 和功能失调的线粒体中的作用的知识。最后，我们讨论了一种基于该知识的新型神经退行性疾病治疗方法。
