中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 983-990.doi: 10.4103/1673-5374.355745

• 综述:脑损伤修复保护与再生 • 上一篇    下一篇

内溶酶体系统在脑缺血中的关键作用

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    国家自然科学基金(81970760);辽宁省自然科学基金(2021-MS-201);中国医科大学附属盛京医院345人才项目(m0370);中国医科大学附属盛京医院345人才项目(M0395)

The critical role of the endolysosomal system in cerebral ischemia

Hui-Yi Zhang1, Ye Tian2, Han-Yan Shi1, Ya Cai1, Ying Xu1, *   

  1. 1Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China;  2Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Ying Xu, PhD, xuy5@sj-hospital.org.
  • Supported by:
    This work was supported the National Natural Science Foundation of China, No. 81970760 (to YT); the Natural Science Foundation of Liaoning Province, No. 2021-MS-201 (to YX); the 345 Talent Project of Shengjing Hospital of China Medical University, No. M0370 (to YT); the 345 Talent Project of Shengjing Hospital of China Medical University, No. M0395 (to YX).

摘要:

脑缺血是一种引发连续病理机制的严重疾病,导致显著的发病率和死亡率。以往大部分关于在脑缺血发病机制的研究只提及了溶酶体是单一细胞器,但最新研究表明,内溶酶体系统是一个高度动态的系统,包括晚期内体,末端溶酶体和内溶酶体一系列细胞器;彼此之间动态转化并承担不同的生物功能,其涉及的不同膜融合功能在脑缺血损伤的生物降解过程中发挥着至关重要的作用。①文章综述了脑缺血后内溶酶体系统的调节及其变化,特别是膜融合功能的最新研究进展发现,该系统的功能受多种蛋白质分子调节,例如N-乙基马来酰亚胺敏感因子(NSF)和溶酶体钾通道跨膜蛋白175(TMEM175)。然而,这些蛋白质在脑缺血损伤后异常表达,破坏了内溶酶体系统内以及自噬体和溶酶体之间膜的正常融合功能,导致内溶酶体系统“成熟”障碍,影响了自噬-溶酶体途径维持的能量代谢平衡,并可导致蛋白质内稳态崩溃。②作为内溶酶体系统的终端,自噬维持着该系统的动态平衡。自噬溶酶体融合过程是自噬的必要组成部分,在维持能量平衡和清除衰老蛋白质方面起着至关重要的作用。③文章以此认为,内溶酶体作为一个高度动态和复杂的系统,应该在脑缺血损伤过程中一起被重视,而不是集中在溶酶体的单个细胞器,未来对该动态系统调节的关注将为脑缺血的治疗提供新的思路。

https://orcid.org/0000-0002-2772-8697 (Ying Xu) 

关键词: 自噬, 生物降解, 脑损伤, 分子伴侣介导的自噬, 内溶酶体系统, 融合, 缺氧缺血, 脑, 有丝分裂, N-乙基马来酰亚胺敏感蛋白, TMEM175

Abstract: Cerebral ischemia is a serious disease that triggers sequential pathological mechanisms, leading to significant morbidity and mortality. Although most studies to date have typically focused on the lysosome, a single organelle, current evidence supports that the function of lysosomes cannot be separated from that of the endolysosomal system as a whole. The associated membrane fusion functions of this system play a crucial role in the biodegradation of cerebral ischemia-related products. Here, we review the regulation of and the changes that occur in the endolysosomal system after cerebral ischemia, focusing on the latest research progress on membrane fusion function. Numerous proteins, including N-ethylmaleimide-sensitive factor and lysosomal potassium channel transmembrane protein 175, regulate the function of this system. However, these proteins are abnormally expressed after cerebral ischemic injury, which disrupts the normal fusion function of membranes within the endolysosomal system and that between autophagosomes and lysosomes. This results in impaired “maturation” of the endolysosomal system and the collapse of energy metabolism balance and protein homeostasis maintained by the autophagy-lysosomal pathway. Autophagy is the final step in the endolysosomal pathway and contributes to maintaining the dynamic balance of the system. The process of autophagosome-lysosome fusion is a necessary part of autophagy and plays a crucial role in maintaining energy homeostasis and clearing aging proteins. We believe that, in cerebral ischemic injury, the endolysosomal system should be considered as a whole rather than focusing on the lysosome. Understanding how this dynamic system is regulated will provide new ideas for the treatment of cerebral ischemia.

Key words: autophagy, biodegradation, brain injury, chaperone-mediated autophagy, endolysosomal system, fusion, hypoxia-ischemia, brain, mitophagy, N-ethylmaleimide-sensitive protein, TMEM175