Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Autophagy. 2024 Aug;20(8):1712-1722. doi: 10.1080/15548627.2024.2333715. Epub 2024 Mar 24.
MCOLN1/TRPML1 is a nonselective cationic channel specifically localized to the late endosome and lysosome. With its property of mediating the release of several divalent cations such as Ca, Zn and Fe from the lysosome to the cytosol, MCOLN1 plays a pivotal role in regulating a variety of cellular events including endocytosis, exocytosis, lysosomal biogenesis, lysosome reformation, and especially in Macroautophagy/autophagy. Autophagy is a highly conserved catabolic process that maintains cytoplasmic integrity by removing superfluous proteins and damaged organelles. Acting as the terminal compartments, lysosomes are crucial for the completion of the autophagy process. This review delves into the emerging role of MCOLN1 in controlling the autophagic process by regulating lysosomal ionic homeostasis, thereby governing the fundamental functions of lysosomes. Furthermore, this review summarizes the physiological relevance as well as molecular mechanisms through which MCOLN1 orchestrates autophagy, consequently influencing mitochondria turnover, cell apoptosis and migration. In addition, we have illustrated the implications of MCOLN1-regulated autophagy in the pathological process of cancer and myocardial ischemia-reperfusion (I/R) injury. In summary, given the involvement of MCOLN1-mediated autophagy in the pathogenesis of cancer and myocardial I/R injury, targeting MCOLN1 May provide clues for developing new therapeutic strategies for the treatment of these diseases. Exploring the regulation of MCOLN1-mediated autophagy in diverse diseases contexts will surely broaden our understanding of this pathway and offer its potential as a promising drug target. CCCP:carbonyl cyanide3-chlorophenylhydrazone; CQ:chloroquine; HCQ: hydroxychloroquine;I/R: ischemia-reperfusion; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MCOLN1/TRPML1:mucolipin TRP cation channel 1; MLIV: mucolipidosis type IV; MTORC1:MTOR complex 1; ROS: reactive oxygenspecies; SQSTM1/p62: sequestosome 1.
MCOLN1/TRPML1 是一种非选择性阳离子通道，特异性定位于晚期内体和溶酶体。由于其介导几种二价阳离子（如 Ca、Zn 和 Fe）从溶酶体释放到细胞质的特性，MCOLN1 在调节多种细胞事件中起着关键作用，包括内吞作用、胞吐作用、溶酶体发生、溶酶体再形成，特别是在巨自噬/自噬中。自噬是一种高度保守的分解代谢过程，通过去除多余的蛋白质和受损的细胞器来维持细胞质的完整性。溶酶体作为终末隔室，对于完成自噬过程至关重要。本综述深入探讨了 MCOLN1 通过调节溶酶体离子稳态来控制自噬过程的新作用，从而控制溶酶体的基本功能。此外，本综述总结了 MCOLN1 协调自噬的生理相关性以及分子机制，从而影响线粒体周转、细胞凋亡和迁移。此外，我们还说明了 MCOLN1 调节的自噬在癌症和心肌缺血再灌注（I/R）损伤的病理过程中的意义。总之，鉴于 MCOLN1 介导的自噬在癌症和心肌 I/R 损伤发病机制中的参与，靶向 MCOLN1 可能为开发治疗这些疾病的新治疗策略提供线索。探索 MCOLN1 介导的自噬在不同疾病背景下的调节作用，必将拓宽我们对该途径的理解，并为其作为有前途的药物靶点提供潜力。CCCP：羰基氰化物 3-氯苯腙；CQ：氯喹；HCQ：羟氯喹；I/R：缺血再灌注；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；MCOLN1/TRPML1：粘脂蛋白 TRP 阳离子通道 1；MLIV：粘脂病 IV 型；MTORC1：MTOR 复合物 1；ROS：活性氧；SQSTM1/p62：自噬体 1。
