MCOLN1/TRPML1 in the lysosome: a promising target for autophagy modulation in diverse diseases

Autophagy. 2024 Aug;20(8):1712-1722. doi: 10.1080/15548627.2024.2333715. Epub 2024 Mar 24.

Abstract

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 Ca2+, Zn2+ and Fe2+ 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.Abbreviation: 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.

Keywords: Autophagy inhibition; MCOLN1; cardiomyocyte death; mitochondria turnover; tumorigenesis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy* / physiology
  • Humans
  • Lysosomes* / metabolism
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Transient Receptor Potential Channels* / metabolism

Substances

  • Transient Receptor Potential Channels
  • MCOLN1 protein, human

Grants and funding

This work was funded by National Natural Science Foundation of China (NSFC) grants [82200107 to M. W, 82101314 to Y. X and 82372205 to D.C], Nature Science Foundation of Liaoning Province (2021-MS-161 to M.W), Natural Science Foundation of Shanghai [23ZR1447900 to D.C], Shanghai Jiao Tong University “Jiao Tong University Star” Plan Medical-Industrial Interdisciplinary Research Fund [YG2021GD03 to D.C], Key University Science Research Project of Jiangsu Province (20KJA310001 to W.W), Major Projects of Jiangsu Provincial Health Commission [ZD2022051 to W.W], Jiangsu Specially-Appointed Professor award to W.W, Jiangsu Province Innovative and Entrepreneurial Talent program to W.W and Jiangsu Province Innovative and Entrepreneurial Team program to W.W.