Radulovic Maja, Yang Chonglin, Stenmark Harald
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Nat Rev Mol Cell Biol. 2025 Aug 4. doi: 10.1038/s41580-025-00873-w.
Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization.
溶酶体是对细胞功能和器官生理学至关重要的膜性细胞器。作为内吞途径的终点站，溶酶体在降解内源性和外源性大分子及颗粒以及受损或多余的细胞器方面发挥着基本作用。此外，溶酶体膜是包括mTOR复合物1（mTORC1）在内的几种信号成分的对接和激活平台，mTORC1协调细胞内的代谢信号传导。其膜的完整性对于溶酶体作为细胞代谢调节枢纽发挥功能至关重要。包括病原体、纳米颗粒和药物在内的各种因素可损害溶酶体膜的完整性。膜通透性增加会导致蛋白酶和阳离子泄漏到细胞质中，从而可诱导细胞死亡途径和先天免疫信号传导。多种途径可修复受损的溶酶体，严重受损的溶酶体则通过自噬过程即溶酶体自噬被降解。此外，溶酶体损伤会激活协调溶酶体生物发生以补充细胞溶酶体池的转录程序。在本综述中，我们讨论了关于确保溶酶体膜稳态维持机制的最新见解，包括溶酶体膜修复的新机制以及溶酶体损伤、修复、溶酶体自噬和溶酶体生物发生之间的相互作用。我们强调了溶酶体膜稳态在细胞功能、生理学、疾病和衰老中的重要性，并讨论了溶酶体膜通透性增加的治疗开发潜力。
