Abstract
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.
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Acknowledgements
M.R. was supported by a Young Research Talents Grant from the Research Council of Norway (grant number 345137). Research in C.Y.’s laboratory is supported by grants from the National Science Foundation of China (grant numbers 32293201 and 92354303) and Program of Yunnan Province Leading Talents in Science and Technology (grant number 202105AB160003). H.S. was supported by Project Grants from the South-Eastern Norway Regional Health Authority (project number 2018081) and the Norwegian Cancer Society (project number 182698), and by an Advanced Grant from the European Research Council (project number 788954). M.R. and H.S. were also supported by the Research Council of Norway through its Centres of Excellence funding scheme (project number 262652).
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Glossary
- Ceramides
-
Bioactive sphingolipids composed of sphingosine and a fatty acid.
- cis-Golgi
-
The entry face of the Golgi apparatus, which receives cargos from the endoplasmic reticulum (ER).
- Endolysosomes, autolysosomes and phagolysosomes
-
Hybrid organelles formed by fusion of lysosomes with late endosomes, autophagosomes or phagosomes, respectively.
- Hemifusion
-
A transient state where outer layers of two membranes merge while the inner leaflets remain separate.
- Intraluminal vesicles
-
(ILVs). Vesicles that form within endosomes via invagination and scission of the endosomal membrane.
- LRRK2
-
(Leucine-rich repeat kinase 2). A large protein kinase whose mutations are the most common cause of familial Parkinson disease (5–6% of cases).
- Membrane contact sites
-
Regions where two organelles come into proximity (<30 nm) to exchange lipids, ions, motor proteins or signalling molecules without fusing.
- Multivesicular endosomes
-
A subset of late endosomes characterized by the presence of multiple intraluminal vesicles (ILVs) formed by the inward budding of the limiting membrane.
- NLRP3 inflammasome
-
A multiprotein complex that is activated in response to diverse cellular stress signals leading to caspase-1 activation and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.
- Protolysosomes
-
Newly formed lysosomes (primary lysosomes) with inactive acid hydrolases.
- Scramblase
-
A protein that mediates translocation of phospholipids between the two leaflets of a cellular membrane in an ATP-independent manner.
- Selective autophagy
-
Autophagy of specific cargos such as damaged organelles, protein aggregates or pathogens, mediated by autophagy receptors that connect cargos with ATG8 (autophagy-related protein 8) family proteins.
- SNARE
-
A group of proteins that mediate membrane fusion through energetically favourable tetrahelical bundles formed by SNAREs in the adjacent membranes.
- Stress granules
-
Cytoplasmic, membraneless biomolecular condensates consisting of RNAs and proteins.
- trans-Golgi network
-
(TGN). The exit face of the Golgi apparatus, composed of interconnected tubules and vesicles, which sends cargos to the plasma membrane and endosomes.
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Radulovic, M., Yang, C. & Stenmark, H. Lysosomal membrane homeostasis and its importance in physiology and disease. Nat Rev Mol Cell Biol 27, 71–87 (2026). https://doi.org/10.1038/s41580-025-00873-w
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DOI: https://doi.org/10.1038/s41580-025-00873-w
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