Lysosomal membrane permeabilization in cell death: Concepts and challenges

• During LMP the luminal contents are released into the cytosol.
• LMP can be triggered by a variety of molecules.
• LMP can initiate apoptosis, pyroptosis or necrosis.
• Determination of LMP in a cell model system is methodologically challenging.
• LMP may prove to be a valuable approach in therapy, especially in cancer.

Late endocytic compartments include late endosomes, lysosomes and hybrid organelles. In the acidic lumen, cargo material derived from endocytosed and phagocytosed extracellular material and autophagy-derived intracellular material is degraded. In the event of lysosomal membrane permeabilization (LMP), the function of endo/lysosomal compartment is affected and the luminal contents are released into the cytosol to various extents. LMP can be a result of osmotic lysis or direct membranolytic activity of the compounds that accumulate in the lumen of endo/lysosomes. In addition to several synthetic compounds, such as dipeptide methyl esters and lysosomotropic detergents, endogenous agents that can cause LMP include ROS and lipid metabolites such as sphingosine and phosphatidic acid. Depending on the cell type and the dose, LMP can initiate the lysosomal apoptotic pathway, pyroptosis or necrosis. LMP can also amplify cell death signaling that was initiated outside the endocytic compartment, and hamper cell recovery via autophagy. However, mechanisms that connect LMP with cell death signaling are poorly understood, with the exception of the proteolytic activation of Bid by aspartic cathepsin D and cysteine cathepsins. Determination of LMP in a cell model system is methodologically challenging. Even more difficult is to prove that LMP is the primary event leading to cell death. Nevertheless, LMP may prove to be a valuable approach in therapy, either as a trigger of cell death or as a mechanism of therapeutic drug release in the case of delivery systems that target the endocytic pathway.