Lysosomal membrane permeabilization and cell death

Abstract

Lysosomes are membrane-enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal-dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage-response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

“…This suggests that abemaciclib impairs the lysosomal function as a platform of mTORC1 signaling. Furthermore, we evaluated lysosomal membrane permeabilization (LMP) by observation of galectin‐3 localization 47 . In nontreated cells, galectin‐3 was diffused in cytosol (Figure , top).…”

“…In nontreated cells, galectin‐3 was diffused in cytosol (Figure , top). As a positive control for LMP, treatment with l ‐leucyl‐ l ‐leucine methyl ester (LLOMe), a well known inducer for LMP, resulted in translocation and puncta formation of galectin‐3 on the damaged lysosomes (containing LAMP2) (Figure , bottom) 47,48 . After treatment with abemaciclib at 10 µmol/L for 24 h, galectin‐3 puncta colocalized to lysosomes were observed in 32% of the cells.…”

“…However, fluorescent dextran taken up into endosomes via macropinocytosis did not extensively co‐localize with most of the abemaciclib‐induced vacuoles containing LAMP1‐mCherry (Figures 6 and ), indicating that cell‐death phenotype induced by abemaciclib is distinct from methuosis. Recently, LMP has come to be recognized to induce many types of cell death 47 . Cationic materials, such as gold nanoparticle, have been shown to induce the rupture of lysosomal compartments through the lysosomal swelling, named proton sponge effect, and subsequently induce apoptosis via the massive calcium influx into the cells caused by lysosomal rupture 49 .…”

Lysosomes as a therapeutic target

“…Discovered in the 1950s by Christian de Duve, lyso somes are membrane bound vesicles containing numerous hydrolytic enzymes that can break down biological polymers such as proteins, lipids, nucleic acids and polysaccharides 1,2 . Lysosomes have long been known to have a key role in the degradation and recycling of extracellular material via endocytosis and phagocytosis, and intracellular material via autophagy (reviewed elsewhere 2-5 ) (Fig.…”

Phosphatidylinositol 3-phosphate and Hsp70 protectPlasmodium falciparumfrom heat-induced cell death

“…Intricate studies including live cell microscopy correlated PI(3)P deficiency with DV permeabilization and subsequent parasite death after heat exposure. The lysosome has long been recognized as an acute sensor for stress stimuli, including oxidative, osmotic, and heat stress, whereby lysosomal membrane destabilization triggers apoptosis or necrosis (25,29,53). Similarly, Plasmodium DV destabilization can result in inefficient hemoglobin digestion, oxidative stress and undesired protein degradation in the parasite cytoplasm, which may eventually lead to impaired growth or cytotoxicity (41).…”