Lysosomal destabilization

The major secondary events are changes in membrane structure and permeability, changes in the cytoskeleton, mitochondrial damage, depletion of ATP and other cofactors, changes in Ca2+ concentration, DNA damage and poly ADP-ribosylation, lysosomal destabilization, stimulation of apoptosis, and damage to the endoplasmic reticulum. 

Secondary events result from primary events, for example, changes in membrane structure/permeability, mitochondrial damage, and lysosomal destabilization. Tertiary events are final observable manifestations, for example, fatty change and phospholipidosis, apoptosis, blebbing, and necrosis. 

Figure 7.33 The renal accumulation and toxicity of gentamycin (G). Gentamycin is filtered in the glomerulus and enters the tubular lumen. Here, it is taken up by proximal tubular cells and in vesicles as part of the uptake process. These fuse with lysosomes (L) inside the cell. The accumulation of gentamycin inside the lysosome destabilizes it, causing it to rupture and release its hydrolytic enzymes (o). These cause damage within the cell. Also, gentamycin can directly damage mitochondria (M).

Oxidized LDL alter cellular functions role in cell death Oxidized LDL seem to be poorly degraded by lysosomal enzymes and accumulate in lysosomes altering in turn their functionality (Dean et al., 1997). It has been proposed that inhibition of oxidized LDL degradation and subsequent lipid accumulation may induce a destabilization of the acidic compartment, and lysosomal rupture with a relocation of lysosomal enzymes in the cytosol (li W et al, 1998). This process, also called endopepsis , occurs early and could precede mitochondrial dysfunction and cell death (Lossel et al., 1994). Moreover, oxidized LDL trigger a dysfunction of the intracellular proteolytic ubiquitin/proteasome pathway (early activation followed by inhibition)... 

Wattiaux, R., Jadot, M., Warnier-Pirotte, M.T., Wattiaux-De Coninck, S. (1997). Cationic lipids destabilize lysosomal membrane in vitro. FEBS Lett., 417, 199-202. 

Figure 11.1 The intracellular trafficking pathway of plasmid DNA complexed by poly cationic lipid (lipoplex). Critical steps are indicated by numbers (1) endocytosis, sorting and recycling via vesicular compartments comprising the early (EE) and sorting endosomes (2) entrapment and degradation in the late-endosomes (LE) and lysosomes (3) destabilization of the endo-lysosomal membrane and release into the cytosol, (the precise location of this step is not known) (4) diffusion toward the nuclear pore complex (NPC) and degradation in the cytoplasm, and (5) nuclear translocation across the NPC.

Figure 29.10. Postulated pathways of aminoglycoside-induced cellular injury. On the left, aminoglycoside (AG) enters the cell by pinocytosis and endocytosis, subsequently fusing with a primary lysosome (L). Aminoglycosides may interfere with normal lysosomal function, forming myeloid bodies (center). Additionally, aminoglycosides may destabilize lysosomes, leading to release of intralysosomal enzymes (lower left). Intracellular aminoglycosides may produce direct injury to intracellular organelles such as mitochondria. (Adapted from G.J. Kaloyanides and E. Pastoriza-Munoz, Kidney Int. 18, 571-582,1980.)...

The acidification of endosomal compartments, as they evolve toward lysosomes is a well-described phenomenon (1) that can be exploited to design drug delivery systems capable of releasing their contents after endocytosis. Enhanced cytoplasmic drug concentrations can therefore be achieved with smart formulations, which are sensitive to acidic pHs. For this purpose, liposomal formulations are attractive, because their deformable phospholipid bilayers can be rapidly disrupted to trigger drug release. In this section, ionizable copolymers of ISTisopropylacrylamide (NIPAM) are anchored in the phospholipid membrane and used to destabilize the bilayer upon acidification of the environment. 

Cationic lipids can destabilize a cellular membrane because of its intrinsic detergent property. Therefore, destabilization of endosomal and/or lysosomal membrane may be a contribution from the cationic lipids itself In the same context, it was shown that the cationic lipid/DOPE or cationic lipid/cholesterol liposome formulation exhibit surface anisotropies in terms of increased liposomal surface pH (161,162). The surface pH of the liposomal formulations exhibits at least two pH units higher than the pH of the solution at which they are made. Therefore, a liposomal solution made at physiological pH may in reality exhibit a surface pH > 9, which is detrimental for both the stability of endosome and activity of lysosomal enzymes. Endosomal disruptions were also done with fusogenic peptides, which promote pH-dependent fusion of small liposomes when associated with lipid bilayer. When these peptides were co-delivered with lipid/DNA complex, they imparted formidable endosomal disruption by changing its usual random coil conformation into amphipathic a-helix conformation at lower pH, resulting in consequent cytoplasmic delivery of DNA (163). 

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