How does chloroquine affect lysosomes?
As a weak base, chloroquine passively diffuses into the acidic compartments of the cell, including endosomes, Golgi vesicles, and lysosomes, where it becomes protonated, trapping it within the organelle. Thus, chloroquine prevents maturation and fusion of endosomes and lysosomes [1].
How does chloroquine accumulate in lysosomes?
The unprotonated form of chloroquine preferentially accumulates in lysosomes as it rapidly diffuses across cell/organelle membranes. Once in the lower pH (4.6), environment of the lysosome chloroquine becomes protonated and can no longer freely diffuse out (16).
What is lysosomal membrane permeabilization?
Lysosomal membrane permeabilization is one mechanism for the induction of cell death. As mentioned above, complete disruption of lysosomes provokes uncontrolled cell death by necrosis. In contrast, partial and selective LMP induces the controlled dismantling of the cell by apoptosis.
How does chloroquine block autophagy?
Chloroquine (CQ), which is frequently used clinically as an antimalarial agent, is a classic inhibitor of autophagy that blocks the binding of autophagosomes to lysosomes by altering the acidic environment of lysosomes, resulting in the accumulation of a large number of degraded proteins in cells (8).
Which of the following inhibits Autophagosome-lysosome fusion?
Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.
What is lysosomal membrane?
The lysosomal membrane, which has a typical single phospholipid bilayer, controls the passage of material into and out of lysosomes, by its permeability and ability to fuse with digestive vacuoles or engulf cytosolic material.
What is lysosomal cell death?
Summary. Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called “lysosomal cell death”.
How is chloroquine metabolized?
In humans, the antimalarial drug chloroquine (CQ) is metabolized into one major metabolite, N-desethylchloroquine (DCQ). Using human liver microsomes (HLM) and recombinant human cytochrome P450 (P450), we performed studies to identify the P450 isoform(s) involved in the N-desethylation of CQ.
What is the effect of chloroquine on lysosomes?
(c) Chloroquine treatment resulted in acridine orange translocation, suggesting an increased permeability of lysosomal membranes. T24 cells were treated with indicated concentrations of chloroquine for 6 or 24 h, stained with acridine orange then proceed immediately for imaging.
Does chloroquine cause lysosome dilation in arpe-19 cells?
Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: possible implications of lysosomal dysfunction in macular degeneration. Cell Biosci. 2011. March 8;1(1):10 PubMed PMID: 21711726.
Can lysosome inhibitors Bafilomycin A1 and chloroquine be used together?
The lysosome inhibitors bafilomycin A1 and chloroquine have both lysosomotropic properties and autophagy inhibition ability, and are promising clinical agents to be used in combination with anticancer drugs. In order to investigate this combination effect, HepG2 cells were treated with bafilomycin A …
The main feature of this form of regulated cell death is lysosomal membrane permeabilization (LMP).