Acidic organelle phospholipid membranes

Acidic organelle phospholipid membranes are the lipid bilayers that define the boundaries of intracellular compartments such as lysosomes and endosomes (Appelqvist et al., 2013). These membranes are characterized by their ability to maintain a significant proton gradient, resulting in an internal pH much lower than the surrounding cytoplasm, typically between 4.5 and 5.5, maintained by V-ATPase proton pumps (Mindell, 2012). This acidic environment is crucial for the optimal function of various hydrolytic enzymes, such as cathepsins, which are involved in the degradation of cellular waste and the recycling of nutrients through autophagy (Boya & Kroemer, 2008). In many pathological states, particularly in cancer, these membranes undergo structural and functional changes, such as increased fragility or altered lipid composition like increased bis(monoacylglycero)phosphate, which can be exploited for therapeutic purposes (Kirkegaard et al., 2010). Drugs targeting these membranes often utilize a mechanism called lysosomotropism, where cationic amphiphilic molecules accumulate preferentially within the acidic lumen (de Duve et al., 1974). Furthermore, certain agents can induce lysosomal membrane permeabilization (LMP), causing the release of digestive enzymes into the cytosol to trigger programmed cell death, offering a strategy to overcome apoptosis resistance in tumor cells (Nylandsted et al., 2004). Additionally, these membranes are involved in the entry and replication cycles of various viruses, making them targets for antiviral intervention (Wang et al., 2020). Beyond cancer and infection, modulating these membranes is relevant in treating lysosomal storage disorders and neurodegenerative diseases (Platt et al., 2012). Overall, they represent a critical subcellular target for a wide range of pharmacological applications.

Other names

Lysosomal membranesEndosomal membranesAcidic vesicle membranesVacuolar membranes

Drugs interact with these membranes primarily through lysosomotropism, a process where weak bases (cationic amphiphilic drugs) diffuse across the membrane and become protonated in the acidic lumen, leading to their entrapment and high-concentration accumulation (de Duve et al., 1974). Another key mechanism is the induction of lysosomal membrane permeabilization (LMP), which involves the destabilization of the phospholipid bilayer, often through the inhibition of acid sphingomyelinase or direct lipid interaction, resulting in the leakage of cytotoxic cathepsins into the cytoplasm (Boya & Kroemer, 2008; Petersen et al., 2013). This leakage triggers alternative cell death pathways, such as necrosis or apoptosis, which are particularly effective against cancer cells that have developed resistance to mitochondrial-mediated apoptosis (Nylandsted et al., 2004).