Phospholipid membranes of acidic intracellular organelles

Phospholipid membranes of acidic intracellular organelles, such as lysosomes and endosomes, are specialized lipid bilayers that maintain a highly acidic internal environment (pH 4.5–5.0) necessary for cellular homeostasis. These membranes are characterized by a unique lipid composition, including bis(monoacylglycero)phosphate (BMP), which supports the activity of acid hydrolases and facilitates membrane fusion events during autophagy and endocytosis [6, 14]. In pharmacology, these membranes act as a target for lysosomotropic agents, which are weakly basic, lipophilic molecules that accumulate within the acidic lumen via ion trapping [7, 10]. This accumulation can be leveraged therapeutically to neutralize organelle pH, inhibit viral entry, or trigger lysosomal membrane permeabilization (LMP) to induce apoptosis in cancer cells [8, 15]. However, chronic interaction with these membranes by cationic amphiphilic drugs can lead to drug-induced phospholipidosis, a condition where the accumulation of drug-lipid complexes interferes with normal lipid metabolism and leads to the formation of lamellar inclusion bodies [1, 4]. Understanding the biophysical properties of these membranes is essential for the development of pH-sensitive drug delivery systems and for managing the safety profiles of many common medications [17, 20].

Other names

Lysosomal membranesEndosomal membranesAcidic compartment membranesIntracellular acidic membranesEndolysosomal membranes

Lysosomotropism: Cationic amphiphilic drugs (CADs) accumulate in acidic compartments via ion trapping. Once inside, they can neutralize pH, inhibit acid hydrolases (such as acid sphingomyelinase), and induce lysosomal membrane permeabilization (LMP) to trigger apoptosis.