Phospholipid membranes of acidic intracellular organelles and vesicle transport system

The phospholipid membranes of acidic intracellular organelles, including lysosomes, endosomes, and the trans-Golgi network, along with the vesicle transport system, represent a complex cellular target involved in degradation and signaling. These compartments maintain a highly acidic environment (pH 4.5–6.0) through the action of V-ATPases, which is necessary for the function of various enzymes and the sorting of proteins and lipids (De Duve et al., 1974). This system plays a pivotal role in diseases such as malaria, where the parasite utilizes acidic vacuoles for hemoglobin digestion, and autoimmune diseases like systemic lupus erythematosus, where endosomal signaling is key to pathogenesis (Schrezenmeier & Dörner, 2020). Pharmacological intervention often involves lysosomotropic agents, such as hydroxychloroquine, which partition into these acidic spaces, raise the pH, and interfere with antigen processing and viral entry mechanisms (Wang et al., 2020). Consequently, while not a single protein target, this system is a critical site for therapeutic modulation in infectious and inflammatory conditions. However, chronic disruption of this system can lead to significant safety concerns, most notably retinal and cardiac toxicities associated with long-term lysosomal dysfunction.

Other names

Acidic intracellular compartmentsEndolysosomal systemLysosomal-endosomal membrane systemVesicular trafficking system

Drugs targeting this system typically act via lysosomotropism, where weak base molecules accumulate in acidic compartments (lysosomes, endosomes) due to protonation, leading to an increase in organelle pH. This pH shift inhibits the activity of acid hydrolases and disrupts the vesicle transport system, including endosomal maturation, phagosome-lysosome fusion, and autophagy (Schrezenmeier & Dörner, 2020; Kaufmann & Krise, 2007).