Acidic intracellular organelles

Acidic intracellular organelles, primarily lysosomes and endosomes, are membrane-bound compartments characterized by a low internal pH (typically 4.5–6.0) maintained by vacuolar H+-ATPases [1, 2]. These organelles are essential for cellular homeostasis, facilitating the degradation of macromolecules via acid hydrolases and the recycling of nutrients through autophagy [3]. They also serve as critical signaling hubs, particularly for the mTORC1 pathway, which coordinates cellular growth with nutrient availability [3]. In various pathologies, these organelles are either dysfunctional or exploited; for example, many viruses utilize the acidic environment of endosomes to trigger membrane fusion and viral uncoating [4]. Pharmacologically, these compartments are targeted by lysosomotropic agents—weakly basic drugs like chloroquine and hydroxychloroquine—which accumulate in the acidic lumen through a process called ion trapping [1, 5]. This accumulation raises the internal pH, thereby inhibiting pH-dependent enzymes and disrupting processes such as viral entry and autophagic flux [5, 6]. While therapeutically useful for conditions like malaria and autoimmune diseases, chronic targeting of these organelles can lead to adverse effects such as drug-induced phospholipidosis and tissue-specific toxicities like retinopathy [6].

Other names

LysosomeEndosomeAcidic compartmentVacuolar systemLytic compartmentAcidic vesicle

Drugs targeting these organelles typically act as lysosomotropic weak bases that accumulate in the acidic lumen through protonation and ion trapping. This accumulation increases the internal pH, thereby neutralizing the environment required for the optimal activity of acid hydrolases and disrupting pH-dependent processes such as viral uncoating, endosomal trafficking, and autophagic degradation.