Endosomal and lysosomal acidic compartments

The endosomal and lysosomal acidic compartments are specialized cellular organelles characterized by a low internal pH, typically ranging from 4.5 to 6.5, which is maintained by the vacuolar H+-ATPase (v-ATPase) (Forgac, 2007, Nat Rev Mol Cell Biol). This acidic environment is essential for the optimal activity of acid hydrolases that degrade proteins, lipids, and nucleic acids, and it plays a vital role in endocytosis, autophagy, and receptor recycling (de Duve et al., 1974, Biochem Pharmacol). In various diseases, these compartments are exploited; for instance, many viruses, including influenza and coronaviruses, require the acidic environment to trigger membrane fusion and release their genetic material (Savarino et al., 2003, Lancet Infect Dis). Pharmacological agents like chloroquine and hydroxychloroquine target these compartments by acting as lysosomotropic weak bases that accumulate within the lumen and neutralize the pH (Ohkuma & Poole, 1978, PNAS). This neutralization effectively blocks viral entry and inhibits the degradation of autophagosomes, making these compartments a target for treating infectious diseases, autoimmune conditions like systemic lupus erythematosus, and certain cancers (Amaravadi et al., 2011, Clin Cancer Res). However, because these compartments are fundamental to cellular homeostasis, therapeutic modulation carries risks of systemic toxicity, such as retinopathy and impaired protein turnover (Marmor et al., 2016, Ophthalmology). Additionally, the inhibition of lysosomal function can lead to the accumulation of undigested material, mimicking lysosomal storage disorders.

Other names

Acidic endosomesAcidic lysosomesEndolysosomal systemLysosomal compartmentAcidic organelles

Drugs targeting these compartments typically act as lysosomotropic weak bases that accumulate in the acidic lumen, leading to an increase in pH (alkalinization). This neutralization inhibits pH-dependent enzymes like cathepsins and prevents the conformational changes in viral proteins required for membrane fusion and uncoating (Savarino et al., 2003, Lancet Infect Dis; Ohkuma & Poole, 1978, PNAS).