Lysosomal pH

Lysosomal pH refers to the highly acidic internal environment of the lysosome, typically maintained between 4.5 and 5.0, which is essential for the optimal activity of over 60 acid hydrolases involved in cellular degradation [NIH, PMC7097195]. This acidification is primarily driven by the Vacuolar-type H+-ATPase (V-ATPase) proton pump, which transports protons into the lumen to facilitate protein turnover, nutrient sensing via the mTORC1 complex, and the regulation of autophagic flux [PubMed 31477883]. Dysregulation of lysosomal pH is a central feature of various diseases; for instance, lysosomal alkalinization is observed in neurodegenerative disorders like Alzheimer's, where it impairs the clearance of toxic protein aggregates, while cancer cells often exploit altered lysosomal acidification to meet high metabolic demands and resist chemotherapy [PMC6854580, PMC7421272]. Pharmacological modulation of lysosomal pH is a recognized therapeutic strategy, with lysosomotropic agents like hydroxychloroquine being used to inhibit autophagy and viral entry by increasing luminal pH [NIH, 2020]. While targeting this physiological state offers broad therapeutic potential, it also presents challenges such as drug-induced phospholipidosis and risks of systemic toxicity [PMC7421272].

Other names

Intralysosomal pHLysosomal acidityVacuolar pHLysosomal acidificationEndolysosomal pH

Drugs modulate lysosomal pH through two primary mechanisms: 1) Lysosomotropic sequestration, where weak bases (e.g., hydroxychloroquine) accumulate in the acidic lumen and protonate, thereby neutralizing the pH; or 2) Direct inhibition of the Vacuolar-type H+-ATPase (V-ATPase), which prevents the active transport of protons into the lysosome.