Lysosomal and endosomal pH (pHlys)

Lysosomal and endosomal pH refers to the tightly regulated acidic environment within the endo-lysosomal system, typically ranging from pH 6.5 in early endosomes to pH 4.5 in lysosomes (NIH, 2021). This acidity is primarily maintained by the vacuolar-type H+-ATPase (V-ATPase) proton pump and is essential for the activation of acid hydrolases, protein degradation, and autophagic flux (Zeng et al., 2023; NIH, 2025). Dysregulation of this pH is a hallmark of various pathologies; for instance, lysosomal alkalinization is linked to protein aggregation in neurodegenerative diseases like Alzheimer's and Parkinson's, while hyperacidification or V-ATPase upregulation in cancer cells promotes tumor invasion and chemoresistance (Lucien et al., 2018; NIH, 2026). Furthermore, many viruses, including SARS-CoV-2 and influenza, exploit the acidic endosomal environment to trigger membrane fusion and viral entry (NIH, 2021; NIH, 2025). Therapeutic strategies targeting this system include lysosomotropic agents like chloroquine, which accumulate in these compartments to raise pH via ion trapping, and V-ATPase inhibitors that directly block proton pumping (NIH, 2022; NIH, 2025). A major challenge in targeting lysosomal pH is achieving organelle specificity and avoiding systemic toxicity, as V-ATPase is ubiquitously expressed and vital for many cellular processes (NIH, 2025).

Other names

Lysosomal acidificationEndosomal acidificationOrganelle pHVacuolar pHIntraluminal pH

Lysosomotropism (ion trapping), V-ATPase inhibition, and pH buffering.