Lysosomal proteins and acidification machinery

The lysosome is a specialized membrane-bound organelle that serves as the cell's primary digestive and recycling center, maintaining cellular homeostasis through the degradation of macromolecules via endocytic and autophagic pathways [3, 4]. Its degradative capacity is strictly dependent on a highly acidic internal environment (pH 4.5–5.0), which is primarily established and maintained by the vacuolar-type H+-ATPase (V-ATPase) proton pump [15, 18]. Within this acidic lumen, a suite of over 60 lysosomal proteins, including acid hydrolases like cathepsins and glucocerebrosidase, catalyze the breakdown of proteins, lipids, and complex sugars [6, 11]. Dysregulation of lysosomal pH or genetic defects in lysosomal proteins are central to the pathogenesis of lysosomal storage diseases (LSDs) and are increasingly implicated in common neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases [2, 7]. Therapeutically, the lysosome is targeted through several distinct strategies depending on the disease context, such as enzyme replacement therapies (ERT) and pharmacological chaperones used to restore the activity of specific defective lysosomal proteins [13]. In neurodegeneration, emerging small molecules and nanoparticles aim to restore lysosomal acidification to enhance the clearance of toxic protein aggregates [5, 10]. Conversely, in oncology, lysosomotropic agents like chloroquine are used to inhibit lysosomal function, thereby blocking autophagy and sensitizing cancer cells to chemotherapy [9, 12]. Additionally, the acidic nature of the lysosome leads to the sequestration of many basic lipophilic drugs, a phenomenon known as lysosomal trapping, which can significantly influence drug pharmacokinetics and safety [14].

Other names

LysosomeLysosomal acidification systemEndolysosomal pathwayLysosomal degradation machinery

Modulation of intralysosomal pH via V-ATPase inhibition or re-acidification, enzyme replacement, and pharmacological chaperoning of lysosomal hydrolases.