Lysosomal acidification machinery (Vacuolar-type H+-ATPase) (V-ATPase)

The lysosomal acidification machinery is a complex system, primarily driven by the Vacuolar-type H+-ATPase (V-ATPase), that maintains the acidic environment (pH 4.5–5.0) of the lysosomal lumen (Forgac, 2007). This acidic pH is crucial for the activation of acid hydrolases, which degrade macromolecules, and for the regulation of intracellular signaling pathways such as autophagy and endocytosis (Mindell, 2012). In the context of autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), this machinery is targeted by hydroxychloroquine (HCQ), a lysosomotropic weak base (Schrezenmeier & Dörner, 2020). HCQ accumulates within the lysosomes and increases their pH, thereby inhibiting the processing of autoantigens and the activation of endosomal Toll-like receptors (TLRs), specifically TLR7 and TLR9 (Kuznik et al., 2011). This disruption of lysosomal function also impairs the fusion of autophagosomes with lysosomes, effectively blocking autophagy, which is often upregulated in cancer cells to survive stress (Mauthe et al., 2018). Furthermore, the machinery is vital for the survival of the Plasmodium parasite, where HCQ interferes with heme detoxification in the acidic food vacuole (Sullivan et al., 1996). Safety concerns associated with long-term modulation of this machinery include retinal toxicity and cardiac conduction disturbances (Marmor et al., 2016).

Other names

Lysosomal proton pumpVacuolar-type H+-ATPase complexLysosomal proton handling systemV-type ATPase

Hydroxychloroquine acts as a lysosomotropic weak base that accumulates within the acidic environment of lysosomes, leading to an increase in intralysosomal pH (Schrezenmeier & Dörner, 2020). This alkalinization inhibits the activity of acid-dependent lysosomal hydrolases and disrupts processes such as autophagy, endosomal TLR signaling, and MHC class II-mediated antigen presentation (Kuznik et al., 2011).