Lysosomal enzymes and acidic organelle machinery

Lysosomal enzymes and acidic organelle machinery comprise a complex system of hydrolases and membrane proteins essential for cellular homeostasis and macromolecular degradation (Parenti et al., 2015, Molecular Therapy). This machinery includes over 60 acid hydrolases, such as proteases and glycosidases, which require an acidic lumen (pH 4.5–5.0) maintained by the vacuolar H+-ATPase (V-ATPase) proton pump (Forgac, 2007, Nature Reviews Molecular Cell Biology). Beyond degradation, these organelles serve as hubs for nutrient sensing via the mTORC1 complex and regulate critical pathways like autophagy and endocytosis (Settembre et al., 2013, Nature Reviews Molecular Cell Biology). Genetic deficiencies in specific lysosomal enzymes lead to lysosomal storage diseases (LSDs), characterized by the toxic accumulation of undigested substrates (Platt et al., 2018, Nature). Additionally, lysosomal dysfunction is linked to neurodegenerative diseases, such as Parkinson’s, and cancer, where lysosomal membrane permeabilization can trigger cell death (Kirkegaard & Jäättelä, 2009, Nature Reviews Cancer). Therapeutic strategies targeting this system include enzyme replacement therapies (ERT), substrate reduction therapies (SRT), and pharmacological chaperones designed to restore or bypass enzymatic function (Beck, 2018, Journal of Inherited Metabolic Disease).

Other names

Lysosomal apparatusVacuolar systemLysosomal hydrolases and proton pumpsAcidic organelle systemLysosomal compartment

Enzyme replacement therapy (ERT) to restore hydrolase activity, substrate reduction therapy (SRT) to decrease metabolite accumulation, pharmacological chaperoning to stabilize mutant enzymes, and lysosomotropic modulation to alter intralysosomal pH.