Lysosomal acidic compartment and autophagy machinery

The lysosomal acidic compartment and autophagy machinery represent a complex cellular system responsible for the degradation and recycling of cytoplasmic components to maintain proteostasis (Mindell, 2012; Mizushima & Komatsu, 2011). The lysosome maintains an acidic internal environment (pH 4.5–5.0) through the action of vacuolar-type H+-ATPases (V-ATPases), which is essential for the function of over 60 different acid hydrolases (Forgac, 2007). Autophagy is the process that delivers cargo, such as damaged organelles or protein aggregates, to these lysosomes via double-membraned vesicles called autophagosomes (Nixon, 2013). In oncology, this machinery is frequently exploited by tumor cells to survive nutrient deprivation and therapy-induced stress, whereas its dysfunction is a hallmark of neurodegenerative diseases like Alzheimer's and Parkinson's (Amaravadi et al., 2019; Nixon, 2013). Pharmacological agents like hydroxychloroquine and chloroquine target this system by accumulating in lysosomes and increasing their pH, thereby inhibiting the final stages of autophagic degradation (Mauthe et al., 2018). Other drugs, such as rapamycin, modulate the system by inhibiting mTORC1 to induce autophagy (Mizushima & Komatsu, 2011). Therapeutic challenges include the potential for systemic toxicity and the double-edged sword nature of autophagy, which can be either cytoprotective or cytotoxic depending on the context (Onorati et al., 2018).

Other names

LysosomeAutophagy pathwayMacroautophagy machineryLysosomal-autophagy systemVacuolar-type H+-ATPase regulated compartment

Modulation of lysosomal pH, inhibition of V-ATPase proton pumps, or inhibition of ATG-mediated autophagosome formation to alter cellular degradative flux.