Lysosomal-autophagy pathway (ALP)

The lysosomal-autophagy pathway is a fundamental cellular degradation and recycling system responsible for maintaining proteostasis and organelle quality control (Mizushima, 2007). It involves the sequestration of cytoplasmic components into double-membrane vesicles called autophagosomes, which subsequently fuse with lysosomes for degradation by acid hydrolases (Klionsky et al., 2021). This pathway plays a dual role in human health; while it protects against neurodegeneration and infection by clearing aggregates and pathogens, it can also be hijacked by cancer cells to survive metabolic stress and chemotherapy (Levy et al., 2017; Nixon, 2013). Pharmacological modulation of this pathway includes autophagy inhibitors like hydroxychloroquine, which blocks lysosomal acidification, and inducers like mTOR inhibitors, which stimulate the process to clear toxic proteins (Amaravadi et al., 2019). Targeting this system requires careful calibration, as both excessive and insufficient autophagy are linked to various pathologies, including lysosomal storage diseases and cardiovascular disorders (Dufour et al., 2018). Because this pathway is essential for the health of almost all cell types, pharmacological intervention carries risks of systemic toxicity and complex pleiotropic effects.

Other names

Autophagy-lysosome pathwayMacroautophagyLysosomal degradation systemAutophagic vacuolar system

Drugs targeting this pathway typically act by either inducing autophagy through the inhibition of the mechanistic target of rapamycin (mTOR) or by inhibiting the process through the disruption of lysosomal acidification and autophagosome-lysosome fusion.