Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis

Lysosomes were once considered terminal degradative organelles responsible for disposing of cellular waste. However, recent studies have revealed that lysosomes serve as dynamic signalling and metabolic hubs at the center of diverse biological processes, including nutrient sensing, metabolic regulation, membrane trafficking, autophagy, inflammation, and cell death. To support this broad functional repertoire, lysosomes must possess robust mechanisms to maintain their integrity in the face of damage or stress. In response to lysosomal membrane damage, cells engage multilayered adaptive mechanisms that act in coordination-membrane repair (Repair), selective removal of damaged organelles (Removal), and de novo biogenesis of lysosomes (Regeneration). These processes are mediated by a range of molecular pathways, including the ESCRT complex, the PITT pathway, lysophagy, and TFEB-dependent lysosomal regeneration. Notably, recent findings highlight the noncanonical autophagy-like pathway known as ATG8ylation (conjugation of ATG8s on single membranes), which is activated via the STING-V-ATPase-ATG16L1 axis and functions as a critical hub connecting multiple arms of the lysosomal damage response. In this review, we systematically outline the molecular basis of lysosomal damage responses, including ATG8ylation, and explore how these networks are implicated in a broad spectrum of pathological conditions such as aging, neurodegeneration, cancer, obesity-related disorders, and immune dysfunction. Understanding these lysosomal quality control mechanisms not only sheds light on the fundamental principles of organelle homeostasis but also opens new avenues for therapeutic innovation.