Lysosomal quality control: molecular mechanisms and therapeutic implications

Damaged lysosomes are replaced, removed, and/or repaired by lysosomal quality control pathways.Lysosomal stress stimulates transcription factor EB (TFEB)/TFE3-mediated transcriptional upregulation of lysosomal biogenesis and exocytosis.Lysophagy degrades damaged lysosomes as a whole, whereas microautophagy degrades selective lysosomal membrane proteins.The endosomal sorting complex required for transport (ESCRT) machineries repair small lysosomal membrane pores by direct membrane sealing.The phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway repairs damaged lysosomes through direct lipid transfer at endoplasmic reticulum–lysosome membrane contact sites.Often deregulated in aging and diseases, lysosomal quality control pathways provide promising therapeutic targets for lysosomal related diseases, aging, infectious diseases, and cancer. Lysosomes are essential catabolic organelles with an acidic lumen and dozens of hydrolytic enzymes. The detrimental consequences of lysosomal leakage have been well known since lysosomes were discovered during the 1950s. However, detailed knowledge of lysosomal quality control mechanisms has only emerged relatively recently. It is now clear that lysosomal leakage triggers multiple lysosomal quality control pathways that replace, remove, or directly repair damaged lysosomes. Here, we review how lysosomal damage is sensed and resolved in mammalian cells, with a focus on the molecular mechanisms underlying different lysosomal quality control pathways. We also discuss the clinical implications and therapeutic potential of these pathways.