Detection and Clearance of Damaged Lysosomes by the Endo-Lysosomal Damage Response and Lysophagy

Abstract

Lysosomal membrane permeabilization or lysosomal rupture is recognized as a common and severe stress condition relevant for infection, cellular degeneration and cancer. However, the cellular response mechanisms that protect cells from the consequences of lysosomal damage and ensure lysosomal quality control and homeostasis have only recently been explored. Key elements of this response involve the specific sensing of the damage followed by extensive modification of the organelles with ubiquitin to mark them for clearance by selective macroautophagy, termed lysophagy. Efficient lysophagy is ensured by additional layers of regulation, including modulation by the ubiquitin-directed AAA-ATPase VCP/p97. Lysophagy shares many features with mitophagy, the macroautophagic removal of damaged mitochondria. This review aims to gather available data from different fields and to define the key steps necessary for sensing and subsequent clearance of damaged lysosomes. We conclude with a discussion of disease implications with a focus on neurodegeneration.

Use of human iPSCs and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy to treat cystinosis

“…This notion is in-line with the discovery that autophagy is involved in the removal/recycling of aged and dysfunctional lysosomes (lysophagy) in order to prevent cell damage caused by the leakage of hydrolytic enzymes 80,81 . At this stage it remains unclear if the basal autophagy block seen in cystinotic cells also results in a lysophagy defect.…”

Lysosomal membrane permeabilization and cell death

“…LMP and lysosomal stress induce several downstream cellular responses. To cope with lysosomal stress, cells have developed multiple strategies, collectively known as “endolysosomal damage‐response mechanisms.” Four mechanisms have been described to date. The first involves the creation of new lysosomes via the mTORC1‐TFEB pathway to compensate for impaired lysosomal function, as described above .…”

“…The first involves the creation of new lysosomes via the mTORC1‐TFEB pathway to compensate for impaired lysosomal function, as described above . The second mechanism is a form of selective autophagy known as lysophagy, which ensures the clearance of damaged lysosomes and the debris remaining after lysosomal rupture . A group of cytosolic galectins act as sensors of endolysosomal damage and LMP by binding lysosomal β‐galactosides that are exposed on the cytosolic side of the lysosomal membrane as a consequence of LMP.…”

“…Some galectins can directly recruit components of the autophagy machinery to initiate autophagy . Moreover, damaged lysosomes undergo extensive ubiquitination, resulting in further recruitment of components of the autophagy initiation machinery and the downstream clearance of damaged lysosomes . It has been suggested that lysophagy senses large holes on the lysosomal membrane (permeable to galectins), and the endosomal sorting complex required for transport (ESCRT) machinery, the third damage‐response mechanism, detects and repairs small proton‐permeable ruptures in the lysosomal membrane .…”

ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival

“…On the other hand, because of their low intraluminal pH and high content of Ca 2+ and enzymes that can potentially trigger cell death, lysosome damage caused by pathogens, sharp crystals, amphiphilic drugs or other membrane-disrupting agents impose a serious threat to cell viability 1,2 . Previous work has uncovered a lysosomeprotective function of heat-shock protein 70 3 , and the existence of an autophagic pathway that sequesters and degrades damaged lysosomes 4,5 .…”