Lysosome repair: Mechanisms and biomedical importance

Both cancer cells and normal cells contain lysosomes - small vesicles that are packed with degradative enzymes. Lysosomes function as the cell's recycling stations which degrade harmful or superfluous material and recycle it to components the cell needs. Even though lysosomes are crucial for the cell, they also represent a potential danger. This is because damage to their surrounding membrane will cause leakage of enzymes that damage the cell. It has been shown that lysosomes of cancer cells are especially prone to damage, and this is something that is utilized in cancer therapy by inducing suicide of cancer cells by compounds that destabilize the lysosome membrane.We have recently co-discovered a cellular mechanism that repairs damaged lysosomes, which we call Lysofix. If we better understand how the Lysofix mechanism works, then we can use this knowledge to inhibit Lysofix in cancer cells and thereby enhance the effect of drugs that damage the cancer cell's lysosomes. In this way we can obtain more efficient cancer therapy with less side effects. A number of rare inherited genetic diseases are caused by errors in lysosome functions. For most of these conditions no therapy exists. In this project we will also investigate cells from patients with various lysosomal diseases to establish whether some of these have hyperactive Lysofix. If this is the case, it can pave the way for new treatment of this type of diseases. We have now identified a new cellular mechanism that mediates repair of damaged lysosomes. Upon damage, the enzyme PI4K2A is activiated to produce the lipid PI4P on the membrane of the damaged lysosome. This leads to recruitment of the PI4P-binding protein ORP1L, whose other end associates with the endpplasmic reticulum, where lipids such as cholesterol are produced. ORP1L mediates transfer of cholesterol from the endoplasmic reticulum to the damaged lysosome, which promotes its repair and protects it from further damage. We have recently published these results in a leading molecular biology journal, EMBO Journal. Now that we have identified this novel mechanism of lysosome repair, it will be interesting to investigate if we can utilize the new knowledge in cancer therapy. If we could inhibit this mechanism in cancer cells that are treated with lysosome-destabilizing drugs, it should be possible to obtain selective killing of cancer cells without affecting normal cells. For this purpose, it will be important to investigate the functional relationship between this new mechanism and the Lysofix mechanism that we have established previously.

Lysosomes have an essential function as the main degradative organelles of the cell, and they also play important roles in cell signalling. Genetic mutations that cause lysosome dysfunctions are associated with a number of severe disorders known as lysosomal storage diseases, and illness can also be caused by pathogens, microcrystals or drugs that damage lysosomes. On the other hand, because rupture of lysosomes is known to cause cell death, pharmacological or photochemical destabilization of cancer cell lysosomes is used in cancer therapies. It is therefore important to know how lysosome integrity is maintained, and we have recently co-discovered a mechanism for repair of damaged lysosomes, which we term the Lysofix pathway. Because this is an entirely unexplored pathway, we would now like to understand exactly how it repairs damaged lysosomes, and what happens with the cell if Lysofix fails. We also propose to investigate whether the Lysofix pathway is activated in various lysosomal storage disorders, and whether inhibition of the Lysofix pathway can be used to potentiate lysosome-directed cancer therapy.