A lysosome‐plasma membrane‐sphingolipid axis linking lysosomal storage to cell growth arrest

What is it about?

Lysosomes are acidic intracellular organelles containing hydrolytic enzymes involved in the degradation and recycling of several macromolecules. Despite lysosomes have been mainly considered inert catabolic organelles, it is now clear that they are also crucial regulators of cell homeostasis. Lysosomal accumulation of uncatabolized material is a hallmark of several diseases, including lysosomal storage disorders, Alzheimer's disease, Parkinson's disease, and brain aging. Nevertheless, the molecular mechanism responsible for the onset of cell damage following lysosomal engulfment remains unknown so far and it represents the main challenge in the field. One of the main issue to perform these studies is the development of cell models characterized by the accumulation of high levels of uncatabolized molecules within the lysosomes as occurs in the cells of affected organs. To this purpose, we used a simple cellular model of lysosomal accumulation represented by human fibroblasts subjected to sucrose loading. The data obtained pointed out that the primary accumulation is responsible for an increased biogenesis of impaired lysosomes resulting in the storage of other undigested materials. In addition, our findings highlight that loaded-cells promote the fusion between lysosomes and the plasma membrane resulting in the abnormal catabolism of plasma membrane lipids which is strictly related with the onset of cell damage. The identification of a new molecular mechanism linking the lysosomal dysfunction with the onset of cell damage could have potential mechanistic and therapeutic implications in different disease conditions characterized by lysosomal impairment due to the accumulation of uncatabolized molecules.

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