Lysosomal adaptation: How cells respond to lysosomotropic compounds

摘要: Lysosomes are acidic organelles essential for degradation and cellular homoeostasis recently lysosomes have been shown as signaling hub to respond the intra extracellular changes (e.g. amino acid availability). Compounds including pharmaceutical drugs that basic lipophilic will become sequestered inside (lysosomotropic). How cells lysosomal stress associated with lysosomotropism is not well characterized. Our goal assess identify pathways involve in changes. Eight chemically diverse lysosomotropic from different therapeutic areas were subjected evaluation using human adult retinal pigmented epithelium cell line, ARPE-19. All tested triggered activation demonstrated by increased lysosotracker red (LTR) lysosensor green staining, cathepsin activity, LAMP2 staining. However, also prompted dysfunction exemplified intracellular substrate accumulation phospholipid, SQSTM1/p62, GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) opsin. Lysosomal observed was likely attributed dysfunction, leading compensatory responses nuclear translocation of transcriptional factors TFEB, TFE3 MITF. The adaptive protective under stress. Mechanistic studies implicate calcium mTORC1 modulation involvement These results indicate compounds could evoke a biogenic response but ultimate consequence functional impairment. This work highlights pathway evidences role MITF response.