Lysosomal adaptation: How cells respond to lysosomotropic compounds

Area of Science:

• Cell Biology
• Molecular Biology
• Pharmacology

Background:

• Lysosomes are vital acidic organelles for cellular homeostasis and degradation.
• Lysosomes act as signaling hubs, responding to intra- and extracellular changes.
• Lysosomotropism occurs when basic, lipophilic compounds accumulate within lysosomes, causing stress.

Purpose of the Study:

• To assess lysosomal changes induced by lysosomotropic drugs.
• To identify signaling pathways involved in cellular responses to lysosomal stress.

Main Methods:

• ARPE-19 cells were treated with eight diverse lysosomotropic drugs.
• Lysosomal activation was measured via LTR, lysosensor green, cathepsin activity, and LAMP2 staining.
• Lysosomal dysfunction was assessed by substrate accumulation (phospholipid, SQSTM1/p62, GAPDH, opsin).
• Nuclear translocation of TFEB, TFE3, and MITF was analyzed.
• Calcium and mTORC1 modulation were investigated.

Main Results:

• All tested lysosomotropic drugs induced lysosomal activation and dysfunction.
• Substrate accumulation indicated impaired lysosomal degradation.
• Lysosomal dysfunction triggered compensatory responses, including TFEB, TFE3, and MITF nuclear translocation.
• Calcium and mTORC1 signaling were implicated in these adaptive changes.

Conclusions:

• Lysosomotropic compounds can induce a compensatory lysosomal biogenic response.
• This response, while protective, ultimately leads to lysosomal functional impairment.
• The study highlights a cellular pathway for responding to lysosomal stress and the roles of TFEB, TFE3, and MITF.