Peroxisome-derived ether lipids regulate lysosomal exocytosis.

Area of Science:

• Cell Biology
• Metabolic Disorders
• Lipid Metabolism

Background:

• Lysosomes and peroxisomes are vital organelles for cellular homeostasis.
• The coordination between lysosome and peroxisome activity is not well understood.
• Mucolipidosis V is a lysosomal storage disorder associated with impaired lysosome function.

Purpose of the Study:

• To investigate the role of peroxisome-derived lipids in regulating lysosomal function.
• To identify novel mechanisms coordinating peroxisome and lysosome activities.
• To explore potential therapeutic targets for lysosomal and peroxisomal diseases.

Main Methods:

• Genome-wide CRISPR/Cas9 screening in mucolipidosis V cells.
• Genetic and pharmacological inhibition of ether lipid synthesis.
• Analysis of lysosomal accumulation, degradative capacity, and exocytosis.
• Supplementation with ether lipid precursors.

Main Results:

• Disruption of ether lipid synthesis or peroxins in LYSET-deficient cells reduced lysosome accumulation and restored degradative capacity.
• Inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted clearance of undigested material.
• Ether lipid precursor supplementation increased lysosome abundance but reduced degradative capacity.
• Ether lipids regulate lysosomal number and function independently of TFEB.

Conclusions:

• Peroxisome-derived ether lipids act as key regulators of lysosomal function.
• A peroxisome-lysosome metabolic axis, mediated by ether lipids, influences cellular homeostasis.
• These findings suggest ether lipids as potential therapeutic targets for lysosomal and peroxisomal disorders.