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Peroxisomes are specialized organelles present in fungi, plant, and animal cells. It can vary in number, size, morphology, and activity depending on the type of tissue and the nutritional state of the cell. For example, cells with active lipid metabolism, such as adipocytes, neurons, and hepatocytes, have more peroxisomes than other cells in the body. Besides their primary role in breaking down complex organic molecules, peroxisomes can also synthesize specific macromolecules and participate in...

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Peroxisome-derived ether lipids regulate lysosomal exocytosis.

Liang Chen¹, Danielle Henn¹, Zhongzheng Dong¹

¹Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.

The EMBO Journal

|May 2, 2026

Summary

Ether lipids from peroxisomes regulate lysosomes, impacting cellular homeostasis. Disrupting ether lipid synthesis improves lysosome function, offering new therapeutic avenues for lysosomal and peroxisomal disorders.

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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.