Peroxisomal stress response and inter-organelle communication in cellular homeostasis and aging (Part 1)

Kim J and Bai H. (2022) Peroxisomal stress response and inter-organelle communication in cellular homeostasis and aging. Antioxidants, 11(192)

Peroxisomes are single membrane-bound organelles involved in cellular metabolism through producing and degrading hydrogen peroxide, as well as being the location for some of the biosynthetic steps of cholesterols, bile acids, polyunsaturated fatty acids, and ether phospholipids. When peroxisomes are dysfunctional, this can lead to peroxisomal biogenesis disorders (PBDs). PBDs are genetic diseases caused by mutations in any of the 13 PEX genes that encode the peroxins responsible for importing membrane or matrix proteins into the peroxisome. This dysfunction is also associated with reduced redox homeostasis, mitochondrial dysfunction, increased endoplasmic reticulum (ER) stress, cell death, and lipid metabolism dysregulation. Plasmalogens are a type of lipid that are affected by peroxisome dysfunction as the beginning of the plasmalogen biosynthetic pathway occurs in the peroxisome. Plasmalogens are a class of lipids that contain a vinyl-ether bond at the sn-1 position, which causes this class to have unique characteristics. The vinyl-ether bond causes plasmalogens to have a more compact structure and influences membrane fluidity and organization and the ability of vesicular fusion to occur. As well, they have antioxidative properties since this bond can scavenge radical oxygen species (ROS). Kim and Bai have composed a review of the literature to discuss the peroxisomal stress response, how organelles communicate to maintain homeostasis, and how this is affected during aging. This blog will cover the peroxisomal stress response and how organelles communicate, while a later blog will explore the link between peroxisomal stress and aging.

Peroxisomal function is essential for cellular homeostasis, and its dysfunction results in a range of responses in the cell. The authors of this review propose a signaling pathway used to sense defective peroxisomes and activate cytoprotective mechanisms, which they have called the peroxisomal stress response pathway. They have also separated the types of peroxisomal stress into seven categories including: transcriptional changes, impaired ROS homeostasis, dysregulated lipid metabolism, mitochondrial dysfunction, ER stress, apoptosis and ferroptosis, and pexophagy. Each type of stress illicit its own cellular alterations and downstream effects in the organism and many can lead to diseases, from mitochondrial dysfunction being reported in individuals with Zellweger syndrome (ZS), dysregulated lipid metabolism causing plasmalogen deficiencies in people with rhizomelic chondrodysplasia punctata (RCDP) or elevated levels of very-long-chain fatty acids in ZS and infantile Refsum’s disease. The authors propose that the peroxisomal stress response pathway recognizes these types of dysfunctions and signals the appropriate cytoprotective mechanisms.

It is obvious that peroxisomes have a wide array of important roles in cells that contribute to cellular signaling, cell fate, immunity, inflammation, and aging. For these functions to occur, peroxisomes must communicate and coordinate with other organelles including mitochondria, endoplasmic reticulum, lysosomes, and lipid droplets, but the alterations that occur from peroxisome dysfunction can also affect the ability of peroxisomes to signal other organelles. For example, very-long-chain fatty acids (VLCFAs) are catabolized in peroxisomes are then oxidized in mitochondria while the intermediates from the fatty acid β-oxidation could act as signals between the peroxisome and mitochondria. The loss of Abcd1, a transporter that delivers VLCFAs to the peroxisome, causes severe mitochondrial abnormalities. Also, peroxisomal dysfunction prevents the production of plasmalogens since the first steps of the biosynthetic pathway occur in this organelle. Animals with mutations in the enzymes in this pathway also demonstrate altered mitochondrial morphology. The authors suggest that this could indicate that peroxisome-derived plasmalogens may be a signaling molecule that acts on the mitochondrial membrane to regulate membrane dynamics.

Peroxisome dysfunction effects many processes but in general alters cell homeostasis and intra-organelle communication. Although different mutations in peroxisomal proteins can cause these effects to occur all throughout life leading to disorders like ZS, Refsum’s disease, and RCDP, aging is also associated with increased peroxisomal stress. In the latter half of the review, the authors investigate the role of peroxisomal dysfunction in aging and explore whether these effects occur and lead to common diseases associated with aging, such as neurodegenerative or metabolic diseases, or if these defects follow the onset of the diseases.