Peroxisomal stress response and inter-organelle communication in cellular homeostasis and aging (Part 2)

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

Peroxisomes are organelles involved in cellular metabolism by producing and degrading hydrogen peroxide and being the location for some of the biosynthetic steps of cholesterols, bile acids, polyunsaturated fatty acids, and ether phospholipids. When peroxisomes are dysfunctional, this leads to peroxisomal biogenesis disorders (PBDs). This dysfunction is associated with reduced redox homeostasis, mitochondrial dysfunction, increased endoplasmic reticulum (ER) stress, cell death, and lipid metabolism dysregulation. Kim and Bai have written a review discussing the peroxisomal stress response, how organelles communicate to maintain homeostasis, and how this is affected during aging. We have explored the peroxisomal stress response and cellular homeostasis in an earlier blog and here we will summarize the role of peroxisomal stress in aging.

Peroxisomal dysfunction is associated with aging and has been seen through a downregulation of peroxisomal proteins with age. Because of this trend, it has also been hypothesized that pathology of age-related neurodegenerative diseases, such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD), and metabolic diseases including nonalcoholic liver disease, obesity, and nonalcoholic liver disease may be caused by peroxisomal dysfunction through increased oxidative stress and reduced plasmalogen levels.

AD is a common disease and is characterized by cognitive decline and memory loss caused by the loss of neurons and synapses in the frontal cortex and hippocampus. The pathology of AD is thought to be caused by the accumulation of beta-amyloid and hyperphosphorylated tau. As well, increased oxidative stress is seen through hippocampal biomarkers of lipid peroxidation and DNA/RNA oxidation being seen in AD mice. Due to the roles of the peroxisome in cells, the authors discuss the strong evidence for peroxisome dysfunction in AD pathology. Very-long-chain fatty acids are found to be accumulated in the cortex of AD patients while a reduction in plasmalogens is also present. The peroxisome is involved in the production of both types of lipids therefore its dysregulation would alter their biosynthesis. What is unknown is which comes first: is altered peroxisomal activity causing AD, is it a coincidence that it occurs, or is it a result of a person developing AD?

Another common disease in the aging population is cardiovascular disease (CVD) and the risk for CVD increases with age. Peroxisomal function has also been associated with CVD as those with Refsum’s disease, a peroxisomal disorder, develop cardiac arrythmia and heart failure later in life. In addition, overexpression of cardiac catalase, largely found in the peroxisome, was able to prevent overt heart failure, while it was also found that significantly reduced catalase activity occurs in failing myocardium.

With increased age, a lot of changes are seen in cells and in the general composition of the body. An example of this is the distribution and composition of adipose tissue, especially showing an increase in fat deposits in white adipose tissue which contributes to insulin resistance and metabolic syndrome. In addition, with increased life expectancy is an increase in obesity in elderly. The authors discuss another study that showed that peroxisomes play an essential role in adipose dysfunction causing obesity. Other research has demonstrated that obese mice have downregulated peroxisomal genes in white adipose tissue. For example, Pex5 mutant mice have been found to have increased reactive oxygen species levels, and catalase knockout mice experienced accelerated obesity compared to control mice.

It is obvious that peroxisomes play important roles in cells and in cellular homeostasis and when this is disturbed there can be incredible defects. The work presented in this review support the hypothesis that peroxisomal stress and dysfunction may play a role in the pathology of aging diseases. With age, peroxisomal function and protein expression reduces, impacting the wide variety of roles that they have in cells. The authors suggest that additional work on peroxisomal stress responses may provide further understanding for the potential of using the peroxisome as a target for future therapies for these aging diseases.