Tissue-specific roles of peroxisomes revealed by expression meta-analysis.

Plessner M, Thiele L, Hofhuis J, and Thoms S. (2024) Tissue-specific roles of peroxisomes revealed by expression meta-analysis. Biology Direct, 19:14

Peroxisomes are membrane enclosed organelles found in most eukaryotic cells, but their abundance and location are dependent on the tissue type and the species. Peroxisomal dysfunction is associated with more then 20 congenital diseases that are caused by single enzyme defects or peroxisome biogenesis disorders (PBDs). The peroxisome is the location of many metabolic pathways including reactive oxygen species (ROS) catabolism, D-amino acid catabolism, very long and branched-chain fatty acid oxidation, and biosynthesis of bile acids, polyunsaturated fatty acids (PUFAs), and plasmalogens. When studying peroxisomes and PBDs, the brain, liver, and kidneys are usually the focus, however cardiomyopathies and heart failure are known to occur in peroxisomal disorders including Refsum disease and Rhizomelic chondrodysplasia punctata (RCDP). Plessner et al were interested in determining how peroxisomal metabolism is different between tissues and were specifically concerned with the heart. A meta-analysis using human and mice data was performed.

To evaluate peroxisomal biogenesis, 16 peroxin (PEX) genes were analyzed in different tissue types including liver, kidney, brain, and heart. PEX5, an important import protein for peroxisomal targeting signal 1 (PTS1)-containing proteins, was shown to be elevated in cerebral tissue in humans, suggesting a preference for PTS1-containing proteins in the brain. Another PEX gene, PEX7, encodes a receptor for PTS2 therefore to determine which combination is enriched in different tissues, PEX7/PEX5 and PTS2/PTS1 mRNA transcript ratios were calculated. Interestingly, a preference for PEX7 and PTS2 was seen in cardiac tissue in human and mouse. PEX19 showed the greatest mRNA and protein levels out of all the PEX genes and most other PEX genes had even expression levels across tissues suggesting similar potential for peroxisomal biogenesis. When looking at the three PEX11 gene paralogs, PEX11B showed the highest levels in humans but not mice, although PEX11 is present in most vertebrates.    

Peroxisomes are required for the production of plasmalogens which are a class of phospholipid that contain a vinyl-ether bond at sn-1. This double bond causes plasmalogens to have a more compact structure, making them important in membrane structure and fluidity. The double bond also gives plasmalogens antioxidative properties since it is able to scavenge ROS. Plasmalogens compose of around 20% of membrane phospholipids and are more than half of the phosphatidylethanolamines in the brain and heart. Through their meta-analysis, the authors analyzed the four factors involved in plasmalogen biosynthesis within the peroxisome including fatty alcohol reductase 1 (FAR1), fatty alcohol reductase 2 (FAR2), glycerone-phosphate O-acyltransferase (GNPAT), and alkylglycerone phosphate synthase (AGPS). GNPAT expression was greatest in human and mouse heart when compared to brain, liver, and kidney tissue.

In the heart the lipidome can vary according to the region studied and because of this Plessner et al used single-cell mRNA expression data for different heart regions and cell types to determine levels throughout the heart. Differential gene expression of datasets were used to compare cardiomyocytes and fibroblasts, left and right regions, as well as atrial and ventricular regions. When comparing cardiomyocytes and fibroblasts they found differently expressed genes including fibroblast-specific growth factor receptor (PDGFRA) and alpha cardiac actin (ACTC1) which is a sarcomere component in cardiomyocytes. In this study, it was demonstrated that differences between cell types were more well defined than the gene expression in region-specific cardiomyocytes. When cardiomyocytes in the left and right regions were evaluated, no significant difference was determined. However, expression differences in some marker genes including ankyrin repeat domain-containing protein 11 (ANKRD11), myosin heavy chain 6 (MYH6), and MYH9 were detected between arterial and ventricular regions. The authors did not find any difference in the comparisons from the peroxisomal gene set therefore they could not substantiate the previous findings of peroxisomal differences between heart regions.

Plessner et al were interested in studying peroxisomal metabolism differences between tissue types and between heart regions. Throughout their meta-analysis, peroxin gene expression levels were analyzed in different tissues to assess the potential for peroxisomal biogenesis. The authors found that cerebral tissue in humans expressed PEX5 which also suggests that PTS1 protein would be present, while cardiac tissue demonstrated an inclination for PEX7 and PTS2, but that their potential for peroxisome biogenesis was similar. Since plasmalogens are synthesized by peroxisomes, the genes that encode enzymes in this biosynthesis process were also assessed. Interestingly, the expression of GNPAT was greatest in both mouse and human heart tissues when compared to the brain, liver, or kidney. They were able to demonstrate tissue-dependent expression of peroxisomal genes causing distinct levels of peroxisomal biogenesis and the downstream products including plasmalogen levels. When the regions of the heart were compared, mRNA expression differences were only noted between cell types and not seen between the different regions. However, no differences were seen in the expression of peroxisomal genes and therefore they could not support the findings seen in earlier studies where differences were observed. Further work into the peroxisomal pathways and their relationship to cardiac function will help elucidate the mechanisms involved and either confirm these results or those found previously.