Regulation of plasmalogen metabolism and traffic in mammals: The fog begins to lift

Abstract

Due to their unique chemical structure, plasmalogens do not only exhibit distinct biophysical and biochemical features, but require specialized pathways of biosynthesis and metabolization. Recently, major advances have been made in our understanding of these processes, for example by the attribution of the gene encoding the enzyme, which catalyzes the final desaturation step in plasmalogen biosynthesis, or by the identification of cytochrome C as plasmalogenase, which allows for the degradation of plasmalogens. Also, models have been presented that plausibly explain the maintenance of adequate cellular levels of plasmalogens. However, despite the progress, many aspects around the questions of how plasmalogen metabolism is regulated and how plasmalogens are distributed among organs and tissues in more complex organisms like mammals, remain unresolved. Here, we summarize and interpret current evidence on the regulation of the enzymes involved in plasmalogen biosynthesis and degradation as well as the turnover of plasmalogens. Finally, we focus on plasmalogen traffic across the mammalian body – a topic of major importance, when considering plasmalogen replacement therapies in human disorders, where deficiencies in these lipids have been reported. These involve not only inborn errors in plasmalogen metabolism, but also more common diseases including Alzheimer’s disease and neurodevelopmental disorders.

Phosphatidylethanolamine homeostasis under conditions of impaired CDP-ethanolamine pathway or phosphatidylserine decarboxylation

“…The unique function of the CDP-Etn pathway is the formation of ether phospholipids known as plasmalogens. The synthesis of plasmalogens begins in the peroxisome, where glycerone phosphate, also known as dihydroxyacetone phosphate, is converted to alkyl-lysophosphatidic acid through a series of enzymatic steps ( 21 – 23 ). In the ER, alkyl-lysophosphatidic acid is converted to alkyl phosphatidic acid then to AAG (1-O-alkyl-2-acyl-sn-glycerol) ( 21 , 24 ).…”

“…The synthesis of plasmalogens begins in the peroxisome, where glycerone phosphate, also known as dihydroxyacetone phosphate, is converted to alkyl-lysophosphatidic acid through a series of enzymatic steps ( 21 – 23 ). In the ER, alkyl-lysophosphatidic acid is converted to alkyl phosphatidic acid then to AAG (1-O-alkyl-2-acyl-sn-glycerol) ( 21 , 24 ). The same way as DAG, AAG is then incorporated into the CDP-Etn Kennedy pathway ( 21 , 25 ).…”

“…In the ER, alkyl-lysophosphatidic acid is converted to alkyl phosphatidic acid then to AAG (1-O-alkyl-2-acyl-sn-glycerol) ( 21 , 24 ). The same way as DAG, AAG is then incorporated into the CDP-Etn Kennedy pathway ( 21 , 25 ). Plasmanyl-PE is the precursor for vinyl-ether phospholipids plasmenyl-PE and plasmenyl-PC ( 26 , 27 ).…”

“…Additionally, PE-plasmalogens are necessary for the formation of PC-plasmalogens, which are less abundant in the cell but play an important role in cardiac tissue ( 42 , 43 ). There is evidence that plasmanyl-PC could be created from AAG independently of plasmanyl-PE or CDP-Etn by choline-ethanolamine phosphotransferase CEPT1 ( 44 ), however, current evidence indicates that plasmenyl-PE is a necessary precursor for plasmenyl-PC ( 21 , 27 ). Thus, the production of CDP-Etn through the Kennedy pathway is a key regulator of plasmalogen homeostasis.…”

“…Studies on patient fibroblasts showed decreased levels of PE species, namely PE with PUFAs were reduced, along with most plasmenyl-PE ( 25 ). Plasmanyl-PC was increased in both patient cells and SELENOI -KO HeLa cells, which is likely due to the decrease in conversion of AAG to plasmanyl-PE, leaving more substrate for CEPT1 to produce plasmanyl-PC ( 21 ). These studies indicate that PE ether lipid homeostasis has a significant impact on neurodevelopment.…”