Alterations in ether lipid metabolism and the consequences for the mouse lipidome.

Lackner K, Sailer S, van Klinken J, Wever E, Pras-Raves ML, Dane AD, Honsho M, Abe Y, Keller MA, Golderer G, Werner-Felmayer G, Fujiki Y, Vaz FM, Werner ER, and Watschinger K. (2023) Alterations in ether lipid metabolism and the consequences for the mouse lipidome. BBA – Molecular and Cell Biology of Lipids

Plasmalogens are a unique class of phospholipids that contain a vinyl-ether bond at the sn-1 position, causing these lipids to have a more compact conformation. This structure allows plasmalogens to have roles in cell membrane fluidity and structure, vesicular fusion, lipid raft formation, and gives antioxidative properties. This class makes up around 20% of total phospholipids in mammals, but are found in the highest levels in the central nervous system. Plasmalogen deficiency causes a rare disease called Rhizomelic chondrodysplasia punctata (RCDP) characterized by severe dwarfism and developmental delays, while reductions in plasmalogen levels is associated with Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. During the plasmalogen biosynthesis pathway the final steps are when alkylglycerol monooxygenase (AGMO) catabolizes plasmanyl lipids and then plasmanylethanolamine desaturase (PEDS1) adds the vinyl-ether bond. Previous work has shown that Agmo knockdown in macrophages alters the lipidome but results in no changes in an Agmo knockout mouse model. In contrast, Tmem189, the gene that encodes PEDS1, knockout mice have significantly reduced plasmalogen levels and are smaller in size. Lackner et al was interested in characterizing both mouse models and determining why one may be more affected than the other.

To complete this work, Agmotm1a(EUCOMM)Wtsi (referred to as Agmo-deficient) mice and Tmem189tm1a(KOMP)Wtsi (referred to as Peds1-deficient) mice were used and compared against wildtype control animals. When lipid species were evaluated in the cerebrum and cerebellum in all, as well as the kidney in the Peds1-deficient mice since that is the tissue with the highest levels of PEDS1 activity and the liver in the Agmo-deficient mice since it has the highest AGMO activity. In the Peds1-deficient cerebrum, 372 lipid species were altered (247 elevated, 125 reduced), while 374 were changed in the cerebellum (243 elevated, 131 reduced). Both of these tissues showed a significant reduction in plasmalogen species and an increase in plasmanyl, likely as a compensatory action. In the kidney there were 163 lipids that were significantly different from the control animals, 69 of which were elevated and 94 that were reduced. Similar to the brain they saw that plasmanyl species were accumulated along with a reduction in plasmalogen species. In the Agmo-deficient mice, less distinct differences were seen compared to the Peds1-deficient mice. In the cerebrum six significantly elevated lipid species were found while only 3 were elevated in the cerebellum. However, in the liver 59 lipid species were increased including plasmalogens and other glycerophospholipids, their lyso-forms, and glycerolipids.

As the Peds1-deficient mice were affected more than the Agmo-deficient animals, Lackner et al wanted to determine how this mutation influenced the regulation of plasmalogens. To accomplish this the balance between plasmanyl and plasmenyl ether lipids was analyzed to study PEDS1 activity. There was a characteristic decrease in plasmenyl, or vinyl-ether containing, ether lipids and an increase in plasmanyl ether lipids in the brain and in the kidneys of Peds1-deficient mice.

Lackner et al were interested in determining how a knockdown of PEDS1 and AGMO activity alter the mouse lipidome and compare the effects of the two. Both mouse models have the activity of an enzyme in the plasmalogen biosynthetic pathway inhibited and this pathway does not have redundancy so it reasons that the lipidome would be expected to be altered in these animals. Interestingly, previous work demonstrated that Peds1-deficient animals have a more distinct phenotype compared to the Agmo-deficient mice which shows no obvious change compared to control animals. This was also confirmed in the lipidome of both with the Peds1-deficient mice having significant reductions in plasmalogens in the two brain regions and the kidneys and the Agmo-deficient mice showed minimal differences in the two brain regions and the liver. As PEDS1 is responsible for adding the vinyl-ether bond it is not surprising that when its activity is inhibited plasmenyl levels drop. However, Lackner et al suggest that this could be due to efficient feedback regulation of ether lipid biosynthesis and possible alternative routes after the vinyl-ether bond is added. They recommend future work to look at whether a large accumulation of plasmanyl lipids, greater than what they witnessed, would result in physiological changes and state that more work to determine if specific lipid species are affected more than others within the plasmanyl and plasmenyl classes would be helpful for other disorders associated with lipidome changes.