Abstract
Despite the fact that the discovery of ether-linked phospholipids occurred nearly a century ago, many unanswered questions remain concerning these unique lipids. Here, we characterize the ether-linked lipids of the nematode with HPLC-MS/MS and find that more than half of the phosphoethanolamine-containing lipids are ether-linked, a distribution similar to that found in mammalian membranes. To explore the biological role of ether lipids in vivo, we target fatty acyl-CoA reductase (fard-1), an essential enzyme in ether lipid synthesis, with two distinct RNAi strategies. First, when fard-1 RNAi is initiated at the start of development, the treated animals have severely reduced ether lipid abundance, resulting in a shift in the phosphatidylethanolamine lipid population to include more saturated fatty acid chains. Thus, the absence of ether lipids during development drives a significant remodeling of the membrane landscape. A later initiation of fard-1 RNAi in adulthood results in a dramatic reduction of new ether lipid synthesis as quantified with 15N-tracers; however, there is only a slight decrease in total ether lipid abundance with this adult-only fard-1 RNAi. The two RNAi strategies permit the examination of synthesis and ether lipid abundance to reveal a relationship between the amount of ether lipids and stress survival. We tested whether these species function as sacrificial antioxidants by directly examining the phospholipid population with HPLC-MS/MS after oxidative stress treatment. While there are significant changes in other phospholipids, including polyunsaturated fatty acid-containing species, we did not find any change in ether-linked lipids, suggesting that the role of ether lipids in stress resistance is not through their general consumption as free radical sinks. Our work shows that the nematode will be a useful model for future interrogation of ether lipid biosynthesis and the characterization of phospholipid changes in various stress conditions.
Highlights
The composition of an individual membrane lipid dramatically affects its impact on the membrane landscape
As C. elegans has recently been introduced as a model for ether lipid deficiency, we sought to determine how the distribution of ether lipids in the nematode compares with humans
We focused on the intact phospholipid molecules which allows for the determination of the overall amount of saturation within the lipid and the distribution of the chains throughout the class, which would be representative of data obtained from gas chromatographymass spectrometry (GC-MS)
Summary
The composition of an individual membrane lipid dramatically affects its impact on the membrane landscape. In the case of ether lipids, an alkenyl-ether group (plasmenyl (P)) replaces the ester bond at the sn-1 position These ether-linked lipids, called plasmalogens, can be found in a wide range of eukaryotic membranes and comprise nearly 20% of the human phospholipidome [1]. The immediate precursors of the plasmalogen population contain an alkyl-ether bond (plasmanyl (O)) and are detected in significant quantities in the phospholipidome as well [2]. The presence of these P- and O- bonds affects the biophysical properties of the entire phospholipid moiety, making assemblies of these lipids less fluid than ester-bonded counterparts, which may help to modulate responses to external stimuli including changes in temperature [3]
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