Biology subjects

Watschinger, K.

Publications and source records attributed to Watschinger, K..

5 recordsLinked to original sources

bioRxiv2026

Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia

Ether glycerophospholipids (ether lipids) are a subclass of glycerophospholipids that are synthesized at the peroxisome and constitute nearly 20% of the total phospholipid content in metazoans. Biochemically, ether lipids have an alkyl chain attached by an ether bond at the sn-1 position of the glycerol backbone (alkyl-ether) primarily containing choline or ethanolamine head groups. Some ether lipids contain a cis bond adjacent to the ether linkage (alkenyl-ether) and are commonly referred to as plasmalogens. While the importance of ether lipids in humans is clear, highlighted by the severity of inherited peroxisomal disorders caused by ether lipid deficiency, the molecular roles of these lipids remain poorly understood. Here, we identify a link between ether lipid metabolism, peroxisome degradation, and oxygen availability. We find Fatty acyl-CoA-reductase 1 (FAR1), the rate-limiting enzyme in peroxisomal ether lipid metabolism, acts as a peroxisome receptor necessary for peroxisome degradation when oxygen is limiting. Hypoxia increases choline ether lipid abundance, promotes autophagy activation, and peroxisome degradation. Mechanistically, FAR1 binds ATG8-family protein LC3B and is necessary and sufficient to control peroxisome degradation under hypoxia. FAR1s enzymatic function as well as its capacity to bind LC3B is necessary to degrade peroxisomes under hypoxia. Similarly, loss of multiple components of peroxisomal ether lipid metabolism blocks peroxisome degradation under hypoxia in cells and in vivo. In mouse models of chronic HIF activation, Far1 is a direct HIF target gene and is necessary for peroxisome degradation in this setting. Increasing ether lipids using ether lipid precursors activates autophagy and promotes autophagy-dependent cardioprotection against ischemic injury. This work reveals FAR1 as a critical regulator of peroxisome homeostasis in the setting of oxygen limitation.

cell biology↗

bioRxiv2026

Beyond the surface: plasmalogens are dispensable for retinal integrity and fertility in the mouse

Ether lipids and their subclass, the plasmalogens, are critical regulators of membrane organization, signaling, and stress responses in multiple tissues. Inborn errors in their anabolism cause severe multi-organ diseases such as Rhizomelic Chondrodysplasia Punctata and related peroxisomal disorders. The Gnpat knockout mouse model, characterized by total ether lipid deficiency, recapitulates key features of this disorder, including dense bilateral cataracts, microphthalmia, and infertility, but the specific contribution of different subclasses like plasmalogens remains elusive. The recent identification of the Peds1 gene allows dissecting the impact of selective plasmalogen deficiency with retention of plasmanyl lipids, another ether lipid subgroup. Here, we performed the first side-by-side comparison of Gnpat and Peds1 knockout in mice on a matched genetic background (C57BL/6 x CD1). In contrast to the situation in Gnpat knockout mice, plasmanyl lipids in Peds1 knockout mice were sufficient to prevent cataract formation and maintain normal ocular structures, despite marked shifts in the ocular phospholipidome. Also, fertility and reproductive function were found to be preserved in Peds1 knockout mice. Our data demonstrate that plasmanyl lipids can partially protect against the severe phenotypes observed in mouse models of total ether lipid deficiency; notably, the ocular and reproductive phenotypes were plasmalogen-independent, indicating that loss of the vinyl ether double bond is not the key determinant of all symptoms in human and murine ether lipid deficiency and can at least partly be compensated by plasmanyl lipids. HighlightsO_LIIn mice, total ether lipid deficiency causes cataracts and infertility. C_LIO_LIThe role of plasmalogens in these phenomena remains unclear. C_LIO_LITwo PEDS1-deficient patients were reported, but cataracts were observed in only one case. C_LIO_LIPeds1-deficient mice have no cataracts or ocular abnormalities. C_LIO_LIMice with a deletion of Peds1 display normal fertility rates. C_LI

biochemistry↗

bioRxiv2026

Plasmalogen metabolism shapes germinal center immunity

Plasmalogens are membrane lipids whose roles in immunity are emerging through identification of the PEDS1 gene and advances in lipid analytics. Because PEDS1 catalyses the final step of plasmalogen biosynthesis, Peds1 knockout models plasmalogen loss. Building on reports of a haematopoietic phenotype in Peds1-deficient mice, we performed extended profiling to characterise haematological and immune phenotypes. In line with these previous investigations, mice showed reduced red blood cell counts and haematocrit, with increased mean platelet volume. At steady state, plasmalogen deficiency was associated with reduced germinal centre (GC) B cell frequencies in mucosal lymphoid tissues and lower basal serum IgG1 levels. Following immunisation, GC B cell frequencies and ovalbumin-specific IgG1 were similar across genotypes, yet GC B cells exhibited elevated mitochondrial superoxide and plasma cells displayed increased lipid peroxidation. To test for B cell-intrinsic effects, we used an in vitro GC culture, where Peds1-deficient B cells showed reduced class switching to IgG1, intracellular IgG1 accumulation and diminished IgG1 secretion. Together, these findings support a role for plasmalogens and PEDS1 as a lipid-metabolic modulator of GC dynamics and IgG1 output, consistent with broader ether lipid perturbations. Plasmalogen metabolism may therefore offer a potential entry point to modulate humoral immunity or haematopoiesis.

immunology↗

bioRxiv2024

Trapped ion mobility spectrometry-guided molecular discrimination between plasmalogens and other ether lipids in lipidomics experiments

Trapped Ion Mobility Spectrometry (TIMS) has demonstrated promissing potential as a powerful discriminating method when coupled with mass spectrometry, enhancing the precision of feature annotation. Such a technique is particularly valuable for lipids, where a large number of isobaric but structurally distinct molecular species often coexist within the same sample matrix. In this study we explored the potential of ion mobility for ether lipid isomer differentiation. Mammalian ether phospholipids are characterized by a fatty alcohol residue at the sn-1 position of their glycerol backbone. Ether lipids can make up to 20% of the total phospholipid mass. They are present in a broad range of tissues where they are for example crucial for nervous system function, membrane homeostasis and inter-as well as intracellular signaling. Molecular ether lipid species are difficult to distinguish analytically, as they occur as 1-O-alkyl and 1-O-alkenyl subclasses, with the latter being also known as plasmalogens. Isomeric ether lipid pairs can be separated with reversed-phase chromatography. However, their precise identification remains challenging due to the lack of clear internal reference points, inherent to the nature of lipid profiles and the lack of sufficient commercially available standard substances. Here, we demonstrate - with focus on phosphatidylethanolamines - that ion mobility measurements allow to discriminate between the ether lipid subclasses through distinct differences in their gas phase geometries. This approach offers significant advantages as it does not depend on the variability of chromatography. However, the current resolution in the ion mobility dimension is not sufficient to baseline separate 1-O-alkyl and 1-O-alkenyl isobars, and the observed differences are not yet accurately represented in existing collision cross section databases. Despite these challenges, the predictable properties of the ion mobility behavior of ether lipid species can significantly support their accurate annotation and hold promise for future advancements in lipid research.

biochemistry↗

bioRxiv2020

Unequivocal mapping of molecular ether lipid species by LC-MS/MS in plasmalogen-deficient mice

Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms. In both humans and mice it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. The latter compounds, better known as plasmalogens, harbor a vinyl ether double bond conferring special chemical and physical properties. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species. Consequently, these lipids are often neglected also in recent lipidomic studies. Here we present a comprehensive LC-MS/MS based approach that allows unequivocal distinction of these two lipid subclasses based on their chromatographic properties. The method was validated using a novel plasmalogen-deficient mouse model which lacks plasmanylethanolamine desaturase and therefore cannot form plasmenyl ether lipids. We demonstrate that plasmanylethanolamine desaturase deficiency causes an accumulation of plasmanyl species, a little studied but biologically important substance class.

biochemistry↗