MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling

Ferroptosis is an iron-dependent form of cell death driven by biochemical processes that promote oxidation within the lipid compartment. Calcium (Ca2+) is a signaling molecule in diverse cellular processes such as migration, neurotransmission, and cell death. Here, we uncover a crucial link between ferroptosis and Ca2+ through the identification of the novel tetraspanin MS4A15. MS4A15 localizes to the endoplasmic reticulum, where it blocks ferroptosis by depleting luminal Ca2+ stores and reprogramming membrane phospholipids to ferroptosis-resistant species. Specifically, prolonged Ca2+ depletion inhibits lipid elongation and desaturation, driving lipid droplet dispersion and formation of shorter, more saturated ether lipids that protect phospholipids from ferroptotic reactive species. We further demonstrate that increasing luminal Ca2+ levels can preferentially sensitize refractory cancer cell lines. In summary, MS4A15 regulation of anti-ferroptotic lipid reservoirs provides a key resistance mechanism that is distinct from antioxidant and lipid detoxification pathways. Manipulating Ca2+ homeostasis offers a compelling strategy to balance cellular lipids and cell survival in ferroptosis-associated diseases.

Mass Spectrometry and Computer Simulation Predict the Interactions of AGPS and HNRNPK in Glioma

Ether lipids are overexpressed in malignant tumor and play an important role in tumor process. Glioma is the most common malignant central nervous system tumor, and the content of ether lipids is higher than that of normal tissues. Alkylglycerone phosphate synthase (AGPS) is a key enzyme in the synthesis of ether esters and plays a vital role in maintaining the morphology and pathogenic properties of tumor cells. The cell proliferation and the content of tumor-related lipid such as monoalkylglycerol ether (MAGe), lysophosphatidic acid ether (LPAe), lysophosphatidylcholine ether (LPCe), lysophosphatidylethanolamine ether (LPEe), phosphatidyl inositol (PI), phosphatidylcholine (PC), and phosphatidylserine (PS) were suppressed after AGPS silencing in U251, H4, and TJ905 cells; however, heterogeneous nuclear ribonucleoprotein K (HNRNPK) could reverse the above phenomenon such as cellar proliferation and ether lipid secretion. We found that HNRNPK was the target protein of AGPS by coimmunoprecipitation and mass spectrometry assay and verified by western blot assay in U251 cells. It confirmed that AGPS and HNRNPK are coexpressed in the cellular nucleus by a confocal laser microscope. The main protein-protein interaction mechanism between AGPS and HNRNPK is hydrogen bond, conjugation bond, hydrophobic bond, and electrostatic force by computer simulation prediction.

Planktonic Archaeal Ether Lipid Origins in Surface Waters of the North Pacific Subtropical Gyre

Thaumarchaeota and Thermoplasmatota are the most abundant planktonic archaea in the sea. Thaumarchaeota contain tetraether lipids as their major membrane lipids, but the lipid composition of uncultured planktonic Thermoplasmatota representatives remains unknown. To address this knowledge gap, we quantified archaeal cells and ether lipids in open ocean depth profiles (0–200 m) of the North Pacific Subtropical Gyre. Planktonic archaeal community structure and ether lipid composition in the water column partitioned into two separate clusters: one above the deep chlorophyll maximum, the other within and below it. In surface waters, Thermoplasmatota densities ranged from 2.11 × 106 to 6.02 × 106 cells/L, while Thaumarchaeota were undetectable. As previously reported for Thaumarchaeota, potential homologs of archaeal tetraether ring synthases were present in planktonic Thermoplasmatota metagenomes. Despite the absence of Thaumarchaeota in surface waters, measurable amounts of intact polar ether lipids were found there. Based on cell abundance estimates, these surface water archaeal ether lipids contributed only 1.21 × 10–9 ng lipid/Thermoplasmatota cell, about three orders of magnitude less than that reported for Thaumarchaeota cells. While these data indicate that even if some tetraether and diether lipids may be derived from Thermoplasmatota, they would only comprise a small fraction of Thermoplasmatota total biomass. Therefore, while both MGI Thaumarchaeota and MGII/III Thermoplasmatota are potential biological sources of archaeal GDGTs, the Thaumarchaeota appear to be the major contributors of archaeal tetraether lipids in planktonic marine habitats. These results extend and confirm previous reports of planktonic archaeal lipid sources, and further emphasize the need for Thermoplasmatota cultivation, to better characterize the membrane lipid constituents of marine planktonic Thermoplasmatota, and more precisely define the sources and patterns of archaeal tetraether lipid distributions in marine plankton.

A lipid droplet-peroxisome network drives longevity by monounsaturated fatty acids via modulating ether lipid synthesis and ferroptosis

Dietary mono-unsaturated fatty acids (MUFAs) are linked to human longevity and extend lifespan in several species1-12. But the mechanisms by which MUFAs promote longevity remain unclear. Here we show that an organelle hub involving lipid droplets and peroxisomes is critical for lifespan extension by MUFAs in C. elegans. MUFA accumulation increases lipid droplet number in fat storage tissues, and lipid droplet synthesis is necessary for MUFA-mediated longevity. Interestingly, the number of lipid droplets in young individuals can predict their remaining lifespan. MUFA accumulation also increases the number of peroxisomes, and peroxisome activity is required for MUFA-mediated longevity. By performing a targeted screen, we uncover a functional network between lipid droplets and peroxisomes in longevity. Interestingly, our screen also identifies ether lipids as critical components of the lipid droplet-peroxisome network. Using lipidomics, we find that the ratio of MUFAs to polyunsaturated fatty acids (PUFAs) in ether lipids is increased by MUFA accumulation. Ether lipids are involved in ferroptosis, a non-apoptotic form of cell death13-17, and MUFAs promote longevity in part via suppression of ferroptosis. Our results identify a mechanism of action for MUFAs to extend lifespan and uncover an organelle network involved in the homeostasis of MUFA-rich ether lipids. Our work also opens new avenues for lipid-based interventions to delay aging.

ARCHAEOSOMES: REVOLUTIONARY TECHNIQUE FOR BOTH CELL-BASED AND DRUG-BASED DELIVERY APPLICATIONS

Archaeosomes, or liposomes formed with one or more ether lipids specific to the Archaeobacteria domain, are a new kind of liposome discovered in Archaea. Archaeol (diether) and/or caldarchaeol (tetraether) are the basic structures of Achaean-type lipids. Archaeosomes may be made using conventional methods (hydrated film sonicated, extrusion, and detergent dialysis) at any temperature in the physiological range or below, allowing thermally stable chemicals to be encapsulated. Its stability is influenced by a variety of physiological and environmental variables. For cancer vaccines, Chagas disease, proteins and peptides, gene delivery, antigen delivery, and delivery of natural antioxidant chemicals, archaeosomes are extensively utilized as drug delivery systems. The main goal of this review paper was to look at the uses of this novel carrier system in the pharmaceutical sector.

Diverse arsenic-containing lipids in the surface ocean

Arsenic is present at nanomolar levels throughout the surface ocean, and microbes assimilate this toxic element due to its similarity to inorganic phosphorus. Although the concentration and characterization of dissolved arsenic has been a focus of ocean studies, the size of the particulate arsenic pool and its partitioning into organic molecules within the microbial community is not known. We measured the particulate pool of arsenic in five surface samples from the open ocean and determined the contribution of arsenic-containing lipids to this pool. Here we show that the accumulation of arsenic into lipids is a widespread phenomenon in the surface ocean. Particulate arsenic concentrations were 15 to 42 pmol/L with 7-20% of the particulate arsenic pool in the form of arsenolipids. We characterized these arsenolipids and found that arsenosugar phospholipids dominated the arsenolipid pools in our samples with a minor component of arsenohydrocarbons and other unidentified lipids. A significant portion of the arsenosugar phospholipids (up to 35%) were present as previously undescribed mixed acyl ether lipids, suggesting a bacterial source.

Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis

It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.