Special Issue on Lipidomics.

Abstract

All organisms rely on membranes to provide boundaries to cells and subcellular structures. Although the composition and architecture of these membranes can be organism-specific, lipids constitute a significant portion of these membranes. Complementing this critical structural role, we now know that lipids are also crucial for many intercellular and intracellular events: they are involved in signaling survival and death; they participate in the formation of numerous pathologies; and they function to maintain cellular and organismal homeostasis. Lipids contribute to life in diverse and essential ways and many exciting roles of lipids in biological processes are yet to be discovered. The advancements in lipidomics have allowed the concurrent analysis of a large number of lipids from different classes at the molecular level in complex biological matrices (cellular and tissue extracts, etc.). Furthermore, it has recently become feasible to assign alterations specific to particular lipid species within lipid categories in a high-throughput manner. This special issue will explore these recent applications of lipidomics, especially with a focus on how structural specificity of lipids affects their function in different biological processes and phenotypes. Within this broader context, this issue features scientists who apply state-of-the-art lipidomics approaches to biological questions at chemical, cellular, and organismal levels. One factor that defines lipid diversity in mammalian cells is the length and the unsaturation of fatty acyl chains. Although fundamental physicochemical differences between lipids are intuitive, the understanding of the biochemical regulation and maintenance of individual lipid species in the cellular environment is still difficult. More difficult is the delineation of the cellular function of individual lipid species. Jose Bocelli and Richard Epand (McMaster University) touch on these general difficulties in their review of the mechanisms by which cells enrich certain phosphatidylinositol species and maintain them at required levels. They then turn our attention to the need for the development of techniques that will provide high spatio-temporal information to make inferences between lipid structure and cellular function. The unsaturation state of lipids determines the transformations that they can undergo in the cell. This process is critical at the molecular and cellular level, because polyunsaturated fatty acyl-containing lipids can easily form toxic lipid hydroperoxides. Giovanni Forcina and Scott Dixon (Stanford University) describe the mechanism of formation of reactive lipid species due to the oxidation of polyunsaturated fatty acids and cholesterol in the context of ferroptosis, an iron-dependent form of regulated cell death. Building upon these fundamentals, the authors also discuss the key roles of glutathione peroxidase 4 as the guardian against lipid hydroperoxides both at the cellular and the organismal level. Work from my group (University at Buffalo) also keeps the focus on the regulation of specific polyunsaturated lipids under cell stress. In particular, we focus on the accumulation of polyunsaturated triacylglycerols during apoptosis. By integrating high resolution mass spectrometry with transcriptomics, we describe a key player that contributes to these accumulations, p38 mitogen-activated protein kinase, defining a new pathway of lipid regulation during apoptosis.1, 2 Lipidomics can be powerful when complemented with perturbation-based approaches in order to obtain mechanistic insights on lipid- and membrane-related phenotypes at the cellular level. Two commonly used perturbation approaches are RNAinterference (RNAi) to inactivate biochemical pathways and the use of lipid-deprived growth conditions in cultured cells. Ulrike Eggert and co-workers (King's College) provide insights on the changes in lipid composition when mammalian cells are exposed to two different types of RNAi transfection reagents highlighting the unexpected lipid changes induced by these transfection reagents. The authors discuss potential venues for validation, for instance including other perturbation approaches that are orthogonal to RNAi, especially when studying lipids and membranes.1, 3 Jonna Frasor (University of Illinois at Chicago) and co-workers analyze the lipid composition of charcoal-dextran and silica treatment serum, commonly used as lipid-deprived serum in the literature. They show that these lipid workups result in different lipid profiles. The authors also study the survival of cultured cells in different types of sera and demonstrate that cultured cells are sensitive to serum types which is underappreciated when interpreting phenotypes observed in the presence of different sera. At the organismal level, individual reports lead by Maureen Kane (University of Maryland) and Stephanie Cologna (University of Illinois at Chicago) use state-of-the-art lipidomic approaches to shed light into the changes in lipid composition in animal models of traumatic brain injury and Nieman Pick Disease. Kane and co-workers describe a state-of-the art ion mobility mass detection workflow to elucidate different ether-linked glycerophosphoethanolamine lipids from mouse cortical lysosomes and use this method to study the lipid composition of a traumatic brain injury model. The authors show that these ether-linked lipids are abundant in specific organelles, as such, may be indicative of organelle-specific damage, paving the way to future mechanistic investigations on the functioning of these lipids in traumatic brain injury. Cologna and co-workers provide a comparative lipidomics of Npc1-/- mice, a model to study Niemann-Pick Disease. The authors describe the significant differences in the lipidome of Npc1-/- mice, especially in polyunsaturated ω-3 and ω-6 fatty acids. Combining these observations at the lipid level with biochemical investigations at the protein level, they provide new insights on disease physiology and suggest altered fatty acid levels as a potential marker for disease monitoring. As represented by these studies, over the past couple decades, lipidomics has expanded rapidly yielding to several important discoveries. This is especially the case for measurements done at an ensemble of entities analyzed (i.e., ensemble of cells from cell culture, ensamples of cells from different tissues). Two key insights that we learned from these studies are how complex the biochemical regulation of lipid diversity is, and how much heterogeneity we observe in these ensamples. Thus, much exciting work remains: How are different lipids regulated at the molecular level? How are they transported within cells and how does structural specificity affect their transport? How can we explore the lipid heterogeneity of samples? And, ultimately, how do these factors contribute to organismal homeostasis?