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Antioxidants & Redox Signaling Jun 2015A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both... (Review)
Review
SIGNIFICANCE
A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences.
CRITICAL ISSUES
IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo.
RECENT ADVANCES
The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells.
FUTURE DIRECTIONS
Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.
Topics: Amyloid; Animals; Blood-Brain Barrier; DNA-Binding Proteins; Fatty Acids, Unsaturated; Humans; Inflammation; Mitochondria; Oxidative Stress; Phosphatidylethanolamines; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Protein Binding; Pyrrolidines; Tubulin
PubMed: 25557218
DOI: 10.1089/ars.2014.6154 -
Proceedings of the National Academy of... Nov 2020The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)-...
The recently identified ferroptotic cell death is characterized by excessive accumulation of hydroperoxy-arachidonoyl (C20:4)- or adrenoyl (C22:4)- phosphatidylethanolamine (Hp-PE). The selenium-dependent glutathione peroxidase 4 (GPX4) inhibits ferroptosis, converting unstable ferroptotic lipid hydroperoxides to nontoxic lipid alcohols in a tissue-specific manner. While placental oxidative stress and lipotoxicity are hallmarks of placental dysfunction, the possible role of ferroptosis in placental dysfunction is largely unknown. We found that spontaneous preterm birth is associated with ferroptosis and that inhibition of GPX4 causes ferroptotic injury in primary human trophoblasts and during mouse pregnancy. Importantly, we uncovered a role for the phospholipase PLA2G6 (PNPLA9, iPLA2beta), known to metabolize Hp-PE to lyso-PE and oxidized fatty acid, in mitigating ferroptosis induced by GPX4 inhibition in vitro or by hypoxia/reoxygenation injury in vivo. Together, we identified ferroptosis signaling in the human and mouse placenta, established a role for PLA2G6 in attenuating trophoblastic ferroptosis, and provided mechanistic insights into the ill-defined placental lipotoxicity that may inspire PLA2G6-targeted therapeutic strategies.
Topics: Animals; Female; Ferroptosis; Glutathione Peroxidase; Group VI Phospholipases A2; Humans; Iron; Lipid Peroxides; Mice; Mice, Knockout; Phosphatidylethanolamines; Phospholipid Hydroperoxide Glutathione Peroxidase; Placenta; Pregnancy; Premature Birth; Signal Transduction; Trophoblasts
PubMed: 33087576
DOI: 10.1073/pnas.2009201117 -
Proceedings of the National Academy of... Oct 2022The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for...
The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.
Topics: Animals; Lysophosphatidylcholines; Lysophospholipids; Lysosomes; Membrane Proteins; Membrane Transport Proteins; Mice; Phosphatidylcholines; Phosphatidylethanolamines; Protons; Zebrafish; Zebrafish Proteins
PubMed: 36161949
DOI: 10.1073/pnas.2210353119 -
The Journal of Cell Biology Aug 2020Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL)... (Review)
Review
Mitochondria, so much more than just being energy factories, also have the capacity to synthesize macromolecules including phospholipids, particularly cardiolipin (CL) and phosphatidylethanolamine (PE). Phospholipids are vital constituents of mitochondrial membranes, impacting the plethora of functions performed by this organelle. Hence, the orchestrated movement of phospholipids to and from the mitochondrion is essential for cellular integrity. In this review, we capture recent advances in the field of mitochondrial phospholipid biosynthesis and trafficking, highlighting the significance of interorganellar communication, intramitochondrial contact sites, and lipid transfer proteins in maintaining membrane homeostasis. We then discuss the physiological functions of CL and PE, specifically how they associate with protein complexes in mitochondrial membranes to support bioenergetics and maintain mitochondrial architecture.
Topics: Animals; Biological Transport; Cardiolipins; Energy Metabolism; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Phosphatidylethanolamines; Phospholipids; Signal Transduction
PubMed: 32614384
DOI: 10.1083/jcb.202003131 -
Nature Communications Oct 2022The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells...
The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.
Topics: Animals; Fatty Acids; Fatty Acids, Monounsaturated; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Phosphatidylethanolamines
PubMed: 36241646
DOI: 10.1038/s41467-022-33735-6 -
International Journal of Molecular... May 2022Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the... (Review)
Review
Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this pathway are linked to a variety of human diseases, including cancer. Altered phosphatidylcholine and phosphatidylethanolamine membrane content, phospholipid metabolite levels, and fatty acid profiles are frequently identified as hallmarks of cancer development and progression. This review summarizes the research on how phospholipid metabolism changes over oncogenic transformation, and how phospholipid profiling can differentiate between human cancer and healthy tissues, with a focus on colorectal cancer, breast cancer, and non-small cell lung cancer. The potential for phospholipids to serve as biomarkers for diagnostics, or as anticancer therapy targets, is also discussed.
Topics: Carcinoma, Non-Small-Cell Lung; Fatty Acids; Humans; Lung Neoplasms; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids
PubMed: 35563655
DOI: 10.3390/ijms23095266 -
Biochimica Et Biophysica Acta.... Jun 2017A fundamental question in cell biology, under investigation for over six decades, is the structural organization of mitochondrial cristae. Long known to harbor electron... (Review)
Review
A fundamental question in cell biology, under investigation for over six decades, is the structural organization of mitochondrial cristae. Long known to harbor electron transport chain proteins, crista membrane integrity is key to establishment of the proton gradient that drives oxidative phosphorylation. Visualization of cristae morphology by electron microscopy/tomography has provided evidence that cristae are tube-like extensions of the mitochondrial inner membrane (IM) that project into the matrix space. Reconciling ultrastructural data with the lipid composition of the IM provides support for a continuously curved cylindrical bilayer capped by a dome-shaped tip. Strain imposed by the degree of curvature is relieved by an asymmetric distribution of phospholipids in monolayer leaflets that comprise cristae membranes. The signature mitochondrial lipid, cardiolipin (~18% of IM phospholipid mass), and phosphatidylethanolamine (34%) segregate to the negatively curved monolayer leaflet facing the crista lumen while the opposing, positively curved, matrix-facing monolayer leaflet contains predominantly phosphatidylcholine. Associated with cristae are numerous proteins that function in distinctive ways to establish and/or maintain their lipid repertoire and structural integrity. By combining unique lipid components with a set of protein modulators, crista membranes adopt and maintain their characteristic morphological and functional properties. Once established, cristae ultrastructure has a direct impact on oxidative phosphorylation, apoptosis, fusion/fission as well as diseases of compromised energy metabolism.
Topics: Acyltransferases; Blood Proteins; Cardiolipins; GTP Phosphohydrolases; Gene Expression Regulation; Humans; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Oxidative Phosphorylation; Phosphatidylcholines; Phosphatidylethanolamines; Prohibitins; Repressor Proteins; Transcription Factors
PubMed: 28336315
DOI: 10.1016/j.bbamem.2017.03.013 -
Antioxidants & Redox Signaling May 2022Professor Valerian Kagan (PhD, 1972, MV Lomonosov Moscow State University; DSci, 1981, USSR, Academy of Sciences, Moscow) is recognized as a Redox Pioneer because he has...
Professor Valerian Kagan (PhD, 1972, MV Lomonosov Moscow State University; DSci, 1981, USSR, Academy of Sciences, Moscow) is recognized as a Redox Pioneer because he has published 4 articles in the field of redox biology that have been cited >1000 times and 138 articles in this field have been cited between 100 and 924 times. The central and most important impact of Dr. Kagan's research is in the field of redox lipidomics-a term coined for the first time by Dr. Kagan in 2004-and consequently the definition of signaling pathways by oxidatively modified phospholipids; this acquires further significance considering that oxygenated phospholipids play multifunctional roles as essential signals coordinating metabolism and physiology. Some examples are the selective oxidation of cardiolipin (CL) by a cytochrome peroxidase activity leading to the activation of the intrinsic apoptotic pathway; the hydroperoxy-arachidonoyl/adrenoyl phosphatidylethanolamine (PE) species, driven by 15-lipoxygenases (15-LOX), as death signals leading to ferroptotic cell death; the regulation of ferroptosis by iNOS/NO in pro-inflammatory conditions by a novel mechanism (realized interactions of 15-LOX reaction intermediates formed from arachidonoyl phosphatidylethanolamine [PE] species) and Ca-independent phospholipase A2 (iPLAβ; elimination of peroxidized PE); the involvement of oxygenated (phospho)lipids in immunosuppression by myeloid cells in the tumor microenvironment; hydrolysis of peroxidized CL by Ca-independent phospholipase A2 (iPLAγ) leading to pro- and anti-inflammatory signals and lipid mediators. Kagan continues his investigations to decipher the roles of enzyme-linked oxygenated phospholipids. 36, 813-823.
Topics: Ferroptosis; Humans; Male; Oxidation-Reduction; Phosphatidylethanolamines; Phospholipids; Valerian
PubMed: 35072541
DOI: 10.1089/ars.2021.0079 -
ACS Chemical Biology Aug 2023-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form...
-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form -acyl-ethanolamines (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators ( and ) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in BMDM or after Nape-pld inhibition. Together, these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.
Topics: Mice; Humans; Animals; Phospholipase D; Phosphatidylethanolamines; Brain; Macrophages; Cardiovascular Diseases
PubMed: 37531659
DOI: 10.1021/acschembio.3c00401 -
Free Radical Biology & Medicine Jun 2016Glycation and glycoxidation of proteins and peptides have been intensively studied and are considered as reliable diagnostic biomarkers of hyperglycemia and early stages...
Glycation and glycoxidation of proteins and peptides have been intensively studied and are considered as reliable diagnostic biomarkers of hyperglycemia and early stages of type II diabetes. However, glucose can also react with primary amino groups present in other cellular components, such as aminophospholipids (aminoPLs). Although it is proposed that glycated aminoPLs can induce many cellular responses and contribute to the development and progression of diabetes, the routes of their formation and their biological roles are only partially revealed. The same is true for the influence of glucose-derived modifications on the biophysical properties of PLs. Here we studied structural, signaling, and biophysical properties of glycated and glycoxidized phosphatidylethanolamines (PEs). By combining high resolution mass spectrometry and nuclear magnetic resonance spectroscopy it was possible to deduce the structures of several intermediates indicating an oxidative cleavage of the Amadori product yielding glycoxidized PEs including advanced glycation end products, such as carboxyethyl- and carboxymethyl-ethanolamines. The pro-oxidative role of glycated PEs was demonstrated and further associated with several cellular responses including activation of NFκB signaling pathways. Label free proteomics indicated significant alterations in proteins regulating cellular metabolisms. Finally, the biophysical properties of PL membranes changed significantly upon PE glycation, such as melting temperature (Tm), membrane surface charge, and ion transport across the phospholipid bilayer.
Topics: Biophysical Phenomena; Diabetes Mellitus, Type 2; Glucose; Glycation End Products, Advanced; Glycosylation; Humans; Lipid Bilayers; Magnetic Resonance Spectroscopy; Oxidation-Reduction; Phosphatidylethanolamines; Proteomics
PubMed: 27012418
DOI: 10.1016/j.freeradbiomed.2016.03.011