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Molecular Cell Jun 2022Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer,... (Review)
Review
Ferroptosis, a newly emerged form of regulated necrotic cell death, has been demonstrated to play an important role in multiple diseases including cancer, neurodegeneration, and ischemic organ injury. Mounting evidence also suggests its potential physiological function in tumor suppression and immunity. The execution of ferroptosis is driven by iron-dependent phospholipid peroxidation. As such, the metabolism of biological lipids regulates ferroptosis via controlling phospholipid peroxidation, as well as various other cellular processes relevant to phospholipid peroxidation. In this review, we provide a comprehensive analysis by focusing on how lipid metabolism impacts the initiation, propagation, and termination of phospholipid peroxidation; how multiple signal transduction pathways communicate with ferroptosis via modulating lipid metabolism; and how such intimate cross talk of ferroptosis with lipid metabolism and related signaling pathways can be exploited for the development of rational therapeutic strategies.
Topics: Ferroptosis; Iron; Lipid Metabolism; Lipid Peroxidation; Phospholipids
PubMed: 35390277
DOI: 10.1016/j.molcel.2022.03.022 -
Traffic (Copenhagen, Denmark) Jan 2015Membranes of mammalian subcellular organelles contain defined amounts of specific phospholipids that are required for normal functioning of proteins in the membrane.... (Review)
Review
Membranes of mammalian subcellular organelles contain defined amounts of specific phospholipids that are required for normal functioning of proteins in the membrane. Despite the wide distribution of most phospholipid classes throughout organelle membranes, the site of synthesis of each phospholipid class is usually restricted to one organelle, commonly the endoplasmic reticulum (ER). Thus, phospholipids must be transported from their sites of synthesis to the membranes of other organelles. In this article, pathways and subcellular sites of phospholipid synthesis in mammalian cells are summarized. A single, unifying mechanism does not explain the inter-organelle transport of all phospholipids. Thus, mechanisms of phospholipid transport between organelles of mammalian cells via spontaneous membrane diffusion, via cytosolic phospholipid transfer proteins, via vesicles and via membrane contact sites are discussed. As an example of the latter mechanism, phosphatidylserine (PS) is synthesized on a region of the ER (mitochondria-associated membranes, MAM) and decarboxylated to phosphatidylethanolamine in mitochondria. Some evidence is presented suggesting that PS import into mitochondria occurs via membrane contact sites between MAM and mitochondria. Recent studies suggest that protein complexes can form tethers that link two types of organelles thereby promoting lipid transfer. However, many questions remain about mechanisms of inter-organelle phospholipid transport in mammalian cells.
Topics: Animals; Biological Transport; Endoplasmic Reticulum; Humans; Mitochondria; Mitochondrial Membranes; Phosphatidylethanolamines; Phospholipids
PubMed: 25243850
DOI: 10.1111/tra.12230 -
ASN Neuro 2022Microglia play an important role in maintaining central nervous system homeostasis and are the major immune cells in the brain. In response to internal or external... (Review)
Review
Microglia play an important role in maintaining central nervous system homeostasis and are the major immune cells in the brain. In response to internal or external inflammatory stimuli, microglia are activated and release numerous inflammatory factors, thus leading to neuroinflammation. Inflammation and microglia iron accumulation promote each other and jointly promote the progression of neuroinflammation. Inhibiting microglia iron accumulation prevents neuroinflammation. Ferroptosis is an iron-dependent phospholipid peroxidation-driven type of cell death regulation. Cell iron accumulation causes the peroxidation of cell membrane phospholipids and damages the cell membrane. Ultimately, this process leads to cell ferroptosis. Iron accumulation or phospholipid peroxidation in microglia releases a large number of inflammatory factors. Thus, inhibiting microglia ferroptosis may be a new target for the prevention and treatment of neuroinflammation.
Topics: Humans; Microglia; Ferroptosis; Neuroinflammatory Diseases; Iron; Phospholipids; Lipid Peroxidation
PubMed: 36285433
DOI: 10.1177/17590914221133236 -
Journal of Cell Science Mar 2022Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling...
Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.
Topics: Animals; Lipid Droplets; Lipid Metabolism; Mammals; Perilipins; Phospholipids; Protein Binding; Proteome
PubMed: 35260890
DOI: 10.1242/jcs.259501 -
The Journal of Physical Chemistry. B Mar 2022Lipid droplets (LDs) are intracellular organelles whose primary function is energy storage. Known to emerge from the endoplasmic reticulum (ER) bilayer, LDs have a... (Review)
Review
Lipid droplets (LDs) are intracellular organelles whose primary function is energy storage. Known to emerge from the endoplasmic reticulum (ER) bilayer, LDs have a unique structure with a core consisting of neutral lipids, triacylglycerol (TG) or sterol esters (SE), surrounded by a phospholipid (PL) monolayer and decorated by proteins that come and go throughout their complex lifecycle. In this Feature Article, we review recent developments in computational studies of LDs, a rapidly growing area of research. We highlight how molecular dynamics (MD) simulations have provided valuable molecular-level insight into LD targeting and LD biogenesis. Additionally, we review the physical properties of TG from different force fields compared with experimental data. Possible future directions and challenges are discussed.
Topics: Endoplasmic Reticulum; Lipid Droplets; Lipid Metabolism; Molecular Dynamics Simulation; Phospholipids; Triglycerides
PubMed: 35263109
DOI: 10.1021/acs.jpcb.2c00292 -
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 -
FEBS Letters Apr 2013Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as... (Review)
Review
Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.
Topics: Gene Expression Regulation; Humans; Models, Genetic; Models, Molecular; Molecular Structure; Phospholipids; Protein Binding; Protein Structure, Tertiary; Signal Transduction; Transcription Factors
PubMed: 23333623
DOI: 10.1016/j.febslet.2013.01.004 -
Biochimica Et Biophysica Acta.... Jan 2020The turnover of phospholipids plays an essential role in membrane lipid homeostasis by impacting both lipid head group and acyl chain composition. This review focusses... (Review)
Review
The turnover of phospholipids plays an essential role in membrane lipid homeostasis by impacting both lipid head group and acyl chain composition. This review focusses on the degradation and acyl chain remodeling of the major phospholipid classes present in the ER membrane of the reference eukaryote Saccharomyces cerevisiae, i.e. phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidylethanolamine (PE). Phospholipid turnover reactions are introduced, and the occurrence and important functions of phospholipid remodeling in higher eukaryotes are briefly summarized. After presenting an inventory of established mechanisms of phospholipid acyl chain exchange, current knowledge of phospholipid degradation and remodeling by phospholipases and acyltransferases localized to the yeast ER is summarized. PC is subject to the PC deacylation-reacylation remodeling pathway (PC-DRP) involving a phospholipase B, the recently identified glycerophosphocholine acyltransferase Gpc1p, and the broad specificity acyltransferase Ale1p. PI is post-synthetically enriched in C18:0 acyl chains by remodeling reactions involving Cst26p. PE may undergo turnover by the phospholipid: diacylglycerol acyltransferase Lro1p as first step in acyl chain remodeling. Clues as to the functions of phospholipid acyl chain remodeling are discussed.
Topics: Acylation; Animals; Endoplasmic Reticulum; Humans; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylinositols; Phospholipids; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 31146038
DOI: 10.1016/j.bbalip.2019.05.006 -
Trends in Plant Science Apr 2021In plants, defense-associated signal transduction involves key membrane-related processes, such as phospholipid-based signaling and membrane trafficking. Coordination of... (Review)
Review
In plants, defense-associated signal transduction involves key membrane-related processes, such as phospholipid-based signaling and membrane trafficking. Coordination of these processes occurs in the lipid bilayer of plasma membrane (PM) and luminal/extracellular membranes. Deciphering the spatiotemporal organization of phospholipids and lipid-protein interactions provides crucial information on the mechanisms that link phospholipid-based signaling and membrane trafficking in plant immunity. In this review, we summarize recent advances in our understanding of these connections, including deployment of key enzymes and molecules in phospholipid pathways, and roles of lipid diversity in membrane trafficking. We highlight the mechanisms that mediate feedback between phospholipid-based signaling and membrane trafficking to regulate plant immunity, including their novel roles in balancing endocytosis and exocytosis.
Topics: Cell Membrane; Endocytosis; Phospholipids; Plant Immunity; Protein Transport; Signal Transduction
PubMed: 33309101
DOI: 10.1016/j.tplants.2020.11.010 -
Journal of Cell Science Mar 2022Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we...
Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we are just starting to understand the molecular components that drive lipophagy, how it is activated in response to nutrient availability, and its potential as a therapeutic target in disease. In this Cell Science at a Glance article and the accompanying poster, we first provide a brief overview of the different structural and enzymatic proteins that comprise the lipid droplet (LD) proteome and reside within the limiting phospholipid monolayer of this complex organelle. We then highlight key players in the catabolic breakdown of LDs during the functionally linked lipolysis and lipophagy processes. Finally, we discuss what is currently known about macro- and micro-lipophagy based on findings in yeast, mammalian and other model systems, and how impairment of these important functions can lead to disease states.
Topics: Animals; Autophagy; Lipid Droplets; Lipid Metabolism; Lipolysis; Mammals; Phospholipids; Proteins; Saccharomyces cerevisiae
PubMed: 35260889
DOI: 10.1242/jcs.259402