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Nature Mar 2017Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of...
Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.
Topics: Animals; Breast Neoplasms; Carboxy-Lyases; Cell Differentiation; Cell Line, Tumor; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Lipid Metabolism; Membrane Proteins; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Mitochondrial Proteins; Phosphatidylethanolamines; Tumor Suppressor Proteins; beta-Lactamases
PubMed: 28329758
DOI: 10.1038/nature21408 -
Journal of Microbiology and... Jul 2022A white-pigmented, non-motile, gram-negative, and rod-shaped bacterium, designated CYS-02, was isolated from soil sampled at Suwon, Gyeonggi-do, Republic of Korea. Cells...
A white-pigmented, non-motile, gram-negative, and rod-shaped bacterium, designated CYS-02, was isolated from soil sampled at Suwon, Gyeonggi-do, Republic of Korea. Cells were strictly aerobic, grew optimally at 20-28ºC and hydrolyzed Tween 40. Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain CYS-02 formed a lineage within the family and clustered as members of the genus . The closest members were DSM 27352 (98.6% sequence similarity), NBRC 15149 (98.5%), and JM-310 (98.3%). The principal respiratory quinone was Q-8 and the major polar lipids contain phosphatidylethanolamine (PE), phosphatidylethanolamine (PG), and diphosphatidylglycerol (DPG). The predominant cellular fatty acids were C, summed feature 3 (C7c and/or C6c) and summed feature 8 (C7c and/or C6c). The DNA GC content was 67.7 mol%. The ANI and dDDH values between strain CYS-02 and the closest members in the genus were ≤ 79.0 and 22.4%, respectively, and the AAI and POCP values between CYS-02 and the other related species in the family were > 70% and > 50%, respectively. The genome of strain CYS-02 showed a putative terpene biosynthetic cluster responsible for antioxidant activity which was supported by DPPH radical scavenging activity test. Based on genomic, phenotypic and chemotaxonomic analyses, strain CYS-02 was classified into a novel species in the genus , for which the name sp. nov., has been proposed. The type strain is CYS-02 (= KACC 22656 = NBRC 115645 [corrected] ).
Topics: Antioxidants; Bacterial Typing Techniques; Comamonadaceae; DNA, Bacterial; Fatty Acids; Phosphatidylethanolamines; Phospholipids; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Soil; Soil Microbiology
PubMed: 35791077
DOI: 10.4014/jmb.2205.05018 -
Proceedings of the National Academy of... Jun 2020Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway...
Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.
Topics: Adult; Animals; Arachidonate 15-Lipoxygenase; Asthma; Autophagy; Bronchoalveolar Lavage Fluid; Cell Line; Cell Survival; Epithelial Cells; Female; Ferroptosis; Gene Knockout Techniques; Humans; Hydroxyeicosatetraenoic Acids; Interleukin-13; Male; Mice; Microtubule-Associated Proteins; Molecular Dynamics Simulation; Phosphatidylethanolamine Binding Protein; Phosphatidylethanolamines; Primary Cell Culture; Protein Binding; Severity of Illness Index
PubMed: 32513718
DOI: 10.1073/pnas.1921618117 -
FEBS Letters Apr 2018Mitochondrial structure and function are influenced by the unique phospholipid composition of its membranes. While mitochondria contain all the major classes of... (Review)
Review
Mitochondrial structure and function are influenced by the unique phospholipid composition of its membranes. While mitochondria contain all the major classes of phospholipids, recent studies have highlighted specific roles of the nonbilayer-forming phospholipids phosphatidylethanolamine (PE) and cardiolipin (CL) in the assembly and activity of mitochondrial respiratory chain (MRC) complexes. The nonbilayer phospholipids are cone-shaped molecules that introduce curvature stress in the bilayer membrane and have been shown to impact mitochondrial fusion and fission. In addition to their overlapping roles in these mitochondrial processes, each nonbilayer phospholipid also plays a unique role in mitochondrial function; for example, CL is specifically required for MRC supercomplex formation. Recent discoveries of mitochondrial PE- and CL-trafficking proteins and prior knowledge of their biosynthetic pathways have provided targets for precisely manipulating nonbilayer phospholipid levels in the mitochondrial membranes in vivo. Thus, the genetic mutants of these pathways could be valuable tools in illuminating molecular functions and biophysical properties of nonbilayer phospholipids in driving mitochondrial bioenergetics and dynamics.
Topics: Animals; Cardiolipins; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Mitochondria; Mitochondrial Proteins; Phosphatidylethanolamines; Protein Transport
PubMed: 29067684
DOI: 10.1002/1873-3468.12887 -
European Review For Medical and... Apr 2021The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to... (Review)
Review
OBJECTIVE
The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to discuss the role of nootropics, in particular, those with cholinergic activity, as promising interventions to preserve and/or improve cognitive performance in patients in the symptomatic pre-dementia stage, known as mild cognitive impairment (MCI).
MATERIALS AND METHODS
Papers were retrieved by a PubMed search, using different combinations of keywords (e.g., cognitive function AND aging AND nootropics), without limitations in terms of publication date or language.
RESULTS
Nootropics modulate the activities of specific brain pathways involving neurotransmitters and neuromodulators that have distinct roles in the cognitive processes. The nootropic L-a-glyceryl-phosphoryl-ethanolamine (L-a GPE), by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets neural stem cell aging, cholinergic depletion, oxidative stress and microglia activation, loss of entorhinal cortex neurons, and reduced hippocampal volume. Cognitive reserve levels may be linked to the resilience and adaptability of the brain to cope with age-related cognitive decline. L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
CONCLUSIONS
The substantial burden of age-related cognitive decline demands effective long-term and well-tolerated interventions aimed at maximizing the span of effective functioning. The use of inappropriate medication may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
Topics: Aging; Cognition; Cognitive Dysfunction; Humans; Nootropic Agents; Phosphatidylethanolamines
PubMed: 33877665
DOI: 10.26355/eurrev_202104_25555 -
Oxidative Medicine and Cellular... 2017Phosphatidylethanolamine (PE) is the second most abundant phospholipid in mammalian cells. PE comprises about 15-25% of the total lipid in mammalian cells; it is... (Review)
Review
Phosphatidylethanolamine (PE) is the second most abundant phospholipid in mammalian cells. PE comprises about 15-25% of the total lipid in mammalian cells; it is enriched in the inner leaflet of membranes, and it is especially abundant in the inner mitochondrial membrane. PE has quite remarkable activities: it is a lipid chaperone that assists in the folding of certain membrane proteins, it is required for the activity of several of the respiratory complexes, and it plays a key role in the initiation of autophagy. In this review, we focus on PE's roles in lipid-induced stress in the endoplasmic reticulum (ER), Parkinson's disease (PD), ferroptosis, and cancer.
Topics: Animals; Disease; Endoplasmic Reticulum Stress; Ethanolamine; Health; Humans; Models, Biological; Phosphatidylethanolamines
PubMed: 28785375
DOI: 10.1155/2017/4829180 -
Biochimica Et Biophysica Acta.... Apr 2017It was first discovered in 1992 that P-glycoprotein (Pgp, ABCB1), an ATP binding cassette (ABC) transporter, can transport phospholipids such as phosphatidylcholine,... (Review)
Review
It was first discovered in 1992 that P-glycoprotein (Pgp, ABCB1), an ATP binding cassette (ABC) transporter, can transport phospholipids such as phosphatidylcholine, -ethanolamine and -serine as well as glucosylceramide and glycosphingolipids. Subsequently, many other ABC transporters were identified to act as lipid transporters. For substrate transport by ABC transporters, typically a classic, alternating access model with an ATP-dependent conformational switch between a high and a low affinity substrate binding site is evoked. Transport of small hydrophilic substrates can easily be imagined this way, as the molecule can in principle enter and exit the transporter in the same orientation. Lipids on the other hand need to undergo a 180° degree turn as they translocate from one membrane leaflet to the other. Lipids and lipidated molecules are highly diverse, so there may be various ways how to achieve their flipping and flopping. Nonetheless, an increase in biophysical, biochemical and structural data is beginning to shed some light on specific aspects of lipid transport by ABC transporters. In addition, there is now abundant evidence that lipids affect ABC transporter conformation, dynamics as well as transport and ATPase activity in general. In this review, we will discuss different ways in which lipids and ABC transporters interact and how lipid translocation may be achieved with a focus on the techniques used to investigate these processes. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Topics: ATP Binding Cassette Transporter, Subfamily B; Binding Sites; Biological Transport; Fatty Acids; Gene Expression; Humans; Models, Molecular; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylserines; Protein Binding; Protein Isoforms; Substrate Specificity
PubMed: 27693344
DOI: 10.1016/j.bbamem.2016.09.023 -
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 -
Nature Communications Nov 2018Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative...
Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.
Topics: Anti-Bacterial Agents; Bacillus anthracis; Bacillus cereus; Caco-2 Cells; Carbohydrate Conformation; Cell Membrane; Cell Survival; Cell Wall; Glycosides; Humans; Kinetics; Lipid Bilayers; Microbial Sensitivity Tests; Microbial Viability; Phase Transition; Phosphatidylethanolamines; Structure-Activity Relationship
PubMed: 30451842
DOI: 10.1038/s41467-018-06488-4 -
The Journal of Cell Biology Mar 2022Glycosylphosphatidylinositol (GPI) is a glycolipid membrane anchor found on surface proteins in all eukaryotes. It is synthesized in the ER membrane. Each GPI anchor...
Glycosylphosphatidylinositol (GPI) is a glycolipid membrane anchor found on surface proteins in all eukaryotes. It is synthesized in the ER membrane. Each GPI anchor requires three molecules of ethanolamine phosphate (P-Etn), which are derived from phosphatidylethanolamine (PE). We found that efficient GPI anchor synthesis in Saccharomyces cerevisiae requires Csf1; cells lacking Csf1 accumulate GPI precursors lacking P-Etn. Structure predictions suggest Csf1 is a tube-forming lipid transport protein like Vps13. Csf1 is found at contact sites between the ER and other organelles. It interacts with the ER protein Mcd4, an enzyme that adds P-Etn to nascent GPI anchors, suggesting Csf1 channels PE to Mcd4 in the ER at contact sites to support GPI anchor biosynthesis. CSF1 has orthologues in Caenorhabditis elegans (lpd-3) and humans (KIAA1109/TWEEK); mutations in KIAA1109 cause the autosomal recessive neurodevelopmental disorder Alkuraya-Kučinskas syndrome. Knockout of lpd-3 and knockdown of KIAA1109 reduced GPI-anchored proteins on the surface of cells, suggesting Csf1 orthologues in human cells support GPI anchor biosynthesis.
Topics: Autophagy; Endoplasmic Reticulum; Glycosylphosphatidylinositols; Mitochondria; Phosphatidylethanolamines; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 35015055
DOI: 10.1083/jcb.202111095