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Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma.Cancer Research Jan 2023The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore,...
UNLABELLED
The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.
SIGNIFICANCE
Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth. See related commentary by Byrne and Bell, p.167.
Topics: Animals; Mice; beta Catenin; Cell Differentiation; Cell Line, Tumor; Epigenome; Ethanolamine; Ethanolamines; Hypoxia; Neuroblastoma; Niclosamide; Warburg Effect, Oncologic; Mitochondria
PubMed: 36318118
DOI: 10.1158/0008-5472.CAN-22-1029 -
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 -
MBio Feb 2018Ethanolamine (EA) is a valuable source of carbon and/or nitrogen for bacteria capable of its catabolism. Because it is derived from the membrane phospholipid... (Review)
Review
Ethanolamine (EA) is a valuable source of carbon and/or nitrogen for bacteria capable of its catabolism. Because it is derived from the membrane phospholipid phosphatidylethanolamine, it is particularly prevalent in the gastrointestinal tract, which is membrane rich due to turnover of the intestinal epithelium and the resident microbiota. Intriguingly, many gut pathogens carry the (ethanolamine utilization) genes. EA utilization has been studied for about 50 years, with most of the early work occurring in just a couple of species of Once the metabolic pathways and enzymes were characterized by biochemical approaches, genetic screens were used to map the various activities to the genes. With the rise of genomics, the diversity of bacteria containing the genes and surprising differences in gene content were recognized. Some species contain nearly 20 genes and encode many accessory proteins, while others contain only the core catabolic enzyme. Moreover, the genes are regulated by very different mechanisms, depending on the organism and the regulator encoded. In the last several years, exciting progress has been made in elucidating the complex regulatory mechanisms that govern gene expression. Furthermore, a new appreciation for how EA contributes to infection and colonization in the host is emerging. In addition to providing an overview of EA-related biology, this minireview will give special attention to these recent advances.
Topics: Animals; Carbon; Enterobacteriaceae; Enterobacteriaceae Infections; Ethanolamine; Gastrointestinal Tract; Gene Expression Regulation, Bacterial; Humans; Metabolic Networks and Pathways; Nitrogen
PubMed: 29463652
DOI: 10.1128/mBio.00066-18 -
Current Opinion in Microbiology Oct 2021Catabolic bacterial microcompartments (BMC), or metabolosomes, are self-assembling structures formed by enzymes enclosed by porous protein shells. They provide a... (Review)
Review
Catabolic bacterial microcompartments (BMC), or metabolosomes, are self-assembling structures formed by enzymes enclosed by porous protein shells. They provide a specialised environment inside bacterial cells separating a short catabolic pathway with reactive or toxic intermediates from the cytoplasm. Substrates for microcompartment metabolism like ethanolamine and 1,2-propanediol are constantly produced in the human intestine by bacterial metabolism of food or host cell components. Enteric pathogens gain a competitive advantage in the intestine by metabolising these substrates, an advantage enhanced by the host inflammatory response. They exploit the intestinal specificity of signature metabolosome substrates by adopting substrate sensors and regulators encoded by BMC operons for governance of non-metabolic processes in pathogenesis. In turn, products of microcompartment metabolism regulate the host immune system.
Topics: Bacteria; Bacterial Proteins; Ethanolamine; Humans; Propylene Glycol; Virulence
PubMed: 34107380
DOI: 10.1016/j.mib.2021.05.009 -
Biomolecules Aug 2022Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological... (Review)
Review
Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.
Topics: Amides; Analgesics; Anti-Inflammatory Agents; Ethanolamines; Palmitic Acid; Palmitic Acids; White Matter
PubMed: 36139030
DOI: 10.3390/biom12091191 -
Chemistry and Physics of Lipids Mar 2019There is considerable interest in the development of membrane mimetics to study the structure, dynamics and function of membrane proteins. Polymer nanodiscs have been... (Review)
Review
There is considerable interest in the development of membrane mimetics to study the structure, dynamics and function of membrane proteins. Polymer nanodiscs have been useful as a membrane mimetic by not only providing a native-like membrane environment, but also have the ability to extract the desired membrane protein directly from the cell membrane. In spite of such great potential, polymer nanodiscs have their disadvantages including lack of size control and instability at low pH and with divalent metals. In this review, we discuss how these limitations have been overcome by simple modifications of synthetic polymers commonly used to form nanodiscs. Recently, size control has been achieved using an ethanolamine functionalization of a low molecular weight polymer. This size control enabled the use of polymer-based lipid-nanodiscs in solution NMR and macro-nanodiscs in solid-state NMR applications. The introduction of quaternary ammonium functional groups has been shown to improve the stability in the presence of low pH and divalent metal ions, forming highly monodispersed nanodiscs. The polymer charge has been shown to play a significant role on the reconstitution of membrane proteins due to the high charge density on the nanodisc's belt. These recent developments have expanded the applications of polymer nanodiscs to study the membrane proteins using wide variety of techniques including NMR, Cryo-EM and other biophysical techniques.
Topics: Ethanolamine; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Membrane Proteins; Nanostructures; Polymers; Polystyrenes
PubMed: 30707909
DOI: 10.1016/j.chemphyslip.2019.01.010 -
Nature Reviews. Microbiology Apr 2010Ethanolamine is a compound that can be readily derived from cell membranes and that some bacteria can use as a source of carbon and/or nitrogen. The complex biology and... (Review)
Review
Ethanolamine is a compound that can be readily derived from cell membranes and that some bacteria can use as a source of carbon and/or nitrogen. The complex biology and chemistry of this process has been under investigation since the 1970s, primarily in one or two species. However, recent investigations into ethanolamine utilization have revealed important and intriguing differences in gene content and regulatory mechanisms among the bacteria that harbour this catabolic ability. In addition, many reports have connected this process to bacterial pathogenesis. In this Progress article, I discuss the latest research on the phylogeny and regulation of ethanolamine utilization and its possible roles in bacterial pathogenesis.
Topics: Bacteria; Cell Membrane; Ethanolamine; Gene Expression Regulation, Bacterial; Genes, Bacterial
PubMed: 20234377
DOI: 10.1038/nrmicro2334 -
MBio Aug 2022Acinetobacter baumannii is an opportunistic pathogen typically associated with hospital-acquired infections. Our understanding of the metabolism and physiology of A....
Acinetobacter baumannii is an opportunistic pathogen typically associated with hospital-acquired infections. Our understanding of the metabolism and physiology of A. baumannii is limited. Here, we report that A. baumannii uses ethanolamine (EA) as the sole source of nitrogen and can use this aminoalcohol as a source of carbon and energy if the expression of the genes encoding ethanolamine ammonia-lyase (EAL) is increased. A strain with an IS element upstream of the genes efficiently used EA as a carbon and energy source. The A. baumannii EAL (EAL) enzyme supported the growth of a strain of Salmonella lacking the entire operon. Remarkably, the growth of the above-mentioned Salmonella strain did not require the metabolosome, the reactivase EutA enzyme, the EutE acetaldehyde dehydrogenase, or the addition of glutathione to the medium. Transmission electron micrographs showed that when Acinetobacter baumannii or Salmonella enterica subsp. serovar Typhimurium strain LT2 synthesized EAL, the protein localized to the cell membrane. We also report that the A. baumannii genome encodes all of the enzymes needed for the assembly of the nucleotide loop of cobamides and that it uses these enzymes to synthesize different cobamides from the precursor cobinamide and several nucleobases. In the absence of exogenous nucleobases, the most abundant cobamide produced by A. baumannii was cobalamin. Acinetobacter baumannii is a Gram-negative bacterium commonly found in soil and water. A. baumannii is an opportunistic human pathogen, considered by the CDC to be a serious threat to human health due to the multidrug resistance commonly associated with this bacterium. Knowledge of the metabolic capabilities of A. baumannii is limited. The importance of the work reported here lies in the identification of ethanolamine catabolism occurring in the absence of a metabolosome structure. In other bacteria, this structure protects the cell against damage by acetaldehyde generated by the deamination of ethanolamine. In addition, the ethanolamine ammonia-lyase (EAL) enzyme of this bacterium is unique in that it does not require a reactivase enzyme to remain active. Importantly, we also demonstrate that the A. baumannii genome encodes the functions needed to assemble adenosylcobamide, the coenzyme of EAL, from the precursor cobinamide.
Topics: Acinetobacter baumannii; Carbon; Cobamides; Ethanolamine; Ethanolamine Ammonia-Lyase; Ethanolamines; Humans; Salmonella typhimurium
PubMed: 35880884
DOI: 10.1128/mbio.01793-22 -
Journal of Lipid Research Aug 2020The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in...
The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in the transfer of ethanolamine phosphate from CDP-ethanolamine to lipid acceptors such as 1,2-diacylglycerol (DAG) for PE production and 1-alkyl-2-acyl-glycerol (AAG) for the generation of 1-alkyl-2-acyl-glycerophosphoethanolamine. Here, we investigated the intracellular location and contribution to ethanolamine phospholipid (EP) biosynthesis of EPT1 and CEPT1 in HEK293 cells. Immunohistochemical analyses revealed that EPT1 localizes to the Golgi apparatus and CEPT1 to the ER. We created EPT1-, CEPT1-, and EPTI-CEPT1-deficient cells, and labeling of these cells with radio- or deuterium-labeled ethanolamine disclosed that EPT1 is more important for the de novo biosynthesis of 1-alkenyl-2-acyl-glycerophosphoethanolamine than is CEPT1. EPT1 also contributed to the synthesis of PE species containing the fatty acids 36:1, 36:4, 38:5, 38:4, 38:3, 40:6, 40:5, and 40:4. In contrast, CEPT1 was important for PE formation from shorter fatty acids such as 32:2, 32:1, 34:2, and 34:1. Brefeldin A treatment did not significantly affect the levels of the different PE species, indicating that the subcellular localization of the two enzymes is not responsible for their substrate preferences. In vitro enzymatic analysis revealed that EPT1 prefers AAG 16-20:4 > DAG 18:0-20:4 > DAG 16:0-18:1 = AAG 16-18:1 as lipid acceptors and that CEPT1 greatly prefers DAG 16:0-18:1 to other acceptors. These results suggest that EPT1 and CEPT1 differ in organelle location and are responsible for the biosynthesis of distinct EP species.
Topics: Ethanolamine; Ethanolaminephosphotransferase; HEK293 Cells; Humans; Intracellular Space; Phospholipids; Protein Transport
PubMed: 32576654
DOI: 10.1194/jlr.RA120000898 -
The Journal of Biological Chemistry 2021The membrane phospholipids phosphatidylcholine and phosphatidylethanolamine (PE) are synthesized de novo by the CDP-choline and CDP-ethanolamine (Kennedy) pathway, in...
The membrane phospholipids phosphatidylcholine and phosphatidylethanolamine (PE) are synthesized de novo by the CDP-choline and CDP-ethanolamine (Kennedy) pathway, in which the extracellular substrates choline and ethanolamine are transported into the cell, phosphorylated, and coupled with diacylglycerol to form the final phospholipid product. Although multiple transport systems have been established for choline, ethanolamine transport is poorly characterized and there is no single protein assigned a transport function for ethanolamine. The solute carriers 44A (SLC44A) known as choline transporter-like proteins-1 and -2 (CTL1 and CTL2) are choline transporter at the plasma membrane and mitochondria. We report a novel function of CTL1 and CTL2 in ethanolamine transport. Using the lack or the gain of gene function in combination with specific antibodies and transport inhibitors we established two distinct ethanolamine transport systems of a high affinity, mediated by CTL1, and of a low affinity, mediated by CTL2. Both transporters are Na-independent ethanolamine/H antiporters. Primary human fibroblasts with separate frameshift mutations in the CTL1 gene (M1= SLC44A1 and M2= SLC44A1) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 in M2 cells reduced the ethanolamine transport, the flux through the CDP-ethanolamine Kennedy pathway, and PE synthesis. In contrast, overexpression of CTL1 in M2 cells improved ethanolamine transport and PE synthesis. These data firmly establish that CTL1 and CTL2 are the first identified ethanolamine transporters in whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the Kennedy pathway and intracellular redistribution of ethanolamine.
Topics: Animals; Antigens, CD; Biological Transport; Cell Line; Cell Membrane; Ethanolamine; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Mitochondria; Models, Molecular; Organic Cation Transport Proteins; Protein Conformation
PubMed: 33789160
DOI: 10.1016/j.jbc.2021.100604