scholarly journals Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels

2021 ◽  
Vol 9 ◽  
Author(s):  
Pascal F. Egea
Keyword(s):  
Cell Membrane ◽  
Cell Biology ◽  
Membrane Lipids ◽  
Atp Synthesis ◽  
Vesicular Trafficking ◽  
Lipid Transfer ◽  
Organelle Biogenesis ◽  
Membrane Contact Sites ◽  
Wide Range ◽  
Membrane Bound

Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several “model” MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis.

scholarly journals Insights into the Mode of Action of Chitosan as an Antibacterial Compound

2008 ◽  
Vol 74 (12) ◽  
pp. 3764-3773 ◽  
Author(s):  
Dina Raafat ◽  
Kristine von Bargen ◽  
Albert Haas ◽  
Hans-Georg Sahl
Keyword(s):  
Antimicrobial Activity ◽  
Cell Wall ◽  
Cell Membrane ◽  
Mode Of Action ◽  
Membrane Lipids ◽  
Expression Profiles ◽  
Transcriptional Response ◽  
Response Analysis ◽  
Sequence Of Events ◽  
Wide Range

ABSTRACT Chitosan is a polysaccharide biopolymer that combines a unique set of versatile physicochemical and biological characteristics which allow for a wide range of applications. Although its antimicrobial activity is well documented, its mode of action has hitherto remained only vaguely defined. In this work we investigated the antimicrobial mode of action of chitosan using a combination of approaches, including in vitro assays, killing kinetics, cellular leakage measurements, membrane potential estimations, and electron microscopy, in addition to transcriptional response analysis. Chitosan, whose antimicrobial activity was influenced by several factors, exhibited a dose-dependent growth-inhibitory effect. A simultaneous permeabilization of the cell membrane to small cellular components, coupled to a significant membrane depolarization, was detected. A concomitant interference with cell wall biosynthesis was not observed. Chitosan treatment of Staphylococcus simulans 22 cells did not give rise to cell wall lysis; the cell membrane also remained intact. Analysis of transcriptional response data revealed that chitosan treatment leads to multiple changes in the expression profiles of Staphylococcus aureus SG511 genes involved in the regulation of stress and autolysis, as well as genes associated with energy metabolism. Finally, a possible mechanism for chitosan's activity is postulated. Although we contend that there might not be a single classical target that would explain chitosan's antimicrobial action, we speculate that binding of chitosan to teichoic acids, coupled with a potential extraction of membrane lipids (predominantly lipoteichoic acid) results in a sequence of events, ultimately leading to bacterial death.

scholarly journals Lipid Metabolism at Membrane Contacts: Dynamics and Functions Beyond Lipid Homeostasis

2020 ◽  
Vol 8 ◽  
Author(s):  
Jiesi Xu ◽  
Xun Huang
Keyword(s):  
Lipid Metabolism ◽  
Intracellular Signaling ◽  
Dynamic Control ◽  
Lipid Synthesis ◽  
Lipid Homeostasis ◽  
Lipid Transfer ◽  
Organelle Biogenesis ◽  
Lipid Trafficking ◽  
Membrane Contact Sites ◽  
Membrane Contacts

Membrane contact sites (MCSs), regions where the membranes of two organelles are closely apposed, play critical roles in inter-organelle communication, such as lipid trafficking, intracellular signaling, and organelle biogenesis and division. First identified as “fraction X” in the early 90s, MCSs are now widely recognized to facilitate local lipid synthesis and inter-organelle lipid transfer, which are important for maintaining cellular lipid homeostasis. In this review, we discuss lipid metabolism and related cellular and physiological functions in MCSs. We start with the characteristics of lipid synthesis and breakdown at MCSs. Then we focus on proteins involved in lipid synthesis and turnover at these sites. Lastly, we summarize the cellular function of lipid metabolism at MCSs beyond mere lipid homeostasis, including the physiological meaning and relevance of MCSs regarding systemic lipid metabolism. This article is part of an article collection entitled: Coupling and Uncoupling: Dynamic Control of Membrane Contacts.

scholarly journals Pex30-like proteins function as adaptors at distinct ER membrane contact sites

2021 ◽  
Vol 220 (10) ◽  
Author(s):  
Joana Veríssimo Ferreira ◽  
Pedro Carvalho
Keyword(s):  
Lipid Droplets ◽  
De Novo ◽  
Membrane Lipids ◽  
Family Members ◽  
Membrane Curvature ◽  
Organelle Biogenesis ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Er Membrane

Membrane lipids and proteins synthesized in the ER are used for de novo assembly of organelles, such as lipid droplets and peroxisomes. After assembly, the growth of these organelles is supported by ER-derived lipids transferred at membrane contact sites (MCSs). How ER sites for organelle biogenesis and lipid transfer are established and regulated is unclear. Here, we investigate how the ER membrane protein Pex30 and its family members Pex28, Pex29, Pex31, and Pex32 target and function at multiple MCSs. We show that different Pex30 complexes function at distinct ER domains and MCSs. Pex30 targets ER–peroxisome MCSs when bound to Pex28 and Pex32, organizes the nuclear–vacuolar junction when bound to Pex29, and promotes the biogenesis of lipid droplets independently of other family members. Importantly, the reticulon homology domain (RHD) mediates the assembly of the various Pex30 complexes. Given the role of RHD in membrane shaping, our findings offer a mechanistic link between MCS and regulation of membrane curvature.

scholarly journals Arachidonic Acid Metabolism and Kidney Inflammation

2019 ◽  
Vol 20 (15) ◽  
pp. 3683 ◽  
Author(s):  
Tianqi Wang ◽  
Xianjun Fu ◽  
Qingfa Chen ◽  
Jayanta Kumar Patra ◽  
Dongdong Wang ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Cell Membrane ◽  
Inflammatory Responses ◽  
Membrane Lipids ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Leukotriene B4 ◽  
P450 Monooxygenase ◽  
Wide Range

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA2 and leukotriene B4 (LTB4) results in inflammatory damage to the kidney. Moreover, the LTB4-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation.

scholarly journals Rational design and implementation of a chemically inducible hetero-trimerization system

2020 ◽  
Author(s):  
Helen D. Wu ◽  
Masaki Kikuchi ◽  
Onur Dagliyan ◽  
Adam K. Aragaki ◽  
Hideki Nakamura ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Rational Design ◽  
Membrane Lipids ◽  
Live Cells ◽  
Cell Functions ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Molecular Events ◽  
Membrane Contact

AbstractChemically inducible dimerization (CID) uses a small molecule to induce binding of two different proteins. CID tools exemplified by the FKBP/FRB/rapamycin system have been widely employed to probe molecular events inside and outside cells. While various CID tools are available, chemically inducible trimerization (CIT) has not been developed, due to inherent challenges in designing or identifying a chemical that simultaneously binds three proteins with high affinity and target specificity. Nevertheless, by introducing a third recruitable component, CIT could enable versatile applications. Here, we devised the CIT by rationally splitting FRB and FKBP. Based on cellular and structural datasets, select split pairs of FRB or FKBP underwent efficient trimerization with full length FKBP or FRB, respectively, upon addition of rapamycin. We also demonstrated its potential for cellular applications by rapidly inducing tri-organellar plasma membrane-ER-mitochondria junctions, and by perturbing intended membrane lipids exclusively at the plasma membrane-ER membrane contact sites. By conferring one additional condition to what is achievable with CID, CIT expands the types of manipulation in single live cells, to address cell biology questions otherwise intractable, and engineer cell functions for future synthetic biology applications.

The Influence of Ultra-Low Concentrations of Potassium Anphen on the Bioenergetic Characteristics of Mitochondria

2020 ◽  
Vol 16 (4) ◽  
pp. 537-542
Author(s):  
Zhigacheva Irina ◽  
Volodkin Aleksandr ◽  
Rasulov Maksud
Keyword(s):  
Functional State ◽  
Membrane Lipids ◽  
Biological Effects ◽  
Dose Dependence ◽  
Stress Factors ◽  
Mitochondrial Membranes ◽  
Oxidation Rates ◽  
Pea Seedlings ◽  
Low Concentrations ◽  
Wide Range

Background: One of the main sources of ROS in stress conditions is the mitochondria. Excessive generation of ROS leads to oxidation of thiol groups of proteins, peroxidation of membrane lipids and swelling of the mitochondria. In this regard, there is a need to search for preparationsadaptogens that increase the body's resistance to stress factors. Perhaps, antioxidants can serve as such adaptogens. This work aims at studying the effect of antioxidant; the potassium anphen in a wide range of concentrations on the functional state of 6 day etiolated pea seedlings mitochondria (Pisum sativum L). Methods: The functional state of mitochondria was studied per rates of mitochondria respiration, by the level of lipid peroxidation and study of fatty acid composition of mitochondrial membranes by chromatography technique. Results: Potassium anphen in concentrations of 10-5 - 10-8 M and 10-13-10-16 prevented the activation of LPO in the mitochondrial membranes of pea seedlings, increased the oxidation rates of NAD-dependent substrates and succinate in the respiratory chain of mitochondria that probably pointed to the anti-stress properties of the drug. Indeed, the treatment of pea seeds with the preparation in concentrations of 10-13 M prevented the inhibition of growth of seedlings in conditions of water deficiency. Conclusion: It is assumed that the dose dependence of the biological effects of potassium anphen and the manifestation of these effects in ultra-low concentrations are due to its ability in water solutions to form a hydrate containing molecular ensembles (structures).

scholarly journals Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

2019 ◽  
Vol 77 (14) ◽  
pp. 2839-2857 ◽  
Author(s):  
Elsa Meneses-Salas ◽  
Ana García-Melero ◽  
Kristiina Kanerva ◽  
Patricia Blanco-Muñoz ◽  
Frederic Morales-Paytuvi ◽  
...  
Keyword(s):  
Late Endosome ◽  
Dependent Manner ◽  
Lipid Transfer ◽  
Cholesterol Accumulation ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Membrane Contact ◽  
Domain 3 ◽  
Niemann Pick ◽  
Mutant Cells

Abstract Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.

scholarly journals Cell penetration efficiency analysis of different atomic force microscopy nanoneedles into living cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marcos Penedo ◽  
Tetsuya Shirokawa ◽  
Mohammad Shahidul Alam ◽  
Keisuke Miyazawa ◽  
Takehiko Ichikawa ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
Cell Membrane ◽  
Cell Biology ◽  
Cell Damage ◽  
Efficiency Analysis ◽  
Living Cells ◽  
Biomolecular Recognition ◽  
Cell Penetration ◽  
Force Microscopy ◽  
Atomic Force

AbstractOver the last decade, nanoneedle-based systems have demonstrated to be extremely useful in cell biology. They can be used as nanotools for drug delivery, biosensing or biomolecular recognition inside cells; or they can be employed to select and sort in parallel a large number of living cells. When using these nanoprobes, the most important requirement is to minimize the cell damage, reducing the forces and indentation lengths needed to penetrate the cell membrane. This is normally achieved by reducing the diameter of the nanoneedles. However, several studies have shown that nanoneedles with a flat tip display lower penetration forces and indentation lengths. In this work, we have tested different nanoneedle shapes and diameters to reduce the force and the indentation length needed to penetrate the cell membrane, demonstrating that ultra-thin and sharp nanoprobes can further reduce them, consequently minimizing the cell damage.

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