scholarly journals 1-Deoxysphingolipids Tempt Autophagy Resulting in Lysosomal Lipid Substrate Accumulation: Tracing the Impact of 1-Deoxysphingolipids on Ultra-Structural Level using a Novel Click-Chemistry Detection

2021 ◽  
Author(s):  
Christian Lamberz ◽  
Marina Hesse ◽  
Gregor Kirfel
Keyword(s):  
Energy Homeostasis ◽  
Lipid Membrane ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Membrane Dynamics ◽  
Autophagic Flux ◽  
Structural Level ◽  
Cellular Energy ◽  
The Impact ◽  
Lipid Substrate

SUMMARYSphingolipids (SLs) are pivotal components of biological membranes essentially contributing to their physiological functions. 1-deoxysphingolipids (deoxySLs), an atypical cytotoxic acting sub-class of SLs, is relevant for cellular energy homeostasis and is known to be connected to neurodegenerative disorders including diabetic neuropathy and hereditary sensory neuropathy type 1 (HSAN1). High levels of deoxySLs affect lipid membrane integrity in artificial liposomes. Accordingly, recent reports questioned the impact of deoxySLs on physiological lipid membrane and organelle functions leading to impaired cellular energy homeostasis.However, DeoxySL-related structural effects on cell membranes resulting in organelle dysfunction are still obscure. To illuminate disease-relevant sub-cellular targets of deoxySLs, we traced alkyne-containing 1-deoxysphinganine (alkyne-DOXSA) and resulting metabolites on ultra-structural level using a new labeling approach for electron microscopy (EM) termed “Golden-Click-Method” (GCM). To complement high-resolution analysis with membrane dynamics, selected intracellular compartments were traced using fluorescent live dyes.Our results conclusively linked accumulating cytotoxic deoxySLs with mitochondria and endoplasmic reticulum (ER) damage triggering Autophagy of mitochondria and membrane cisterna of the ER. The induced autophagic flux ultimately leads to accumulating deoxySL containing intra-lysosomal lipid crystals. Lysosomal lipid substrate accumulation impaired physiological lysosome functions and caused cellular starvation. Lysosomal exocytosis appeared as a mechanism for cellular clearance of cytotoxic deoxySLs. In sum, our data define new ultra-structural targets of deoxySLs and link membrane damage to autophagy and abnormal lysosomal lipid accumulation. These insights may support new conclusions about diabetes type 2 and HSNA1 related tissue damage.

scholarly journals Plasma membrane integrity: implications for health and disease

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dustin A. Ammendolia ◽  
William M. Bement ◽  
John H. Brumell
Keyword(s):  
Plasma Membrane ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Whole Body ◽  
Plasma Membrane Integrity ◽  
Plasma Membrane Damage ◽  
Cellular Environment ◽  
Health And Disease ◽  
Repair Pathways ◽  
The Impact

AbstractPlasma membrane integrity is essential for cellular homeostasis. In vivo, cells experience plasma membrane damage from a multitude of stressors in the extra- and intra-cellular environment. To avoid lethal consequences, cells are equipped with repair pathways to restore membrane integrity. Here, we assess plasma membrane damage and repair from a whole-body perspective. We highlight the role of tissue-specific stressors in health and disease and examine membrane repair pathways across diverse cell types. Furthermore, we outline the impact of genetic and environmental factors on plasma membrane integrity and how these contribute to disease pathogenesis in different tissues.

scholarly journals Escherichia coli response to subinhibitory concentration of Colistin: Insights from study of membrane dynamics and morphology.

2022 ◽  
Author(s):  
Ilanila Ilangumaran Ponmalar ◽  
Jitendriya Swain ◽  
Jaydeep Kumar Basu
Keyword(s):  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Lipid Membrane ◽  
Membrane Dynamics ◽  
Correlation Spectroscopy ◽  
Membrane Properties ◽  
Bacterial Response ◽  
Lipid Dynamics ◽  
The Impact ◽  
Altered Lipid

Prevalence of wide spread bacterial infections bring forth a critical need in understanding the molecular mechanisms of the antibiotics as well as the bacterial response to those antibiotics. Improper usage of antibiotics, which can be in sub-lethal concentrations is one among the multiple reasons for acquiring antibiotic resistance which makes it vital to understand the bacterial response towards sub-lethal concentrations of antibiotics. In this work, we have used colistin, a well-known membrane active antibiotic used to treat severe bacterial infections and explored the impact of its subminimum inhibitory concentration (MIC) on the lipid membrane dynamics and morphological changes of E. coli. Upon investigation of live cell membrane properties such as lipid dynamics using fluorescence correlation spectroscopy, we observed that colistin disrupts the lipid membrane at sub-MIC by altering the lipid diffusivity. Interestingly, filamentationlike cell elongation was observed upon colistin treatment which led to further exploration of surface morphology with the help of atomic force spectroscopy. The changes in the surface roughness upon colistin treatment provides additional insight on the colistin-membrane interaction corroborating with the altered lipid diffusion. Although altered lipid dynamics could be attributed to an outcome of lipid rearrangement due to direct disruption by antibiotic molecules on the membrane or an indirect consequence of disruptions in lipid biosynthetic pathways, we were able to ascertain that altered bacterial membrane dynamics is due to direct disruptions. Our results provide a broad overview on the consequence of the cyclic polypeptide, colistin on membrane specific lipid dynamics and morphology of a live Gram-negative bacterial cell.

Effects of salinity stress on cellular location of elements and photosynthesis in Ramalina canariensis Steiner

2011 ◽  
Vol 43 (2) ◽  
pp. 155-164 ◽  
Author(s):  
Paula MATOS ◽  
João CARDOSO-VILHENA ◽  
Rui FIGUEIRA ◽  
A. Jorge SOUSA
Keyword(s):  
Sea Water ◽  
Water Solution ◽  
Membrane Damage ◽  
Photochemical Efficiency ◽  
Membrane Integrity ◽  
Photosynthetic Apparatus ◽  
Saline Stress ◽  
Ion Distribution ◽  
Cellular Location ◽  
The Impact

AbstractThe impact of incubation in saline solutions of different concentrations on the uptake and cellular location of essential elements (Na+, K+, Mg2+ and Ca2+), and its effects on membrane integrity and on the photosynthetic apparatus, were investigated in the lichen Ramalina canariensis Steiner. Saline incubation resulted in a rapid uptake of Na+ and Mg2+ in the cell wall fraction, whereas in the intracellular fraction the accumulation of Na+ was slower. No changes were observed for intracellular Mg2+, suggesting that no generalized membrane damage occurred. Concomitantly with the increase in intracellular Na+, there was a specific loss of K+ from the cell interior, indicating that membrane permeability may have been compromised. Incubation in a 100% artificial sea water solution reduced the maximum photochemical efficiency of Photosystem II (Fv/Fm) by 17% after 5 min, and this inhibition increased with incubation time. In samples incubated in 100% artificial sea water solution for 2 h followed by 2 h incubation in deionized water, ion distribution and Fv/Fm did not recover to control values. The present findings show the importance of determining the cellular location of elements when assessing their physiological impact. Results indicate that saline stress may irreversibly impair photosynthesis, thus compromising lichen vitality.

The Impact of Two Combined Oral Contraceptives Containing Ethinyl Estradiol and Drospirenone on Whole Blood Clot Viscoelasticity and the Biophysical and Biochemical Characteristics of Erythrocytes

2018 ◽  
Vol 24 (6) ◽  
pp. 713-728 ◽  
Author(s):  
Odette Emmerson ◽  
Janette Bester ◽  
Barend G. Lindeque ◽  
Albe C. Swanepoel
Keyword(s):  
Whole Blood ◽  
Ethinyl Estradiol ◽  
Blood Clot ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Biochemical Properties ◽  
Sem Analysis ◽  
Long Term Effects ◽  
Biochemical Characteristics ◽  
The Impact

AbstractVenous thrombosis is associated with combined oral contraceptive (COC) use. We investigated the impact of two ethinyl estradiol (EE) and drospirenone (DRSP) containing COCs (3 mg DRSP/20µg EE and 3µg DRSP/30µg EE) on the viscoelasticity of whole blood clots along with the biophysical and biochemical characteristics of erythrocytes. Thromboelastography (TEG) analysis showed a tendency toward a hypercoagulable state in the COCs groups that was more pronounced with higher EE concentrations. Light microscopy and scanning electron microscopy (SEM) showed rouleaux formation of erythrocytes and alterations to the erythrocyte shape for both COC groups, which was attributed to membrane damage. SEM analysis showed spontaneous activation of fibrin and platelets in the COC groups, along with interactions between erythrocytes and platelets and/or fibrin. Confocal microscopy confirmed compromised membrane integrity in the COC groups compared to controls. Global thrombosis test analysis showed increased platelet activation and low thrombolysis in both COC groups when compared to controls. In conclusion, DRSP/EE formulations impact erythrocytes’ biophysical and biochemical properties to cause a shift in hemostasis to a prothrombotic state. Although these effects are mostly subclinical the long-term effects and risks involved with the use of these hormones should be considered carefully for each individual.

IMPACT OF SORBITOL- INDUCED OSMOTIC STRESS ON SOME BIOCHEMICAL TRAITS OF POTATO IN VITRO

2020 ◽  
Vol 51 (4) ◽  
pp. 1038-1047
Author(s):  
Mawia & et al.
Keyword(s):  
Ascorbic Acid ◽  
Osmotic Stress ◽  
Cytoplasmic Membrane ◽  
Genotypic Variation ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Culture Collection ◽  
Nutritive Medium ◽  
Starting Point

This study had as principal objective identification of osmotic-tolerant potato genotypes by using "in vitro" tissue culture and sorbitol as a stimulating agent, to induce water stress, which was added to the  culture nutritive medium in different concentration (0,50, 110, 220, 330 and 440 mM).  The starting point was represented by plantlets culture collection, belonging to eleven potato genotypes: Barcelona, Nectar, Alison, Jelly, Malice, Nazca, Toronto, Farida, Fabulla, Colomba and Spunta. Plantlets were multiplied between two internodes to obtain microcuttings (in sterile condition), which were inoculated on medium. Sorbitol-induced osmotic stress caused a significant reduction in the ascorbic acid, while the concentration of proline, H2O2 and solutes leakage increased compared with the control. Increased the proline content prevented lipid peroxidation, which played a pivotal role in the maintenance of membrane integrity under osmotic stress conditions. The extent of the cytoplasmic membrane damage depends on osmotic stress severity and the genotypic variation in the maintenance of membranes stability was highly associated with the ability of producing more amounts of osmoprotectants (proline) and the non-enzymic antioxidant ascorbic acid in response to osmotic stress level. The results showed that the genotypes Jelly, Nectar, Allison, Toronto, and Colomba are classified as highly osmotic stress tolerant genotypes, while the genotypes Nazca and Farida are classified as osmotic stress susceptible ones.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

scholarly journals Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

2021 ◽  
Vol 22 (9) ◽  
pp. 4646
Author(s):  
Alexey A. Tinkov ◽  
Monica M. B. Paoliello ◽  
Aksana N. Mazilina ◽  
Anatoly V. Skalny ◽  
Airton C. Martins ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Mitochondrial Dysfunction ◽  
Synaptic Dysfunction ◽  
Future Research ◽  
Protective Mechanism ◽  
Autophagic Flux ◽  
Future Research Directions ◽  
The Impact

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

scholarly journals Mitochondrial O-GlcNAc Transferase Interacts with and Modifies Many Proteins and Its Up-Regulation Affects Mitochondrial Function and Cellular Energy Homeostasis

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2956
Author(s):  
Paweł Jóźwiak ◽  
Piotr Ciesielski ◽  
Piotr K. Zakrzewski ◽  
Karolina Kozal ◽  
Joanna Oracz ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Energy Homeostasis ◽  
Glucose Sensor ◽  
Single Gene ◽  
Mitochondrial Proteins ◽  
Mitochondrial Activity ◽  
Ros Generation ◽  
Inner Mitochondrial Membrane ◽  
Glcnac Transferase ◽  
The Impact

O-GlcNAcylation is a cell glucose sensor. The addition of O-GlcNAc moieties to target protein is catalyzed by the O-Linked N-acetylglucosamine transferase (OGT). OGT is encoded by a single gene that yields differentially spliced OGT isoforms. One of them is targeted to mitochondria (mOGT). Although the impact of O-GlcNAcylation on cancer cells biology is well documented, mOGT’s role remains poorly investigated. We performed studies using breast cancer cells with up-regulated mOGT or its catalytic inactive mutant to identify proteins specifically modified by mOGT. Proteomic approaches included isolation of mOGT protein partners and O-GlcNAcylated proteins from mitochondria-enriched fraction followed by their analysis by mass spectrometry. Moreover, we analyzed the impact of mOGT dysregulation on mitochondrial activity and cellular metabolism using a variety of biochemical assays. We found that mitochondrial OGT expression is glucose-dependent. Elevated mOGT expression affected the mitochondrial transmembrane potential and increased intramitochondrial ROS generation. Moreover, mOGT up-regulation caused a decrease in cellular ATP level. We identified many mitochondrial proteins as mOGT substrates. Most of these proteins are localized in the mitochondrial matrix and the inner mitochondrial membrane and participate in mitochondrial respiration, fatty acid metabolism, transport, translation, apoptosis, and mtDNA processes. Our findings suggest that mOGT interacts with and modifies many mitochondrial proteins, and its dysregulation affects cellular bioenergetics and mitochondria function.

scholarly journals Stigma, gay men and biomedical prevention: the challenges and opportunities of a rapidly changing HIV prevention landscape

Sexual Health ◽  
2017 ◽  
Vol 14 (1) ◽  
pp. 111 ◽  
Author(s):  
Graham Brown ◽  
William Leonard ◽  
Anthony Lyons ◽  
Jennifer Power ◽  
Dirk Sander ◽  
...  
Keyword(s):  
Hiv Prevention ◽  
Gay Men ◽  
Sexual Minorities ◽  
Research Policy ◽  
Scale Up ◽  
People Living With Hiv ◽  
Structural Level ◽  
Biomedical Technologies ◽  
Living With Hiv ◽  
The Impact

Improvements in biomedical technologies, combined with changing social attitudes to sexual minorities, provide new opportunities for HIV prevention among gay and other men who have sex with men (GMSM). The potential of these new biomedical technologies (biotechnologies) to reduce HIV transmission and the impact of HIV among GMSM will depend, in part, on the degree to which they challenge prejudicial attitudes, practices and stigma directed against gay men and people living with HIV (PLHIV). At the structural level, stigma regarding gay men and HIV can influence the scale-up of new biotechnologies and negatively affect GMSM’s access to and use of these technologies. At the personal level, stigma can affect individual gay men’s sense of value and confidence as they negotiate serodiscordant relationships or access services. This paper argues that maximising the benefits of new biomedical technologies depends on reducing stigma directed at sexual minorities and people living with HIV and promoting positive social changes towards and within GMSM communities. HIV research, policy and programs will need to invest in: (1) responding to structural and institutional stigma; (2) health promotion and health services that recognise and work to address the impact of stigma on GMSM’s incorporation of new HIV prevention biotechnologies; (3) enhanced mobilisation and participation of GMSM and PLHIV in new approaches to HIV prevention; and (4) expanded approaches to research and evaluation in stigma reduction and its relationship with HIV prevention. The HIV response must become bolder in resourcing, designing and evaluating programs that interact with and influence stigma at multiple levels, including structural-level stigma.

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