Biophysical Implications of Sphingosine Accumulation in Membrane Properties at Neutral and Acidic pH

Zupančič, Eva; Carreira, Ana C.; Almeida, Rodrigo F.M. de; Silva, Liana C.

doi:10.1021/jp501167f

Cited by 21 publications

(41 citation statements)

References 54 publications

(111 reference statements)

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“…The ordering effect of sphingosine on fluid PC membranes or on PC/sphingomyelin/cholesterol raft-mimicking membranes was shown to depend on sphingosine concentration and on pH. Gel domains enriched in sphingosine were more easily formed at neutral pH where most of sphingosine molecules are uncharged [46]. Model membranes were shown to be permeabilized by sphingosine [47] and the extent of permeabilization was shown to depend on the lipid composition.…”

Section: Model Membrane Permeabilization By Sphingosinementioning

confidence: 99%

Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Giraldo

Appelqvist

Ederth

et al. 2014

Biochemical Society Transactions

110

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Lysosomes are acidic organelles essential for degradation, signalling and cell homoeostasis. In addition, they play a key role in cell death. Permeabilization of the lysosomal membrane and release of hydrolytic enzymes to the cytosol accompanies apoptosis signalling in several systems. The regulatory mechanism of lysosomal stability is, however, poorly understood. Lipophilic or amphiphilic compounds with a basic moiety will become protonated and trapped within lysosomes, and such lysosomotropic behaviour is also found in many pharmacological drugs. The natural sphingolipid sphingosine exhibits lysosomotropic detergent ability and is an endogenous candidate for controlling lysosomal membrane permeabilization. The lysosomotropic properties of certain detergents might be of use in lysosome-targeting anticancer drugs and drug delivery system in the future. The present review summarizes the current knowledge on the targeting and permeabilizing properties of lysosomotropic detergents from a cellular and physicochemical perspective.

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Section: Model Membrane Permeabilization By Sphingosinementioning

confidence: 99%

Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Giraldo

Appelqvist

Ederth

et al. 2014

Biochemical Society Transactions

110

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“…We have also shown that sphingosine kills bacteria at rather low concentrations [18]. Further biophysical studies show that sphingosine and ceramide interact in the same membrane domains [22,23]. It is therefore tempting to speculate, although unproven that the "ceramide coat" of the bacteria might interact with sphingosine and might protect them from the bactericidal effect of sphingosine present in the luminal membranes of the enterocytes.…”

Section: Discussionmentioning

confidence: 89%

Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut

Hoehn

Seitz

Jernigan

et al. 2016

Cell Physiol Biochem

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Background: Intestinal ischemia/reperfusion injury (I/R) is a significant cause of morbidity and mortality in surgical patients. Ceramide is a mediator of apoptosis and has been implicated as increasing bacterial infection susceptibility. The metabolite of ceramide, sphingosine, was recently shown to play an important role in the cell-autonomous, innate immune response of the upper respiratory tract by killing bacterial pathogens. The role of ceramide and/or sphingosine after mesenteric I/R is unknown. We investigated the specific effects of intestinal I/R on tissue ceramide and sphingosine concentration and resulting susceptibility to bacterial invasion. Methods: To simulate intestinal I/R, C57BL/6 mice underwent 30 minutes of vascular clamp-induced occlusion of the superior mesenteric artery followed by variable reperfusion times. Jejunum segments and intraluminal contents were analyzed for ceramide, sphingosine and bacteria using immunohistochemistry. Jejunum samples were also homogenized and cultured to quantify bacterial presence in the proximal intestine. Results: We hypothesized that I/R induces an increase of ceramide in the intestine resulting in increased permeability, while a concomitant decrease of sphingosine may permit bacterial overgrowth. Control mice had no measurable bacteria in their proximal jejunum as measured by tissue culture and immunohistochemistry. After I/R, bacterial counts in the jejunum increased in a time-dependent manner, reaching a peak at 12 hours after reperfusion. Immunohistochemical analysis revealed a marked increase in ceramide in the vasculature of jejunal villi. In contrast, while ceramide concentrations in the epithelial cells decreased after I/R, sphingosine levels appeared to remain unchanged. Surprisingly, bacteria present in the jejunal lumen following I/R contained a ceramide coat. Conclusion: These data indicate that intestinal I/R leads to small intestine bacterial overgrowth as well as ceramide formation in the jejunal vasculature, which may contribute to the gut permeability associated with this injury. Moreover, our novel finding of ceramide in bacterial membranes represents a new opportunity to investigate the dynamic pathogenicity of the gut microbiome. The hypothesis that a decrease of sphingosine after I/R permits bacterial overgrowth in the intestine was not confirmed.

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“…In addition, to further show the importance of developing adequate synthetic systems to address lipid-lipid interactions, comparison with standard vesicles (without pH gradient across the membrane) prepared under neutral, i.e., pH 7.4 in /7.4 out , and acidic, pH 5.0 in /5.0 out , conditions, was performed (Fig. 1), based both on new as well as available literature data 26 .…”

Section: Resultsmentioning

confidence: 99%

“…To test whether this experimental set up would compromise the stability of the vesicles altering its size, and to evaluate if the expected changes in surface charge were taking place upon changing the outer membrane pH from an acidic to a neutral environment 26 , analysis of vesicle size and surface charge was performed before and after separating the vesicles through the chromatographic column (Fig. 2) The ζ-potential of the ternary POPC/SM/Chol mixtures before size exclusion chromatography (i.e., when displaying pH 5.0 in /5.0 out ) was slightly positive, as expected since these lipid mixtures are at pH of 5.0 26 . A change in ζ-potential towards slightly negative values was observed upon creation of the pH gradient across the bilayer (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It was demonstrated that Sph has the ability to change the membrane physical organization, promoting the formation of more ordered domains 18, 20–26 . The order of these domains depends not only on membrane lipid composition but also on the surrounding pH environment 21, 26, 27 . It is likely that Sph-induced alterations in membrane properties are closely related to the physico-chemical changes experienced by this lipid.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of lysosome-mimicking vesicles to study the effect of abnormal accumulation of sphingosine on membrane properties

Carreira

Almeida

Silva

2017

Sci Rep

Self Cite

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Synthetic systems are widely used to unveil the molecular mechanisms of complex cellular events. Artificial membranes are key examples of models employed to address lipid-lipid and lipid-protein interactions. In this work, we developed a new synthetic system that more closely resembles the lysosome – the lysosome-mimicking vesicles (LMVs) – displaying stable acid-to-neutral pH gradient across the membrane. To evaluate the advantages of this synthetic system, we assessed the distinct effects of sphingosine (Sph) accumulation in membrane structure and biophysical properties of standard liposomes (no pH gradient) and in LMVs with lipid composition tuned to mimic physiological- or NPC1-like lysosomes. Ternary 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/Sphingomyelin (SM)/Cholesterol (Chol) mixtures with, respectively, low and high Chol/SM levels were prepared. The effect of Sph on membrane permeability and biophysical properties was evaluated by fluorescence spectroscopy, electrophoretic and dynamic light scattering. The results showed that overall Sph has the ability to cause a shift in vesicle surface charge, increase membrane order and promote a rapid increase in membrane permeability. These effects are enhanced in NPC1- LMVs. The results suggest that lysosomal accumulation of these lipids, as observed under pathological conditions, might significantly affect lysosomal membrane structure and integrity, and therefore contribute to the impairment of cell function.

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Biophysical Implications of Sphingosine Accumulation in Membrane Properties at Neutral and Acidic pH

Cited by 21 publications

References 54 publications

Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death

Ischemia/Reperfusion Injury Alters Sphingolipid Metabolism in the Gut

Development of lysosome-mimicking vesicles to study the effect of abnormal accumulation of sphingosine on membrane properties

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