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PubMed2002

The apoptotic protein tBid promotes leakage by altering membrane curvature.

The apoptotic protein tBid is effective in promoting both leakage and lipid mixing in liposomes composed of cardiolipin and phosphatidylcholine at a molar ratio of 1:2 in the presence of calcium. When half of the phosphatidylcholine component of these liposomes is replaced with phosphatidylethanolamine, a lipid that promotes negative membrane curvature, the rates of both leakage and lipid mixing caused by tBid are substantially increased. Replacement of cardiolipin with phosphatidylglycerol, a lipid that is structurally similar to cardiolipin but does not promote negative membrane curvature in the presence of calcium, prevents the tBid from promoting leakage. The promotion of leakage by tBid is also inhibited by several substances that promote positive membrane curvature, including lysophosphatidylcholine, tritrpticin, a potent antimicrobial peptide, and cyclosporin A, a known inhibitor of cytochrome c release from mitochondria. We directly measured the effect of tBid on membrane curvature by (31)P NMR. We found that tBid promotes the formation of highly curved non-lamellar phases. All of these data are consistent with the hypothesis that tBid promotes negative curvature, and as a result it destabilizes bilayer membranes. Bcl-X(L) inhibits leakage and lipid mixing induced by tBid. Bcl-X(L) is anti-apoptotic. It reduces the promotion of non-bilayer phases by tBid, although by itself Bcl-X(L) is capable of promoting their formation. Bcl-X(L) has little effect on liposomal integrity. Our results suggest that the anti-apoptotic activity of Bcl-X(L) is not a consequence of its interaction with membranes, but rather with other proteins, such as tBid.

Apoptosis↗
PubMed2004

Blockade of electron transport during ischemia protects cardiac mitochondria.

Subsarcolemmal mitochondria sustain progressive damage during myocardial ischemia. Ischemia decreases the content of the mitochondrial phospholipid cardiolipin accompanied by a decrease in cytochrome c content and a diminished rate of oxidation through cytochrome oxidase. We propose that during ischemia mitochondria produce reactive oxygen species at sites in the electron transport chain proximal to cytochrome oxidase that contribute to the ischemic damage. Isolated, perfused rabbit hearts were treated with rotenone, an irreversible inhibitor of complex I in the proximal electron transport chain, immediately before ischemia. Rotenone pretreatment preserved the contents of cardiolipin and cytochrome c measured after 45 min of ischemia. The rate of oxidation through cytochrome oxidase also was improved in rotenone-treated hearts. Inhibition of the electron transport chain during ischemia lessens damage to mitochondria. Rotenone treatment of isolated subsarcolemmal mitochondria decreased the production of reactive oxygen species during the oxidation of complex I substrates. Thus, the limitation of electron flow during ischemia preserves cardiolipin content, cytochrome c content, and the rate of oxidation through cytochrome oxidase. The mitochondrial electron transport chain contributes to ischemic mitochondrial damage that in turn augments myocyte injury during subsequent reperfusion.

Animals↗
PubMed2005

The osmotic activation of transporter ProP is tuned by both its C-terminal coiled-coil and osmotically induced changes in phospholipid composition.

Transporter ProP of Escherichia coli (ProPEc) senses extracellular osmolality and mediates osmoprotectant uptake when it is rising or high. A replica of the ProPEc C terminus (Asp468-Arg497) forms an intermolecular alpha-helical coiled-coil. This structure is implicated in the osmoregulation of intact ProPEc, in vivo. Like that from Corynebacterium glutamicum (ProPCg), the ProP orthologue from Agrobacterium tumefaciens (ProPAt) sensed and responded to extracellular osmolality after expression in E. coli. The osmotic activation profiles of all three orthologues depended on the osmolality of the bacterial growth medium, the osmolality required for activation rising as the growth osmolality approached 0.7 mol/kg. Thus, each could undergo osmotic adaptation. The proportion of cardiolipin in a polar lipid extract from E. coli increased with extracellular osmolality so that the osmolality activating ProPEc was a direct function of membrane cardiolipin content. Group A ProP orthologues (ProPEc, ProPAt) share the C-terminal coiled-coil domain and were activated at low osmolalities. Like variant ProPEc-R488I, in which the C-terminal coiled-coil is disrupted, ProPEc derivatives that lack the coiled-coil and Group B orthologue ProPCg required a higher osmolality to activate. The amplitude of ProPEc activation was reduced 10-fold in its deletion derivatives. The coiled-coil structure is not essential for osmotic activation of ProP per se. However, it tunes Group A orthologues to osmoregulate over a low osmolality range. Coiled-coil lesions may impair both coiled-coil formation and interaction of ProPEc with amplifier protein ProQ. Cardiolipin may contribute to ProP adaptation by altering bulk membrane properties or by acting as a ProP ligand.

Amino Acid Sequence↗
PubMed2001

Specific roles of protein-phospholipid interactions in the yeast cytochrome bc1 complex structure.

Biochemical data have shown that specific, tightly bound phospholipids are essential for activity of the cytochrome bc1 complex (QCR), an integral membrane protein of the respiratory chain. However, the structure and function of such phospholipids are not yet known. Here we describe five phospholipid molecules and one detergent molecule in the X-ray structure of yeast QCR at 2.3 A resolution. Their individual binding sites suggest specific roles in facilitating structural and functional integrity of the enzyme. Interestingly, a phosphatidylinositol molecule is bound in an unusual interhelical position near the flexible linker region of the Rieske iron-sulfur protein. Two possible proton uptake pathways at the ubiquinone reduction site have been identified: the E/R and the CL/K pathway. Remarkably, cardiolipin is positioned at the entrance to the latter. We propose that cardiolipin ensures structural integrity of the proton-conducting protein environment and takes part directly in proton uptake. Site-directed mutagenesis of ligating residues confirmed the importance of the phosphatidylinositol- and cardiolipin-binding sites.

Binding Sites↗
PubMed1991

Dietary essential fatty acids change the fatty acid profile of rat neural mitochondria over time.

This experiment examined the time course over which the amount of dietary essential fatty acids (EFA) affects brain mitochondrial fatty acids. Weanling rats were fed 20% (wt/wt) fat diets that contained either 4 or 15% (wt/wt of diet) EFA for 1, 2, 3 or 6 wk or a 10% EFA diet for 3 or 6 wk. The EFA ratio [18:2(n-6)/18:3(n-3)] of all diets was approximately 30. Fatty acid analysis of brain mitochondrial phosphatidylethanolamine, phosphatidylcholine and cardiolipin revealed that the largest dietary effect was on 18:2(n-6), which was 30% higher in rats fed the 15 vs. 4% EFA diets after 1 wk. This difference increased to twofold by 3 wk and was still twofold after 6 wk. These results demonstrate several facts: 1) the response of 18:2(n-6) in cardiolipin to dietary EFA is very fast and large, relative to changes in other quantitatively major fatty acids observed in weanling rats; 2) the 18:2(n-6) level in neural cardiolipin stabilizes after 3 wk of feeding at a level dependent upon the amount of dietary EFA; and 3) at least one neural fatty acid, 18:2(n-6), is very sensitive to amounts of dietary EFA that are well above the animal's EFA requirement.

Animals↗
PubMed2002

Acidic phospholipids with unsaturated fatty acids inhibit the binding of origin recognition complex to origin DNA.

Origin Recognition Complex (ORC) is a candidate initiator of chromosomal DNA replication in eukaryotes. We recently reported that cardiolipin inhibits the interaction of Origin Recognition Complex ORC with origin DNA, as is the case of DnaA, the initiator of chromosomal DNA replication in prokaryotes. We report here that another acidic phospholipid, phosphatidylglycerol (PG), also inhibits the interaction. Synthetic PG with only unsaturated fatty acids inhibits ORC-binding to origin DNA more strongly than PG with only saturated fatty acids. On the other hand, phosphatidylcholine (neutral phospholipid) does not affect the ORC-origin interaction, regardless of the presence of saturated or unsaturated fatty acids. These results suggest that an acidic moiety and unsaturated fatty acids are important factors for the inhibitory effect of phospholipids on ORC binding to origin DNA, as is the case for DnaA. The inhibitory effect of cardiolipin on ORC binding to origin DNA was more apparent at 30 degrees C than at 4 degrees C. Furthermore, chlorpromazine restored the ORC-origin interaction in the presence of cardiolipin. Since the presence of unsaturated fatty acids, low incubation temperatures, and the addition of chlorpromazine all decrease membrane fluidity, these results suggest that membrane fluidity is important for the inhibitory effect of acidic phospholipids on ORC-binding to origin DNA, as is the case for DnaA.

Adenosine Triphosphate↗
PubMed1990

Mode of action of sapecin, a novel antibacterial protein of Sarcophaga peregrina (flesh fly).

Sapecin is an antibacterial protein purified from the culture medium of NIH-Sape-4, an embryonic cell line of Sarcophaga peregrina [Matsuyama, K. & Natori, S. (1988) J. Biol. Chem. 236, 17112-17116]. As this protein inhibited the growth of Gram-positive bacteria better than that of Gram-negative bacteria, we studied its mode of action with special reference to its effects on S. aureus and Escherichia coli. Results showed that sapecin had high affinity for cardiolipin, which is a major phospholipid of S. aureus. Moreover, a mutant of E. coli with a defect in cardiolipin synthesis was more resistant to sapecin than wild type E. coli, suggesting that cardiolipin is a target for sapecin. Lipopolysaccharide of E. coli was also found to be a barrier for the antibacterial activity of sapecin.

Animals↗
PubMed2006

Role of anionic phospholipids in the adaptation of Bacillus subtilis to high salinity.

The importance of the content of anionic phospholipids [cardiolipin (CL) and phosphatidylglycerol (PG)] in the osmotic adaptation and in the membrane structure of Bacillus subtilis cultures was investigated. Insertion mutations in the three putative cardiolipin synthase genes (ywiE, ywnE and ywjE) were obtained. Only the ywnE mutation resulted in a complete deficiency in cardiolipin and thus corresponds to a true clsA gene. The osmotolerance of a clsA mutant was impaired: although at NaCl concentrations lower than 1.2 M the growth curves were similar to those of its wild-type control, at 1.5 M NaCl (LBN medium) the lag period increased and the maximal optical density reached was lower. The membrane of the clsA mutant strain showed an increased PG content, at both exponential and stationary phase, but no trace of CL in either LB or LBN medium. As well as the deficiency in CL synthesis, the clsA mutant showed other differences in lipid and fatty acids content compared to the wild-type, suggesting a cross-regulation in membrane lipid pathways, crucial for the maintenance of membrane functionality and integrity. The biophysical characteristics of membranes and large unilamellar vesicles from the wild-type and clsA mutant strains were studied by Laurdan's steady-state fluorescence spectroscopy. At physiological temperature, the clsA mutant showed a decreased lateral lipid packing in the protein-free vesicles and isolated membranes compared with the wild-type strain. Interestingly, the lateral lipid packing of the membranes of both the wild-type and clsA mutant strains increased when they were grown in LBN. In a conditional IPTG-controlled pgsA mutant, unable to synthesize PG and CL in the absence of IPTG, the osmoresistance of the cultures correlated with their content of anionic phospholipids. The transcriptional activity of the clsA and pgsA genes was similar and increased twofold upon entry to stationary phase or under osmotic upshift. Overall, these results support the involvement of the anionic phospholipids in the growth of B. subtilis in media containing elevated NaCl concentrations.

Adaptation, Physiological↗
PubMed1991

Augmentation and suppression of release of tumor necrosis factor from macrophages by negatively charged phospholipids.

We recently reported that some lipid species of cell membranes and lipoproteins induced the growth of peripheral macrophages. In this study, the effects of phospholipids on tumor necrosis factor (TNF)-releasing activity of macrophages were examined. Ten to 20 micrograms/ml of cardiolipin, which is a suboptimal concentration for macrophage growth-stimulation, augmented macrophage TNF release triggered by lipopolysaccharide (LPS) in vitro. This priming effect appeared with 1 day of preincubation and was still potent on day 3, whereas the priming effect of interferon-gamma (IFN-gamma) peaked at 3 h and then gradually decreased. In contrast, a high concentration of cardiolipin (40 micrograms/ml) which is optimal for the induction of macrophage growth, completely suppressed LPS-triggered TNF release from not only untreated macrophages but also IFN-gamma-primed macrophages. The suppressive effect was potent even with 3 h preincubation, was still potent on day 3, and was not abolished by indomethacin. Cardiolipin had scarcely any effect on the triggering activity of LPS. Similar augmentative and suppressive activities were observed in peroxidized phosphatidylserine, which is also highly active in inducing macrophage growth, but was not found in native phosphatidylserine, which is less active in inducing macrophage growth, but was not found in native phosphatidylserine, which is less active, nor in phosphatidylcholine, which is an inactive species toward macrophage growth. These results suggest that lipids may be important endogenous factors in regulating both activation and growth states of peripheral macrophages.

Animals↗
PubMed1992

Some 'antiphospholipid antibodies' bind to beta 2-glycoprotein I in the absence of phospholipid.

Some antiphospholipid antibodies (aPL) only bind to anionic phospholipids in the presence of a serum cofactor, beta 2-glycoprotein I (beta 2GPI). Whether these aPL can bind to beta 2GPI in the absence of phospholipid is controversial. We have purified anticardiolipin antibodies (aCL) from the plasma of four patients and beta 2GPI from normal plasma by solid phase affinity methods. All four aCL bound to cardiolipin and phosphatidylserine in the presence of beta 2GPI but not in its absence. The binding of two of the antibodies to cardiolipin and phosphatidylserine at various concentrations of human beta 2GPI was compared with that obtained using 10% bovine serum. The two antibodies responded differently to increasing beta 2GPI concentrations, and binding to phosphatidylserine was relatively greater than to cardiolipin using human beta 2GPI. All four aCL bound to plastic plates coated with beta 2GPI in the absence of phospholipid, and beta 2GPI in the fluid phase had no effect on binding. Binding to beta 2GPI coated plates was increased equally when bovine serum or bovine albumin were used as the sample diluent in place of gelatine. These findings and those of others have important implications for the design of assays for antiphospholipid antibodies.

Antibodies, Anticardiolipin↗
PubMed2005

The association of anti-phospholipid antibodies with parity in placental malaria.

Anti-phospholipid antibodies (aPL) are autoantibodies associated with both infections and the pathogenesis of certain pregnancy complications. In the latter, but not the former, aPL are dependent on a co-factor, beta(2) glycoprotein I (beta2GPI), which can also be used as an antigen for detection of such aPL in pregnancy. A cross-sectional study was carried out on serum samples from Kumasi, Ghana, to determine the occurrence and beta2GPI-dependence of aPL in placental malaria. Anti-cardiolipin, anti-phosphatidylserine and anti-beta2GPI enzyme-linked immunosorbent assays (ELISAs) were performed on sera from 103 HIV-non-infected gravid women. Placental malaria, both active and past infection, was diagnosed in 33/103 (32%) based on placental histology. In multiparae, beta2GPI-independent IgM antibodies to cardiolipin (P = 0.018) and phosphatidylserine (P = 0.009) were observed, which were most pronounced in past placental malaria infection. In primiparae, no association emerged between aPL and placental malaria. Trends for improved clinical parameters were identified in infected women with levels of anti-cardiolipin beyond the 99th multiple of the median for a healthy, non-malarious population. This study in placental malaria reports parity associations of beta2GPI-independent aPL profiles, and does not support a role for beta2GPI-dependent aPL. It is of significance in the context of the known parity differences in pregnancy malaria immunity.

Adult↗
PubMed1984

Binding of adriamycin-Fe3+ complex to membrane phospholipids.

Binding of adriamycin-Fe3+ complex to phospholipids has been examined by phase partitioning in a hexane-water system. Formation of a stable ternary adriamycin-Fe3+-lipid complex with the negatively charged phospholipids cardiolipin and phosphatidylglycerol (both isolated from Escherichia coli) and synthetic dioleoyl glycerophosphoglycerol is demonstrated. Binding of adriamycin-Fe3+ complex to phospholipid bilayers was assessed by incubation of the complex with aqueous phospholipid dispersions prepared from synthetic dimyristoyl glycerophosphocholine, E. coli phosphatidylethanolamine or E. coli cardiolipin and from mixtures of these lipids. Binding of the complex to the phospholipids took place with an affinity for cardiolipin greater than phosphatidylethanolamine greater than phosphatidylcholine. The ternary adriamycin-Fe3+-ADP complex formed in the presence of 1 mM ADP (ADP in 25-fold molar excess to adriamycin) showed low affinity for binding to phospholipid.

Cardiolipins↗
PubMed1994

Isolation and characterization of new phosphatidylglycerol acetals of plasmalogens. A family of ether lipids in clostridia.

A new phosphatidylglycerol acetal of cardiolipin plasmalogen has been isolated from Clostridium innocuum. The structure was derived from the results of quantitative group analyses, the identification of the products of acid hydrolysis, alkaline methanolysis, hydrolysis by a cardiolipin-specific phospholipase D and by one- and two-dimensional proton NMR. Two other minor ether phospholipids: the lyso form of the phosphatidylglycerol acetal of cardiolipin plasmalogen, and the phosphatidylglycerol acetal of plasmenylglycerol have been identified in C. innocuum lipid extracts.

Acetals↗
PubMed1975

Characterization of the lipids of mesosomal vesicles and plasma membranes from Staphylococcus aureus.

Mesosomal vesicles and plasma membranes were isolated from Staphylococcus aureus ATCC 6538P by protoplasting and differential centrifugation. The lipids of each of the two membrane fractions were extracted with pyridine-acetic acid-N-butanol, and the nonlipid contaminants were removed by Sephadex treatment. The lipids were then separated by passage through diethylaminoethyl-cellulose columns and characterized by thin-layer chromatographic, chemical, and spectral analyses. The lipids were separated into four discrete diethylaminoethyl fractions: (i) vitamin K2, carotenoids, C55 isoprenoid alcohol, and monoglucosyl diglyceride; (ii) cardiolipin, carotenoids, phosphatidyl glycerol, diglucosyl diglyceride, and an unidentified ninhydrin-positive component; (iii) cardiolipid and phosphatidyl glyderol; (iv) cardiolipin, phosphatidyl glycerol, and phosphatidyl glucose. Qualitatively, no difference in lipid composition between mesosomal vesicles and plasma membranes was found. However, based on equal dry weights of membrane materials, a relative quantitative difference in the amount of specific lipids in mesosomal vesicles and plasma membranes was observed. There are 4 times more monoglucosyl diglyceride, 2.6 times more diglucosyl diglyceride, 3.8 times more phosphatidyl glucose, 2 times more carotenoids, and 2 times more vitamin K2 found in mesosomal vesicles than in plasma membranes. The concentration of cardiolipin and phosphatidyl glycerol is 3.6 and 6 times greater, respectively, in mesosomal vesicles.

Cardiolipins↗
PubMed1976

Inhibition of wall autolysis in Streptococcus faecalis by lipoteichoic acid and lipids.

Fully acylated lipoteichoic acid (LTA) isolated from Streptococcus faecalis ATCC9790 (S. faecium) inhibited autolysis of walls from the same organism at concentrations (1.0 to 1.5 nmol of LTA per mg of wall) comparable to those found in intact cells. Partially deacylated LTA isolated from S. faecalis or chemically deacylated LTA failed to inhibit significantly in the same concentration range. Beef heart cardiolipin and commercially obtained dipalmitoyl phosphatidyl glycerol were also found to inhibit wall autolysis in S. faecalis. Chemical deacylation of beef heart cardiolipin also removed the inhibitory activity of this molecule. Lipid fractions isolated from S. faecalis that inhibited wall autolysis were: diphosphatidyl glycerol (cardiolipin), phosphatidyl glycerol, aminoacyl phosphatidyl glycerol, and a neutral lipid fraction. Glycolipids were not found to be effective inhibitors. The possible role of LTA and/or certain lipids as regulators of cellular autolytic activity is discussed.

Acylation↗
PubMed1977

Phospholipid composition and phenotypic correction of an envC division mutant of Escherichia coli.

The cytoplasmic and outer membranes of a nonconditional chain-forming mutant, Escherichia coli PM61 envC, were separated by sucrose density gradient centrifugation. The phosphatidylglycerol/cardiolipin ratio in both membrane fractions was about one-third as high as in the parental strain P678. The increased level of cardiolipin in PM61 membranes is the result of an alteration of the polyglycerophosphatide cycle. It was found that the turnover rate of phosphatidylglycerol is more rapid in PM61 than in the parental strain but that its cardiolipin turnover is not significantly different. The envC mutation can be corrected phenotypically by increasing the osmolarity of the medium. In the presence of 0.6 M sucrose, the population of PM61 is composed of short rods, and the phosphatidylglycerol/cardiolipin ratio is shifted to that of the parent. The phosphatidylglycerol turns over more slowly, whereas the cardiolipin turns over more rapidly in both strains. Thus, the increase of external osmolarity acts on phospholipid metabolism as well as on an unknown step involved in the mechanism of cell division of the envC mutant.

Cardiolipins↗
PubMed1977

Outer membrane phospholipase A from Acinetobacter sp. HO1-N.

A phospholipase A1 activity that hydrolyzed cardiolipin to triacyl- and diacyl-lysocardiolipin was localized in outer membrane preparations derived from Acinetobacter sp. HO1-N. The specific activity of the enzyme derived from hexadecane-grown cells was 2.5 to 3 times higher than that derived from NBYE-grown cells. An apparent Km of 2.22 mM was determined, although inhibition kinetics resulted at the higher cardiolipin substrate concentrations. Optimal reaction conditions established on metal requirements. Enzyme activity was obligately dependent on Triton X-100 (0.5%) and was inhibited by cationic and anionic detergents. Cardiolipin-specific phospholipase D converted triacyl-lysocardiolipin to lysophosphatidylglycerol and phosphatidic acid. The specific activity of this enzyme was approximately 100 times greater than that reported for other membrane preparations derived from microorganisms.

Acinetobacter↗
PubMed1978

Membrane phospholipid asymmetry in Bacillus amyloliquefaciens.

The phospholipid distribution in the membrane of Bacillus amyloliquefaciens was studied by using phospholipase C (B. cereus), phospholipase A2 (Crotalus), and the nonpenetrating chemical probe trinitrobenzenesulfonic acid. After treatment of intact protoplasts of B. amyloliquefaciens with either phospholipase, about 70% of total membrane phospholipid was hydrolyzed; specifically, about 90, 90, and 30% of phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin, respectively. Under these conditions, protoplasts remained intact and sealed. However, when protoplasts that were permeabilized by cold-shock treatment were incubated with either of the phospholipases, up to 80% of cardiolipin was hydrolyzed and phosphatidylglycerol and phosphatidylethanolamine were hydrolyzed virtually to completion. In intact cells, 92% of the phosphatidylethanolamine could be labeled with trinitrobenzenesulfonic acid under conditions in which the reagent did not penetrate the membrane to any significant extent. These results indicate that 70% of total phospholipid of this bacillus exists in the outer half of the bilayer. The distribution of phosphatidylethanolamine in this bilayer is highly asymmetric with it being located predominantly in the outer half. The results with phospholipases suggest that the distributions of cardiolipin and phosphatidylglycerol are also asymmetric but independent confirmation of this is required.

Bacillus↗