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At least 19 recordsLinked to original sources

PubMed1991

Molecular species of cardiolipin in relation to other mitochondrial phospholipids. Is there an acyl specificity of the interaction between cardiolipin and the ADP/ATP carrier?

Molecular species in the three major mitochondrial lipids cardiolipin, phosphatidylcholine and phosphatidylethanolamine were analysed in bovine heart and Saccharomyces cerevisiae. In both organisms cardiolipin contains mainly diacylglycerol moieties with two unsaturated chains and a significant higher proportion of C18-C18 species than phosphatidylcholine and phosphatidylethanolamine. To study whether the specific acyl composition of cardiolipin has a functional significance in lipid-protein interaction, experiments were made with the isolated ADP/ATP carrier of bovine heart mitochondria since this dimeric protein is known to be tightly associated with six molecules of cardiolipin [Beyer, K. and Klingenberg, M. (1985) Biochemistry 24, 3821-3826]. This association seems to be very strong as protein-bound cardiolipin does not exchange with soluble cardiolipin on a time scale of hours. Analysis of the species composition suggests that one carriers dimer is associated with four molecules of tetralinoleoyl cardiolipin and two molecules of trilinoleoyl-monolinolenoyl cardiolipin. Catalytic hydrogenation of the acyl chains of carrier-bound cardiolipin does not result in release of cardiolipin as judged by 31P-NMR spectroscopy. The ADP/ATP carrier was reconstituted with saturated phosphatidylcholines and spin-labelled cardiolipin whose double bonds were subsequently saturated by catalytic hydrogenation. ESR spectroscopy shows that saturation of spin-labelled cardiolipin has no significant impact on its association with the ADP/ATP carrier. However, precipitation of the detergent-solubilized ADP/ATP carrier can only be induced by addition of unsaturated but not by saturated cardiolipin. It is concluded that the specific acyl composition of cardiolipin is not a prerequisite of its high affinity for the ADP/ATP carrier, at least when the protein is reconstituted in a saturated phosphatidylcholine environment.

Animals↗

PubMed2002

Expression of monolysocardiolipin acyltransferase activity is regulated in concert with the level of cardiolipin and cardiolipin biosynthesis in the mammalian heart.

BACKGROUND: Monolysocardiolipin acyltransferase (MLCL AT) catalyzes the acylation of monolysocardiolipin to cardiolipin in mammalian tissues. We previously reported that cardiac cardiolipin levels, MLCL AT and cardiolipin synthase activities were all elevated in rats made hyperthyroid by thyroxine treatment. In this study, we examined if cardiac mitochondrial MLCL AT activity was dependent upon the biosynthesis and level of cardiolipin in the heart. Rat heart mitochondrial MLCL AT activity was determined under conditions in which the levels of cardiac cardiolipin and cardiolipin synthase activity were either reduced or unaltered using four different disease models in the rat. In addition, these parameters were examined in a murine model of cardiac cell differentiation. RESULTS: In rats made hypothyroid by treatment with 6-n-propyl-2-thiouracil in the drinking water for 34 days, cardiac cardiolipin content was decreased 29% (p < 0.025) and this was associated with a 32% decrease (p < 0.025) in cardiolipin synthase and a 35% reduction (p < 0.025) in MLCL AT activities. Streptozotocin-induced diabetes or hyperinsulinemia in rats did not affect cardiac cardiolipin content nor MLCL AT and cardiolipin synthase activities. Finally, cardiolipin content, MLCL AT and cardiolipin synthase activities were unaltered during murine P19 teratocarcinoma cell differentiation into cardiac myocytes. In all models, phospholipase A2 activities were unaltered compared with controls. CONCLUSION: We propose a general model in which the expression of MLCL AT activity is regulated in concert with the biosynthesis and level of cardiolipin in the heart.

Acyltransferases↗

PubMed1975

Electron spin resonance studies on the lipid-protein interaction between cardiolipin and anti-cardiolipin antibodies.

Electron spin resonance measurements were performed in order to investigate the influence of anti-cardiolipin antibodies on cardiolipin-containing liposomes. The physical state of the lipid structures and the alterations caused by the interaction with specific antibody were determined by measuring the freedom of motion of spin-labeled stearic acid derivatives incorporated into the lipid structures. The interaction of the cardiolipin-containing liposomes with the anti-cardiolipin antibodies reduced the mobility of the spin-labeled stearic acid probe I (12, 3), whose nitroxide group is assumed to be located near the polar region of the lipid bilayer. The restricted mobility, which qualitatively resembles the interaction of cardiolipin liposomes with calcium ions, is probably the result of a tighter packing of the polar groups in their crystalline array. The binding sites of the cardiolipin structures for anti-cardiolipin antibodies and Ca2 ions seem to be identical. As indicated by the spin-labeled stearic acid probe I (1, 14), the apolar region of the lipid bilayer is not affected by the interaction of the cardiolipin-containing liposomes with the anti-cardiolipin antibodies.

Antigen-Antibody Reactions↗

PubMed1990

Activation of beef-heart cytochrome c oxidase by cardiolipin and analogues of cardiolipin.

Beef-heart cytochrome c oxidase lacking endogenous lipids can be prepared by cholate-mediated exchange with dimyristoylphosphatidylcholine (Powell, G. L., Knowles, P. F. and Marsh, D. (1985) Biochim. Biophys. Acta 816, 191-194). These preparations retained practically no endogenous cardiolipin (less than 0.19 mol cardiolipin per mol of oxidase) but in Tween 80 they retained unaltered electron transport activity. Resupplementation of the dimyristoylphosphatidylcholine-substituted cytochrome oxidase with cardiolipin and cardiolipin analogues with different numbers of acyl chains or with a methylated headgroup enhanced the activity of the reconstituted enzyme to an extent dependent on the structure of the cardiolipin derivative. The Eadie-Hofstee plot showed biphasic kinetic behavior for all reconstituted preparations, even those completely lacking cardiolipin. This biphasic substrate dependence of the kinetics was simulated using the model of Brzezinski, P. and Malmström, B. G. (Proc. Natl. Acad. Sci. USA 83 (1986) 4282-4286), which implicates two interconverting enzyme conformations in the proton transport step. The activation of cytochrome c oxidase by the cardiolipin analogues could be explained in terms of an electrostatic enhancement of the surface concentrations of both cytochrome c and protons, and a facilitated interconversion between the two enzyme conformations.

Animals↗

PubMed1995

Immunoglobulin gene sequence analysis of anti-cardiolipin and anti-cardiolipin idiotype (H3) human monoclonal antibodies.

Heavy and light chain variable region nucleotide sequences were derived from 6 human hybridoma antibodies which bear characteristics of antibodies associated with the phospholipid antibody syndrome. All antibodies originated from non-autoimmune individuals and were polyspecific. Four of these reacted with cardiolipin (and other antigens) and three carried the H3 idiotype which is expressed on a high percentage of disease-associated anti-cardiolipin antibodies. This idiotype was localized to the lambda light chain of the H3 monoclonal antibody and found on two other antibodies which like H3 expressed V lambda 4 or the related V lambda 3 subgroup light chains. The H3 idiotype however did not define these subgroups nor was it required or sufficient for anti-cardiolipin activity. Anti-cardiolipin binding was found in VH1, VH3 and VH4 heavy chain families and in a V kappa 1 light chain. The D region was diverse in both length and gene usage. Although all cardiolipin binding antibodies showed little deviation from germline variable (V) gene sequences, where mutations occurred they tended to be replacement mutations and clustered in complementarity determining regions (CDR) suggesting these B cells were derived from antigen-driven responses. These results from our panel of hybridomas and their comparison to other human antibodies provide extensive information on the diversity of genetic elements which can be used by cardiolipin-binding antibodies. We also show gene sequences which encode the disease-associated H3 idiotype and its location on lambda light chains, which imply that some labda light chains may be preferentially utilized in auto-reactive hybridomas.

Amino Acid Sequence↗

PubMed1987

Cholesterol effects on the interaction of cardiolipin with anti-cardiolipin antibody.

Human antibodies to cardiolipin, phosphatidic acid and phosphatidylserine were assessed by binding to nitrocellulose paper and subsequent reaction with an enzyme-linked or radioactively labelled second antibody to human IgG. The addition of cholesterol to constant amounts of cardiolipin impregnated in the nitrocellulose paper resulted in a profound fall in antibody binding beginning at a 0.5 to 1 molar ratio of cholesterol to cardiolipin and stabilizing at about 15% of the original level. Antibody binding to phosphatidic acid and phosphatidylserine also showed extensive cholesterol-induced inhibition beginning at a slightly lower molar ratio of cholesterol to phospholipid. The structural array of neither the cardiolipin alone impregnated in nitrocellulose nor the phospholipid together with cholesterol is known. It is possible that the specific cardiolipin phase structure required for human antibody recognition was disrupted by cholesterol.

Autoantibodies↗

PubMed1988

Synthesis of cardiolipin derivatives with protection of the free hydroxyl: its application to the study of cardiolipin stimulation of cytochrome c oxidase.

Cardiolipin derivatives retaining the free hydroxyl on the polar head group were synthesized. With the use of a tetrahydropyranyl ether to protect this hydroxyl, fatty acyl substitutions were made at both of the 2-positions of cardiolipin (CL). The disubstituted derivatives were obtained in high yields. The stimulation of delipidated cytochrome c oxidase activity shows a hyperbolic dependence on the concentration of these CL derivatives. Both activation parameters, the apparent dissociation constant (Kd,app) and the maximum change in molecular activity (delta Actmax), depend on the chain length of the tails, with less dependence on the degree of saturation. Natural CL (92% C18:2, 8% C18:1) and CL disubstituted with oleic acid (47% C18:2, 52% C18:1) were equally effective at stimulating cytochrome c oxidase activity, with an apparent dissociation constant of approximately 1 microM when incubated in 0.3% Triton X-100 and assayed in lauryl maltoside. CL disubstituted with hexanoic acid, however, is a poorer activator, with an apparent dissociation constant of 6.8 microM and a delta Actmax that is 50% of that achieved with natural CL. Dilysocardiolipin, with complete removal of two of the fatty acid tails, shows negligible stimulation of cytochrome c oxidase activity.

Cardiolipins↗

PubMed1985

Cardiolipin vesicles can accommodate cholesterol up to 0.80 mole fraction, i.e. one molecule per cardiolipin fatty acid chain.

Cardiolipin-cholesterol interactions were studied by time-resolved fluorescence spectroscopy with 1,6-diphenyl-1,3,5-hexatriene as probe. The residual anisotropy parameter, r infinity (reflecting the fatty acid chain packing), was measured in the liquid crystalline phase as a function of cholesterol addition. Two main results are reported: (i) a slight increase of the order parameter, S, computed from the r infinity value as S = (r infinity/r0)1/2, in the physiological concentration range of cholesterol; (ii) a sharp enhancement of S from a cholesterol mole fraction (X chl) of 0.20 and up to X chl of 0.80. This is in contrast to unsaturated lecithin systems for which a continuous increase of the order parameter was monitored, culminating at X chl = 0.50, the well-known maximum level of incorporation of cholesterol into lecithin model membranes.

Animals↗

PubMed1992

Implications of modifying cardiolipin acyl composition by diet. 1. Cardiolipin acyl chain is an important determinant in the binding to antiphospholipid antibodies in SLE sera.

Antiphospholipid antibodies (aPL), prevalent in sera of patients with systemic lupus erythematosus (SLE), have been linked to thrombosis, thrombocytopenia, recurrent miscarriages, neurological disorders and ischemic heart disease. Most evidence suggests that phosphodiester-linked phosphate groups are the reactive epitope of cardiolipin (CL) in binding to aPL. Little attention has been given to the acyl moiety. To address this problem we have evaluated the ELISA binding of 12 highly positive IgG anticardiolipin antibody-positive SLE sera to: bovine CL (86.1% 18:2n-6), monolyso CL (MLCL; bovine CL minus 1 fatty acid), dilyso CL (DLCL; minus 2 fatty acids), tetraoleoyl CL (TOCL), myristoyl CL (MCL) and E. coli CL. The reductions in binding of the IgG aPL antibodies relative to bovine CL were as follows: DLCL 83%; MLCL 70.7%; MCL 58%; and TOCL 14% (P less than 0.05). These data suggest that the number of acyl chains and the unsaturation of the acyl chain of CL may be important determinants in the binding to aPL present in SLE sera. To investigate the nutritional relevance of this finding, we examined the incorporation of several dietary fatty acid classes into the CL pool of mice. Mice were fed diets containing n-6 (safflower oil), n-9 (olive oil) or n-3 fatty acids as either 18:3n-3 (linseed oil) or 20:5n-3/22:6n-3 (fish oil) for a 5 month period. The feeding of fish oil and olive oil resulted in replacement of a substantial portion of 18:2n-6 with 22:6n-3 or 18:1n-9, respectively. These results suggest that there may be therapeutic value in modifying the CL acyl composition by nutritional means with respect to binding to pathogenic aPL.

Animals↗

PubMed1990

Cardiolipin-depleted bovine heart cytochrome c oxidase: binding stoichiometry and affinity for cardiolipin derivatives.

Detergent-solubilized bovine heart cytochrome c oxidase requires 2 mol of tightly bound cardiolipin (CL) per mole of monomeric complex for functional activity. Four lines of evidence support this conclusion: (1) Phospholipid depletion shows that two tightly bound CL's must remain associated with cytochrome c oxidase in order to maintain full electron transport activity. (2) Removal of the two tightly bound CL's correlates with decreased activity that is restored by reassociation of 2 mol of exogenous CL. (3) CL-depleted cytochrome c oxidase has two high-affinity binding sites for 2-[14C]acetylcardiolipin (AcCL), Kd,app less than 0.1 microM, that are not present in enzyme containing endogenous CL. An additional 2-3 lower affinity AcCL binding sites, Kd,app = 4 microM, are present in the CL-depleted complex, but these sites are also present in enzyme containing endogenous CL. (4) CL, monolysocardiolipin (MLCL), and dilysocardiolipin (DLCL) compete for AcCL binding with approximately the same relative affinities as those measured by the restoration of electron transport activity (MLCL competes much better than DLCL). However, MLCL and DLCL are only 60% and 15% as effective as CL in restoring maximum activity when they are bound to the high-affinity sites. The binding specificity of CL, MLCL, DLCL, and some of their acylated derivatives indicates that the apolar tails are most important for binding, not the polar head group. The presence or absence of hydroxyl groups in CL, MLCL, or DLCL also has little effect upon binding affinities. Binding specificity clearly favors CL since phosphatidylglycerol, phosphatidic acid, and phosphatidylcholine each have very low affinity for the CL binding sites (Kd,app greater than 20 microM). We, therefore, conclude that restoration of activity to CL-depleted cytochrome c oxidase is highly specific and requires the reassociation of CL, or structurally similar compounds, with two high-affinity binding sites.

Animals↗

PubMed1998

Anti-cardiolipin antibody and anti-cardiolipin beta-2-glycoprotein I antibody in patients with recurrent fetal miscarriage.

To elucidate the association between anticardiolipin antibody (aCL-Ab) or anti-cardiolipin beta-2-glycoprotein I-antibody (aCL-beta-2-GP I-Ab) and recurrent fetal miscarriage, the positive rates of aCL-Ab were assessed in 667 patients with recurrent fetal miscarriages and those of aCL-beta-2-GP I-Ab were assessed in 208 patients. The rates were then compared with the control group. The positive rate of aCL-Ab in the patients group (17.4%) was significantly higher than that in the control group (4.0%). The rate of aCL-Ab was especially high in patients who had experienced two or more fetal miscarriages including at least one or more intrauterine fetal deaths during the second or third trimester (41.3%). The positive rate of aCL-beta-2-GP I-Ab in patients with recurrent fetal miscarriage (3/208 cases, 1.4%) was not significantly different from the control group (0/100 cases, 0%). However, the rate of aCL-beta-2-GP I-Ab was significantly higher in patients who had experienced two or more fetal miscarriages including at least one or more intrauterine fetal deaths during the second or third trimester (8.3%) compared with the control group. In conclusion, the implication of aCL-Ab in the genesis of recurrent fetal miscarriage was confirmed. It was suggested that aCL-beta-2-GP I-Ab was associated with the generation of intrauterine fetal death, although it had little association with the genesis of recurrent fetal miscarriage during the first trimester.

Abortion, Habitual↗

PubMed1957