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PubMed1980

Composition of cardiolipin molecular species in Escherichia coli.

The composition of the molecular species of acidic phospholipids in Escherichia coli B during the late exponential growth phase at 37 degrees C was determined. Two phosphatidyl groups of cardiolipin, the 3-(3-sn-phosphatidyl) and 1-(3-sn-phosphatidyl) moieties of cardiolipin, were isolated by limited hydrolysis with phospholipase C. No significant difference in the composition of the molecular species was found between the 3-(3-sn-phosphatidyl) and 1-(3-sn-phosphatidyl) moieties. On the other hand, the composition of the molecular species of phosphatidylglycerol was different from that of cardiolipin. Phosphatidylglycerol contained more of the 1-palmitoyl 2-cis-9,10-methylenehexadecanoyl and 1-palmitoyl 2-cis-11,12-methyleneoctadecanoyl species than did cardiolipin. The difference in the composition of the molecular species between cardiolipin and phosphatidylglycerol may depend on the difference in the turnover rates of both phospholipids.

Cardiolipins↗

PubMed1990

Mechanism and localization of cardiolipin biosynthesis revisited: evidence for the identical mechanism and different localization in mitochondrial and submitochondrial membranes isolated from guinea pig and rat liver.

The mechanism of cardiolipin (diphosphatidylglycerol) biosynthesis was examined in mitochondria and outer and inner mitochondrial membranes prepared from guinea pig and rat livers to determine whether this formation from phosphatidylglycerol was absolutely dependent on cytidinediphosphodiglyceride, as previously reported for intact mitochondria. Experimental results confirmed that the biosynthesis of cardiolipin, from the membrane-bound radioactive phosphatidylglycerol in intact mitochondria isolated from guinea pig and rat liver, was absolutely dependent on CDP-diglycerides and required the addition of divalent cations. Furthermore, the same mechanism for the biosynthesis of cardiolipin was operational in the outer and inner mitochondrial membranes. This biosynthesis was associated with both the outer and inner mitochondrial membranes prepared from guinea pig liver, but only with the inner mitochondrial membranes prepared from rat liver. The release of radioactive glycerol was also measured, but the amount obtained did not satisfy the stoichiometric requirement for CDP-diglyceride-independent biosynthesis of cardiolipin from 2 mol of phosphatidylglycerol with the liberation of 1 mol of glycerol. Therefore, it was concluded that this mechanism is not involved in the biosynthesis of cardiolipin in mitochondrial and submitochondrial membranes prepared from guinea pig and rat liver.

Animals↗

PubMed2001

Myocardial ischemia selectively depletes cardiolipin in rabbit heart subsarcolemmal mitochondria.

Mitochondria contribute to myocyte injury during ischemia. After 30 and 45 min of ischemia in the isolated perfused rabbit heart, subsarcolemmal mitochondria (SSM), located beneath the plasma membrane, sustain a decrease in oxidative phosphorylation through cytochrome oxidase. In contrast, oxidation through cytochrome oxidase in interfibrillar mitochondria (IFM), located between the myofibrils, remains unaffected. Cytochrome oxidase activity in the intact membrane requires an inner mitochondrial membrane lipid environment enriched in cardiolipin. During ischemia, the content of cardiolipin decreased only in SSM, whereas the content of other phospholipids was preserved. Ischemia did not alter the composition of the cardiolipin that remained in SSM. Cardiolipin content was preserved in IFM during ischemia. Thus cardiolipin is a relatively early target of ischemic mitochondrial damage, leading to loss of oxidative phosphorylation through cytochrome oxidase in SSM.

Animals↗

PubMed2006

Selective remodeling of cardiolipin fatty acids in the aged rat heart.

BACKGROUND: The heart is rich in cardiolipin, a phospholipid acylated in four sites, predominately with linoleic acid. Whether or not aging alters the composition of cardiolipin acyl chains is controversial. We therefore measured the fatty acid concentration of cardiolipin in hearts of 4, 12 and 24 month old rats that consumed one diet, adequate in fatty acids for the duration of their life. RESULTS: The concentration (nmol/g) of linoleic acid was decreased in 24 month old rats (3965 +/- 617, mean +/- SD) vs 4 month old rats (5525 +/- 656), while the concentrations of arachidonic and docosahexaenoic acid were increased in 24 month old rats (79 +/- 9 vs 178 +/- 27 and 104 +/- 16 vs 307 +/- 68 for arachidonic and docosahexaenoic acids, 4 months vs 24 months, respectively). Similar changes were not observed in ethanolamine glycerophospholipids or plasma unesterified fatty acids, suggesting specificity of these effects to cardiolipin. CONCLUSION: These results demonstrate that cardiolipin remodeling occurs with aging, specifically an increase in highly unsaturated fatty acids.

Aging↗

PubMed2003

Osmotic shock stimulates de novo synthesis of two cardiolipins in an extreme halophilic archaeon.

The present report illustrates the response to osmotic stress of an extreme halophilic archaeon, Halorubrum sp., isolated from the saltern ponds of Margherita di Savoia in southern Italy. The hypotonic stress induces relevant changes in the membrane lipid composition: archaeal cardiolipin content markedly increases, whereas phosphatidylglycerol (PG) decreases. Membranes isolated from this archaeon after cell disruption by osmotic shock are highly enriched in archaeal cardiolipin and reveal the presence of a novel phospholipid. Electrospray ionization mass spectrometry and NMR analyses revealed that this novel lipid has the structure of a sulfo-diglyco-diether-phosphatidic acid, i.e., a phospholipid dimer or a novel cardiolipin analogue. As NMR analyses showed that the sugars in the novel phospholipid dimer are the same and in the same order of a sulfated diglycosyl diphytanylglycerol diether (S-DGD-5) present as a major lipid component in the archaeon membranes, the novel phospholipid dimer was named S-DGD-5-PA. We conclude that osmotic shock induces a specific increase in the membrane content of the two cardiolipins and suggest that PG and S-DGD-5 are intermediates for the de novo synthesis of archaeal cardiolipin and S-DGD-5-PA, respectively.

Cardiolipins↗

PubMed1998

Activation of the 20S proteasome of Xenopus oocytes by cardiolipin: blockage of the activation of trypsin-like activity by the substrate.

The effects of an activator, cardiolipin, on the three peptidase activities of the 20S proteasome of Xenopus oocytes were examined. The trypsin-like activity was activated when the enzyme was treated with cardiolipin before the addition of the substrate, but there was no appreciable activation when cardiolipin was added concomitantly with the substrate. On the other hand, the chymotrypsin-like peptidase and peptidylglutamylpeptide hydrolase (PGPH) were activated regardless of the sequence of addition. When very low concentrations of the substrate (e.g. 0.1-0.5 microM; about 1/100 of the K(m)) were used, cardiolipin strongly activated trypsin-like peptidase by the simultaneous addition but not after substrate addition. These results suggest that the trypsin-type substrate produces a conformational change in the enzyme in a concentration-dependent manner which makes the activator sites inaccessible to cardiolipin.

Animals↗

PubMed2000

Oxidative phosphorylation in cardiolipin-lacking yeast mitochondria.

The role of cardiolipin in mitochondrial energy transformation was studied by comparing oxidative phosphorylation in the Saccharomyces cerevisiae cardiolipin synthase null mutant crd1Delta, and in isogenic wild type. Oxygen consumption experiments and membrane potential kinetics during the phosphorylation cycle in isolated mitochondria indicated that the absence of cardiolipin causes only a moderate deficiency of mitochondrial energy-transforming machinery at 25 degrees C. However, at 40 degrees C, respiration was completely uncoupled from phosphorylation for the mutant mitochondria, in contrast with that for the wild-type. Membranepotential kinetics demonstrated an increased susceptibility of the mutant mitochondria to gradual deterioration during in vitro incubation. These results suggest that cardiolipin, although normally associated with several of the major enzymes of oxidative phosphorylation and required in vitro for their maximal activity, is not absolutely necessary for mitochondrial energy transformation under optimal conditions. The role of cardiolipin is, rather, to improve efficiency of oxidative phosphorylation and its resistance to unfavourable conditions, such as increased temperature.

Adenosine Triphosphate↗

PubMed1975

Adaptive changes in cardiolipin content of Staphylococcus aureus grown in different salt concentrations.

Adaptive changes in cardiolipin content were examined in Staphylococcus aureus 209P using the 32P pulse-labelling method. Cardiolipin synthesis showed increased adaptation when cells grown in normal medium were transferred into high NaCl containing medium. When S. aureus cultured in 10% NaCl medium was transferred back to normal medium, cardiolipin concentration decreased to the normal level within 3 hours. The catabolic rate of cardiolipin in the cells was much slower in the 5% NaCl medium than in normal medium. The cardiolipin synthetase activity was examined by isolated membrane fraction from S. aureus grown both in normal and 10% NaCl medium. The activity was higher by two-fold in membrane fractions from cells cultured in 10% NaCl-containing medium than in membranes from cells cultured in normal medium.

Adaptation, Biological↗

PubMed2005

[Recurrent miscarriage or failed in-vitro fertilization: antibodies against annexin V, cardiolipin, beta-2-glycoprotein-1 and APC-resistance].

UNLABELLED: Antibodies against annexin-V, a potent anticoagulant abundant in placental tissues, were recently controversially reported to be associated with recurrent miscarriages or failures of in-vitro-fertilization (IVF) attempts. PATIENTS, MATERIAL, METHODS: We screened 56 women (34.7 +/- 4.3 years of age: mean +/- 1 SD) with recurrent IVF failures and/or early pregnancy losses for resistance against activated protein C, lupus anticoagulant and antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. Among them the prevalence of APC-R (8/56, 14%) and elevated levels of IgG- or IgM-anti-cardiolipin antibodies (7/56, 12%) were more common than elevated levels of (IgG or IgM) antibodies against beta(2)-glycoprotein-1 (3/56, 5%) or annexin-V (1/56, 2%). 42 (75%) of the women had another IVF-attempt after this haemostaseological evaluation and received low molecular weight heparin and/ or acetylsalicylic acid in the case of positivity for APC-resistance, lupus anticoagulant or antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. RESULTS: The outcome of these IVF-attempts were 19 pregnancies (34%): 4 early miscarriages (7%) and 15 so far uncomplicated pregnancies (27%). The only woman with an elevated anti-annexin V (IgG) level had had 7 IVF before and received 40 mg Enoxaparin (Lovenox) subcutaneously once daily during the 8(th) IVF, which resulted in a healthy pregnancy. DISCUSSION, CONCLUSION: Our findings suggest that among women with recurrent IVF failures anti-annexin V antibody positivity is less prevalent than APC-resistance, lupus anticoagulant (LA) or elevated levels of antibodies against cardiolipin, beta(2)-glycoprotein-1 and that the IVF-result of women with APC-R, LA or with elevated levels of antibodies against annexin V, cardiolipin or beta(2)-glycoprotein might be positively influenced by low molecular weight heparin.

Abortion, Habitual↗

PubMed1989

[Clinical analysis of anti-cardiolipin antibody positive patients with systemic lupus erythematosus].

We have analyzed the relationship between anti-cardiolipin antibody titer and manifestations in 68 patients with systemic lupus erythematosus (SLE), 25 patients with progressive systemic sclerosis (PSS), 37 patients with Sjögren's syndrome and 16 patients with anaphylactoid purpura. Elevated anti-cardiolipin antibody titer was observed in SLE and Sjögren's syndrome. Clinical manifestations correlated with elevated anti-cardiolipin antibody titer included discoid lesion, thrombotic lesion, thrombocytopenia, elevated titer of ds-DNA antibodies, lower serum CPK level, and liver dysfunctions. Anti-cardiolipin antibody titer also correlated with the score of diagnostic criteria for SLE and the history of corticosteroid therapy. These results suggested that anti-cardiolipin antibody positive SLE patients are much more prone to develop thrombotic lesions and that cell bound antibody might play some role for the induction of vascular injury and thrombocytopenia in SLE.

Antibodies↗

PubMed1988

Monoclonal hybridoma anti-cardiolipin antibodies from SLE mice.

To determine whether the anti-cardiolipin antibodies are identical with the lupus anticoagulant and other antibodies to phospholipids and DNA, we prepared monoclonal hybridoma autoantibodies to cardiolipin from SLE-prone MRL/lpr mice and characterized their specificity. Using a somatic cell hybridization technique, we established three hybridoma clones which produce antibodies to cardiolipin (CAL-1: IgG2b, k, CAL-2: IgM, k and CAL-3: IgM, k). These hybridoma antibodies preferentially reacted with cardiolipin and phosphatidylserine, weakly reacted with phosphatidylinositol, but not with other phospholipids such as phosphatidylcholine, sphingomyelin, phosphatidylethanolamine and VDRL antigen. Two hybridoma anti-cardiolipin antibodies bound to ssDNA and were found to act as the lupus anticoagulant when mixing activated partial thromboplastin time with cephalin. These autoantibodies may prove to be good tools for elucidating mechanisms of thrombosis, thrombocytopenia, fetal loss and other related manifestations found in patients with systemic lupus erythematosus.

Animals↗

PubMed1987

Anti-mitochondrial type M5 and anti-cardiolipin antibodies in autoimmune disorders: studies on their association and cross-reactivity.

In a series of 42 positive sera, anti-mitochondrial type M5 antibodies (AMA-M5) were found most frequently in patients with SLE (24) and SLE-like syndromes. Patients with AMA-M5 displayed a higher prevalence of thrombocytopenia, thrombosis, biological false positive seroreactions for syphilis, lupus-like anticoagulant activity and anti-cardiolipin antibodies in comparison with a group of 43 SLE AMA-M5 negative patients. The strong association between anti-phospholipid and AMA-M5 antibodies cannot be explained entirely by cross-reactivity between these two groups of antibodies, as indicated by absorption experiments and studies using affinity purified antibody preparations. However, cardiolipin liposomes were able to reduce partially the titres of AMA-M5 sera, suggesting that a small population of AMA-M5 antibodies exists that cross-reacts with cardiolipin. The existence of this population was further substantiated by our demonstration that an IgM monoclonal antibody, from a patient with Waldenström's macroglobulinaemia, displayed both anti-cardiolipin and AMA-M5 activity, and AMA-M5 activity was completely inhibited by cardiolipin.

Adult↗

PubMed1985

Affinity purified anti-cardiolipin and anti-DNA antibodies.

Recent studies have raised questions concerning the specificity of anticardiolipin antibodies and their relationship to anti-DNA antibodies, the lupus anticoagulant, the biological false positive test for syphilis, and reagin, the antibody detected in syphilis. In an attempt to answer some of these questions, 3 IgG and 2 IgM affinity purified anticardiolipin antibodies, as well as 3 affinity purified anti-DNA antibodies were studied. Affinity purified anti-cardiolipin antibodies showed high binding to negatively charged phospholipids but not to ssDNA by solid phase radioimmunoassay. On the other hand, affinity purified anti-DNA antibodies did not bind cardiolipin. Inhibition experiments showed that negatively charged phospholipids and VDRL liposomes inhibited the binding of anticardiolipin antibodies to phosphatidylserine, but ssDNA, alpha-glycerol phosphate and hyaluronic acid did not. Similar studies of sera from patients with high anticardiolipin antibody levels supported the results obtained with affinity purified anticardiolipin antibodies. These results suggest that anticardiolipin antibodies bind negatively charged phospholipids and there appears to be little crossreactivity with DNA or unrelated negatively charged polymers such as hyaluronic acid. Both the negatively charged phosphodiester group and glyceride portions of the phospholipid molecules appear important for their antigenicity. Four of the 5 affinity purified anti-cardiolipin antibodies had lupus anticoagulant activity providing further evidence to suggest that these 2 groups of antibodies have the same or very similar specificities. Studies of sera from 3 patients with syphilis showed that VDRL liposomes inhibited reagin activity to a greater extent than did cardiolipin. On the other hand, in patients with autoimmune disorders, cardiolipin inhibited anticardiolipin antibody activity to a greater extent than did VDRL liposomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗

PubMed1995

Kinetic analysis of cardiolipin synthase: a membrane enzyme with two glycerophospholipid substrates.

Mitochondrial cardiolipin synthase catalyzes the transfer of a phosphatidyl moiety from phosphatidyl-CMP (PtdCMP) to phosphatidylglycerol (PtdGro) in the presence of specific divalent cations. The synthase was solubilized from Saccharomyces cerevisiae mitochondria and purified about 300-fold. The partially enzyme was part of a medium-size, mixed micelle which had to bind to a foreign substrate/detergent micelle before catalysis could occur. The kinetics of cardiolipin synthase were studied by changing the molar fraction of substrate in the micelles. The enzyme obeyed Michaelis-Menten kinetics in relation to PtdCMP with a Km of 0.03 mol%. PtdGro caused sigmoidal kinetics with a low apparent affinity. It is speculated that it was involved in docking the enzyme to the substrate/detergent micelle. Cardiolipin synthase did not catalyze isotope exchange between [14C]CMP and PtdCMP, virtually excluding a ping-pong catalytic mechanism. Mg2+ stimulated the activity by increasing the turnover number rather than the substrate affinity, a mechanism which was also found for the Co(2+)-activation of rat liver cardiolipin synthase. It is concluded that a direct association of the metal ion and the enzyme forms the active cardiolipin synthase which has a very high affinity for PtdCMP and a lower affinity for PtdGro.

Animals↗

PubMed1991

Effect of thyroxine on the activity of mitochondrial cardiolipin synthase in rat liver.

Cardiolipin is a major mitochondrial membrane lipid and plays a vital role in mitochondrial function. The effect of thyroxine on the activity of liver mitochondrial cardiolipin synthase was examined in this study. Treatment with thyroxine (250 micrograms/100 g) for 5 days increased cardiolipin synthase activity by 52%. Mitochondrial levels of cardiolipin appear to be regulated in part by the effect of thyroid hormone on the activity of cardiolipin synthase.

Animals↗

PubMed2001

Reactive oxygen species generated by the mitochondrial respiratory chain affect the complex III activity via cardiolipin peroxidation in beef-heart submitochondrial particles.

The aim of this study was to investigate the effect of reactive oxygen species (ROS), produced by the mitochondrial respiratory chain, on the activity of complex III and on the cardiolipin content in bovine-heart submitochondrial particles (SMP). ROS were produced by treatment of nicotinamide adenine dinucleotide (NADH) respiring SMP with rotenone. This treatment resulted in a production of superoxide anion, detected by the epinephrine method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to mitochondrial-mediated ROS generation resulted in a marked loss of complex III activity and in a parallel loss of mitochondrial cardiolipin content. Both these effects were completely abolished by SOD + catalase. Exogenous added cardiolipin was able to almost completely prevent the ROS-mediated loss of complex III activity. No effect was obtained with other major phospholipid components of the mitochondrial membrane such as phosphatidylcholine and phosphatidylethanolamine, or with peroxidized cardiolipin. The results demonstrate that mitochondrial-mediated ROS generation affects the activity of complex III via peroxidation of cardiolipin, which is required for the functioning of this multisubunit enzyme complex. These results may prove useful in probing molecular mechanisms of ROS-induced peroxidative damage to mitochondria, which have been proposed to contribute to those physiopathological conditions characterized by an increase in the basal production of ROS such as aging, ischemia/reperfusion and chronic degenerative diseases.

Journal Article↗

PubMed1997

Dietary fat affects lipids and anti-cardiolipin antibody levels in autoimmune-prone NZB/W F1 mice.

Studies in autoimmune-prone NZB/W F1 mice have demonstrated that the amount of dietary fat can affect autoantibody production and the disease course of autoimmune diseases. Anti-cardiolipin antibodies have been found to play a major role in thrombus formation and the increase of abortion rate in both human lupus patients and murine lupus. The present study investigated further the effect of dietary fat on lipid and anti-cardiolipin antibody production in autoimmune-prone mice. Two groups of NZB/W F1 mice were fed on diets containing 200 g dietary fat/kg and 50 g dietary fat/kg respectively, the fat being composed of equal amounts of lard and soyabean oil. Serum levels of lipids, immunoglobulin (Ig) anti-single stranded DNA and anti-cardiolipin antibodies were followed regularly every month and mice were killed for in vitro experiments after 5 months on the experimental diets. The results showed that serum triacylglycerol concentration was lower in mice fed on the high-fat diet than in those fed on 50 g fat/kg. There was no significant difference in hepatic lipid contents; however, the fatty acid contents were different between these two groups. Hepatic linoleic acid (18:2n-6) and arachidonic acid (20:4n-6) concentrations were higher in mice fed on the high-fat diet. There were no significant differences in serum IgM concentrations or IgM anti-cardiolipin antibody levels between these two groups. However, IgG anti-cardiolipin antibody levels were higher in mice fed on the high-fat diet at the age of 3-4 months. Total serum IgG concentration was noted to be higher, but in contrast, serum IgA was lower, in the high-dietary-fat group. These findings suggest that high dietary fat may affect lipid metabolism and autoantibody levels in autoimmune diseases.

Animals↗

PubMed1994

Biosynthesis of Cardiolipin in Plant Mitochondria.

The properties of cardiolipin synthase were investigated in mitochondria and submitochondrial fractions from etiolated mung bean (Vigna radiata L.) seedlings. Direct evidence is presented that the enzyme utilizes CDP-diacylglycerol in addition to phosphatidylglycerol for the synthesis of cardiolipin. Cardiolipin synthase had an alkaline pH optimum of about 9 and required divalent cations for activity. Maximal activity was obtained in the presence of 16 mM MnCl2. The apparent Km values for CDP-diacylglycerol and phosphatidylglycerol were 0.8 and 50 [mu]M, respectively. Cardiolipin synthase was localized predominantly in the inner membrane of mung bean mitochondria and displayed a substrate species specificity. Highest activities were measured with the dioleoyl species of both CDP-diacylglycerol and phosphatidylglycerol, and somewhat lower activities were measured with mixed species of the two substrates containing a palmitoyl and an oleoyl group. On the other hand, the cardiolipin synthase hardly used the dipalmitoyl species and strongly discriminated against CDP-dipalmitoylglycerol from a mixture with CDP-dioleoylglycerol.

Journal Article↗