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PubMed1989

IgG anti-cardiolipin antibodies in murine lupus.

The frequency and nature of IgG anti-cardiolipin and anti-ds-DNA antibodies among MRL/lpr, MRL/+ and NZB/W F1 mice (murine lupus strains) and non-autoimmune inbred strains of mice (NIH/Swiss and Balb/c) were analysed by ELISA. High titres of anti-ds-DNA were detected in autoimmune strains (MRL/lpr, 69%; MRL/+, 50%; and NZB/W, 80% positive), whereas anti-cardiolipin antibodies were detected only in MRL/lpr (69%) and MRL/+ (17%) mice. IgG subclass analysis of these antibodies in 20 MRL/lpr sera revealed that all four subclasses were represented. When tested for fine antigenic specificity, anti-cardiolipin antibodies in MRL/lpr and MRL/+ mice bound to acidic phospholipids rather than to neutral phospholipids and were not inhibited by DNA. In MRL/lpr mice, anti-cardiolipin antibodies were first detected at 2 months, peaked around 5 months and then declined preterminally. To determine whether complications associated with anti-cardiolipin antibodies were present in MRL/lpr mice, blood counts were performed and litter sizes were determined. Although no significant decreases in the red and white blood cell counts were observed in MRL/lpr mice, platelet counts were significantly lower compared with NIH/Swiss (P < 0.001) and Balb/c (P < 0.005) mice. MRL/lpr mice had significantly fewer pups per delivery compared with a normal strain (MRL/lpr, 5.3+2.6; NIH/Swiss, 72 +/- 2.1; P < 0002). These observations indicate that the serological characteristics of IgG anti-cardiolipin antibodies in MRL/ lpr mice are similar to those of anti-cardiolipin antibodies in humans with lupus. Whether these autoantibodies are pathogenetically related to thrombocytopenia and a small litter size in MRL/lpr mice remains to be determined.

Animals↗

PubMed2002

Determination of the cardiolipin content of individual mitochondria by capillary electrophoresis with laser-induced fluorescence detection.

We report the application of capillary electrophoresis (CE) with postcolumn laser-induced fluorescence (LIF) detection to measure the cardiolipin content of individual mitochondria from cultured NS1 cells. Mitochondria were isolated by differential centrifugation and stained with the fluorescent dye 10-N-nonyl acridine orange which stoichiometrically binds to cardiolipin in a 1:1 or 2:1 ratio depending on the dye concentration. The green fluorescence resulting from the 1:1 complex was chosen for analysis because it is substantially more intense than the red fluorescence resulting from the 2:1 complex. Two dye concentrations that resulted in maximal and submaximal formation of the 1:1 10-N-nonyl acridine orange-cardiolipin complex were identified by spectrofluorometry. Individual mitochondria stained with both dye concentrations were separated and detected by CE with LIF detection. The data from mitochondria dosed with the lower dye concentration, where it is assumed that all the dye added to the mitochondrial sample was bound to cardiolipin, were used to derive a sensitivity factor relating fluorescence intensity of a mitochondrial event to its cardiolipin content. Using this factor, the cardiolipin contents of individual mitochondria stained with the higher dye concentration were determined, and ranged from 1.2 to 920 amol, with a median value of 4 amol. These results suggest a new strategy for estimating the organellar content of compounds that can be fluorescently tagged.

Aminoacridines↗

PubMed1991

The interaction of cardiolipin with rat liver carbamoyl phosphate synthetase I.

A selective interaction of rat liver carbamoyl phosphate synthetase I with cardiolipin, and other anionic phospholipids, has been demonstrated. The enzymatic activity of the synthetase is inhibited by cardiolipin and, to a lesser extent, by phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine. This group of anionic phospholipids also induced a conformational change in the synthetase, yielding a species with increased exposure of the linkages between independently folded domains of the enzyme, as determined by limited proteolysis under nondenaturing conditions. The interaction of cardiolipin with carbamoyl phosphate synthetase I was a fairly slow process, with complex kinetics, and was apparently irreversible. The inclusion of Mg2+ or of MgATP in the incubation mixture prevented the cardiolipin effects. The zwitterionic phospholipids phosphatidylcholine and phosphatidylethanolamine had negligible effects on the structure and activity of the synthetase. This interaction between cardiolipin and carbamoyl phosphate synthetase I potentially constitutes one of the mechanisms by which the synthetase forms its loose association with the inner mitochondrial membrane. Multiple mechanisms, including synthetase conformational changes, cardiolipin phase changes, and ATP/ADP binding site involvement, are possibly involved in the phospholipid/synthetase interaction and the resulting potential regulatory mechanism(s) for urea cycle activity.

Adenosine Triphosphate↗

PubMed1981

Thermal adaptation of Tetrahymena membranes with special reference to mitochondria. Role of cardiolipin in fluidity of mitochondrial membranes.

During temperature acclimation of Tetrahymena pyriformis, the changes in fluidity and composition of total lipids from three membrane fractions, mitochondria, pellicles and microsomes were studied by a spin-label technique using a stearate probe and thin-layer and gas-liquid chromatography. The increase of fluidity observed in microsomal and pellicular lipids following the temperature shift from 39 to 15 degrees C corresponds with the increase of the ratio of total unsaturated to saturated fatty acid content. However, despite the increase of this ratio, the fluidity of mitochondrial lipids was found to be constant up to 10 h after the temperature shift. The fluidity of total lipids of mitochondria isolated from Tetrahymena cells grown at 39 degrees C was not changed by removal of cardiolipin, whereas cardiolipin-depleted lipids of mitochondria from 15 degrees C-acclimated cells showed a decrease in fluidity. The re-addition of cardiolipin to the mitochondrial lipids depleted of cardiolipin restored the fluidity to the initial level, thereby confirming the rigidifying effect of cardiolipin in cold-acclimated cells. These results suggest that cardiolipin may be implicated in maintaining consistent fluidity of mitochondrial membranes against change in thermal environment.

Animals↗

PubMed1988

Spin label studies on the selectivity of lipid-protein interaction of cardiolipin analogues with the Na+/K+-ATPase.

The selectivity of lipid-protein interaction for various spin-labelled cardiolipin analogues in Na+/K+-ATPase membranes from Squalus acanthias has been investigated by ESR spectroscopy. Cardiolipin derivatives with different numbers of acyl chains, or in which the headgroup charge has been removed by methylation of the phosphate groups, all show a pronounced selectivity relative to phosphatidylcholine. Maximally three times more of the cardiolipin analogue is associated with the protein, than is phosphatidylcholine. The selectivity pattern in the absence of salt is in the order: cardiolipin approximately monolysocardiolipin greater than or equal to acylcardiolipin greater than dimethylcardiolipin much greater than phosphatidylcholine, where acylcardiolipin has the spin label chain attached to the centre-OH group of the headgroup. The degree of association of the negatively charged cardiolipins with the protein is reduced by salt, corresponding to the lower selectivity for dimethylcardiolipin. It is concluded that the selectivity of the Na+/K+-ATPase for cardiolipin is not solely of electrostatic origin, nor is it likely to originate in the larger number of fatty acid chains relative to diacyl phospholipids.

Animals↗

PubMed1994

Effect of divalent cations on lipid organization of cardiolipin isolated from Escherichia coli strain AH930.

Escherichia coli strain AH930 is a lipid biosynthetic mutant, which is unable to synthesize phosphatidylethanolamine. Instead it produces large amounts of phosphatidylglycerol and cardiolipin and has an absolute requirement for certain divalent cations. Cardiolipin was isolated from this mutant strain and its interaction with divalent cations was studied by various biophysical techniques. Monolayer measurements showed that the cations decrease the molecular surface area of cardiolipin in the order Ca2+ approximately Mg2+ > Sr2+ > Ba2+. 31P-NMR and X-ray diffraction measurements demonstrated a comparable sequence for the ability of the cations to promote HII phase formation in dispersions of the E. coli cardiolipin: Ca2+ and Mg2+ induced HII phase formation at 50 degrees C, Sr2+ at 75 degrees C, while Ba2+ was found to be unable to promote HII phase formation in the temperature range measured. Furthermore, all divalent cations were found to increase the temperature at which the transition to the liquid-crystalline phase takes place, which was below 5 degrees C for the lipid in the absence of divalent cations. In the presence of Sr2+, Mg2+ and Ba2+ and at 25 degrees C two lamellar phases were observed, one corresponding to a liquid-crystalline phase, the other to either a gel or a crystalline phase. In the presence of Ca2+ at 25 degrees C and even at 45 degrees C no evidence for a liquid-crystalline phase was obtained and only a crystalline phase could be observed. The ability of the different cations to promote HII phase formation in the isolated E. coli cardiolipin was found to correlate with their ability to support growth of the mutant strain (De Chavigny, A., Heacock, P.N., Dowhan, W. (1991) J. Biol. Chem. 266, 5323-5332), suggesting that cardiolipin with divalent cations can replace the role of phosphatidylethanolamine in the mutant strain, and that this role involves the preference of these lipids for organization in non-bilayer lipid structures.

Cardiolipins↗

PubMed1975

Further studies on the formation of cardiolipin and phosphatidylglycerol in rat liver mitochondria. Effect of divalent cations and the fatty acid composition of CDP-diglyceride.

The divalent cation requirement for mitochondrial cardiolipin biosynthesis has been further investigated. The relative order of divalent cation activity was Co-2+ greater than Mn-2+ greater than Mg-2+. Cardiolipin was not formed in the incubations with Zn-2+, Fe-2+, Cu-2+, Hg-2+, and Ca-2+. Cardiolipin synthesis in the presence of optimal cincentration of Co-2+ was inhibited by Ca-2+. A series of CDP-diglycerides was synthesized having differences in fatty acid chain lenth and degree of unsaturation. These compounds were tested in mitochondrial cardiolipin and phosphatidylglycerol synthesis. Although there were some minor differences between phosphatidylglycerol and cardiolipin synthesis, in general, saturated shorter chain CDP-diglycerides (dilauroyl and dimyristoyl) were better substrates than the longer chain dipalmitoyl and distearoyl homologues. Introduction of double bonds into distearoyl CDP-diglyceride resulted in more rapid rates of synthesis (e.g. dioleoyl and dilinoleoyl CDP-diglyceride). Significance of the results is dicussed with regard to possible mechanisms of linoleic acid incorporation into rat liver cardiolipin.

Animals↗

PubMed1995

Cardiolipin is synthesized from exogenous phosphatidylglycerol in rat heart.

De novo biosynthesis of phosphatidylglycerol and cardiolipin in the isolated intact rat heart was shown to occur from newly synthesized phosphatidic acid via the formation of cytidine-5'-diphosphate-1,2-diacylglycerol (Hatch, G.M. (1994) Biochem. J. 297, 201-208). The biosynthesis of new cardiolipin was investigated in isolated rat hearts perfused with exogenous phosphatidylglycerol. Phosphatidylglycerol was rapidly (within 5 min) incorporated into the heart when hearts were perfused with either phosphatidyl-[14C]glycerol or NBD-phosphatidylglycerol. In hearts perfused with phosphatidyl-[14C]glycerol for up to 30 min the amount of radioactivity observed in phosphatidylglycerol was maximum by 5 min of perfusion and remained constant throughout the perfusion period. In the presence of 1-50 microM phosphatidylglycerol, the amount of radioactive phosphatidylglycerol incorporated into the heart was not affected. There was a time-dependent accumulation of radioactivity incorporated into cardiolipin. In addition, radioactivity was incorporated with time into lysophosphatidylglycerol. No significant amount of radioactivity was associated with other phospholipids involved in the biosynthesis of cardiolipin, including phosphatidic acid and cytidine-5'-diphosphate-1,2-diacylglycerol, precursors of cardiolipin biosynthesis via the CDP-DG pathway. We postulate that cardiac cardiolipin may be synthesized from exogenous phosphatidylglycerol independent of phosphatidylglycerol synthesized within the heart.

Animals↗

PubMed1995

Interaction of cytochrome c with cardiolipin: an infrared spectroscopic study.

The interactions of cytochrome c (cyt c) with cardiolipin, a major anionic phospholipid of mitochondrial membranes, and dioleoylphosphatidylglycerol (DOPG), have been compared by infrared (IR) spectroscopy. The Fourier self-deconvoluted IR spectra of the lipid carbonyl groups indicate that both cyt c3+ and cyt c2+ perturb and/or dehydrate the interfacial region of cardiolipin bilayers. Only a slight perturbation, if any, is observed in the interfacial region of DOPG bilayers. However, the phosphate head region of DOPG is perturbed by cyt c3+, which was not detected in cardiolipin. The results suggest that cytochrome c in both redox states can partially penetrate into cardiolipin but not into DOPG bilayers. The interaction of cyt c with cardiolipin and DOPG is mainly hydrophobic and electrostatic, respectively. The Fourier self-deconvoluted IR spectra in the amide I region reveal that ca. 10% of the cyt c3+ alpha-helix unfolds to random coil upon binding to cardiolipin bilayers. However, only very slight secondary structural changes, if any, were detected when cyt c3+ binds to DOPG bilayers.

Amides↗

PubMed2005

Molecular symmetry in mitochondrial cardiolipins.

Cardiolipin is a unique mitochondrial phospholipid with an atypical fatty acid profile, but the significance of its acyl specificity has not been understood. We explored the enormous combinatorial diversity among cardiolipin species, which results from the presence of four fatty acids in each molecule, by integrated use of high-performance liquid chromatography, mass spectrometry, diacylglycerol species analysis, fatty acid analysis, and selective cleavage of fatty acids by phospholipase A2. The most abundant cardiolipin species from various organisms and tissues (human heart, human lymphoblasts, rat liver, Drosophila, sea urchin sperm, yeast, mung bean hypocotyls) contained only one or two types of fatty acids, which generated a high degree of structural uniformity and molecular symmetry. However, an exception was found in patients with Barth syndrome, in whom an acyltransferase deficiency led to loss of acyl selectivity and formation of multiple molecular species. These results suggest that restriction of the number of fatty acid species, rather than the selection of a particular kind of fatty acid, is the common theme of eukaryotic cardiolipins. This limits the structural diversity of the cardiolipin species and creates molecular symmetry with implications for the stereochemistry of cardiolipin.

Acyltransferases↗

PubMed2006

Identification and characterization of human cardiolipin synthase.

The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. In this study, we identified a human candidate gene/cDNA for cardiolipin synthase, C20orf155. Expression of this candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed that it indeed encodes human cardiolipin synthase. Purified mitochondria of the crd1Delta expressing human cardiolipin synthase were used to characterize the enzyme. It has an alkaline pH optimum, requires divalent cations for activity and appears to have a different substrate preference for cytidinediphosphate-diacylglycerol species when compared to phosphatidylglycerol species. The possible implications for CL synthesis and remodeling are discussed.

Cardiolipins↗

PubMed2005

Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain.

Mitochondrial electron transport is a major source of reactive oxygen species (ROS) during cardiac ischemia and reperfusion. In the isolated rabbit heart, 30 and 45 min of ischemia decrease the contents of cardiolipin and cytochrome c in subsarcolemmal mitochondria (SSM) located beneath the plasma membrane. In contrast, interfibrillar mitochondria (IFM) in the interior of the myocyte do not sustain a decrease in cardiolipin. We proposed that the depletion of cardiolipin and the accompanying cytochrome c loss during ischemia were critical events that amplified ROS production by mitochondria. The total production of H2O2 was measured in submitochondrial particles (SMP) prepared from rabbit heart SSM and IFM after 0, 15, 30, and 45 min of ischemia. With NADH as substrate, total H2O2 production was increased only in SMP from SSM after 30 and 45 min ischemia, when ischemia decreased the content of cardiolipin and cytochrome c. In contrast, ischemia did not augment H2O2 generation in SMP from IFM with preserved cardiolipin and cytochrome c content. Thus, during the evolution of ischemic injury, H2O2 production from the electron transport chain increased after depletion of cardiolipin and the loss of cytochrome c.

Animals↗

PubMed2005

Analysis of cardiolipin in human muscle biopsy.

Cardiolipin is a phospholipid that is specific to the inner mitochondrial membrane and essential for numerous mitochondrial functions. Accordingly, a quantitative assay for cardiolipin can be a valuable aspect of assessing mitochondrial content and functional capacity. The current study was undertaken to develop a simple and reliable method for direct analysis of the major molecular species of cardiolipin and with particular application for analysis of human skeletal muscle. The method that is presented is based on derivatization of cardiolipin in a total lipid extract with 1-pyrenyldiazomethane (PDAM), to form stable, fluorescent 1-pyrenylmethyl esters. The derivatization reaction takes 30 min on ice in a two-phase system (chloroform:methanol:H(2)O:H(2)SO(4)) containing 0.5-1.0mM PDAM and detergent. The contents of the major cardiolipin species in the derivatization mixture can be estimated by HPLC separation with fluorescent detection during a 20 min run on a reverse phase column and with HPLC grade ethanol/0.5mM H(3)PO(4) as the mobile phase. The recovery is about 80%. The method is specific and sensitive with quantitation limits of 0.5-1 pmol cardiolipin. The response of the fluorescence detector (peak area) is linear across a range 5-40 pmol. The assay is linear over the range between 0.3 and 3.0mg of tissue (R(2)=0.998). The assay provides good reproducibility and accuracy (within 5-10%).

Biopsy↗

PubMed2006

Cardiolipin metabolism and Barth Syndrome.

Many advances have occurred in the field of Barth Syndrome biology in the 26 years since it was first described as an X-linked cardiomyopathy. Barth Syndrome is the first human disease recognized in which the primary causative factor is an alteration in cardiolipin remodeling. Cardiolipin is required for the optimal function of many proteins within the mitochondria, particularly in the respiratory chain and is involved in the mitochondrial-mediated apoptotic process. The appropriate content of cardiolipin appears to be critical for these functions. Cardiolipin is synthesized de novo in mitochondria and is rapidly remodeled to produce CL enriched in linoleic acid. The Barth Syndrome gene TAZ has been identified and expression of the gene yields proteins known as tafazzins. Mutations in TAZ result in a decrease in tetra-linoleoyl species of cardiolipin and an accumulation of monolysocardiolipin within cells from Barth Syndrome patients. Although the protein product of the TAZ gene shows sequence homology to the glycerolipid acyltransferase family of enzymes, its precise biochemical function remains to be elucidated. In this review we highlight some of the recent literature on cardiolipin metabolism and Barth Syndrome.

Acyltransferases↗

PubMed1997

Cardiolipin-dependent decrease of cytochrome c oxidase activity in heart mitochondria from hypothyroid rats.

Cardiolipin plays an important role in mitochondrial membrane structure and function. We have recently reported a decrease in the cytochrome c oxidase activity in heart mitochondria from hypothyroid rats (G. Paradies et al. (1993) Arch. Biochem Biophys. 307, 91-95). A possible involvement of cardiolipin in such a decrease has been proposed. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to hypothyroid mitochondria is able to reverse, in situ, their decreased cytochrome oxidase activity. The method of fusion of liposomes with mitochondria developed by Hackenbrock (Hackenbrock and Chazotte (1986) Methods Enzymol. 125, 35-45) was employed in order to enrich the mitochondrial cardiolipin content. We demonstrate that the decreased activity of this enzyme complex in heart mitochondria from hypothyroid rats can be completely restored to the level of control rats by exogenously added cardiolipin but not by other phospholipids. These data provide strong evidence for the involvement of cardiolipin in the thyroid hormone induced changes of mitochondrial cytochrome oxidase activity.

Animals↗

PubMed1997

Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin.

Cardiolipin is a major mitochondrial membrane lipid and plays a pivotal role in mitochondrial function. We have recently suggested a possible involvement of this phospholipid in the age-linked decline of cytochrome c oxidase activity in rat heart mitochondria [G. Paradies et al. (1993) Arch. Gerontol. Geriatr. 16, 263-272]. The aim of this work was to test our earlier proposal. We have investigated whether addition of exogenous cardiolipin to mitochondria is able to reverse, in situ, the age-linked decrease in the cytochrome oxidase activity. The method of fusion of liposomes with mitochondria developed by Hackenbrock [Hackenbrock and Chazotte (1986) Methods Enzymol. 125, 35-45] was employed in order to enrich the mitochondria cardiolipin content. We demonstrate that the lower cytochrome c oxidase activity in heart mitochondria from aged rats can be fully restored to the level of young control rats by exogenously added cardiolipin. No restoration was obtained with other phospholipids or with peroxidized cardiolipin. Our data support a key role for cardiolipin in the age-linked decline of rat heart mitochondrial cytochrome c oxidase activity.

Aging↗

PubMed1992

Cardiolipin antibody levels are not influenced by leukocyte immunotherapy in patients experiencing recurrent spontaneous abortion.

OBJECTIVE: To confirm that leukocyte immunotherapy stimulates the production of cardiolipin antibodies and to relate changes to pregnancy outcome. PATIENTS: Fifty patients with idiopathic recurrent abortion were studied. Thirty-six patients received injections of their partners' leukocytes; 14, injected with their own cells, served as controls. DESIGN: Cardiolipin antibodies were measured a month before and after leukocyte immunization. Patients who became pregnant were immunized a second time in early pregnancy, and cardiolipin antibodies were again measured a month later. RESULTS: Thirty-six patients immunized with their partners' leukocytes showed no appreciable change in cardiolipin antibody levels a month after vaccination. Twenty-nine of them subsequently became pregnant and were immunized again in early pregnancy: again, no change in cardiolipin antibody level was observed. There was no difference between the minority who aborted again and the majority who subsequently had successful pregnancies nor between those who responded to immunotherapy by producing cytotoxic antilymphocyte antibodies and those who did not. CONCLUSION: Leukocyte immunotherapy does not stimulate cardiolipin antibody production in women with normal pretreatment levels of the autoantibody.

Abortion, Habitual↗

PubMed1982

Cardiolipin-protein interactions in the phosphate binding activity of a proteolipid from yeast mitochondria. Action of phospholipases A2 and C and of cations.

A proteolipid able to bind phosphate has been isolated from yeast mitochondria. During the purification the active protein was always associated with cardiolipin. The cardiolipin requirement for the phosphate binding activity of this proteolipid has been studied using controlled lipid depletion with two phospholipases A2 and with phospholipase C. Only phospholipase A2 from pig pancreas, that deacylated cardiolipin, promoted inhibition of the proteolipid activity (but never more than 70 per cent). Phospholipase A2 from snake venom did not inhibit the binding activity of the proteolipid. Using thin layer chromatography with two sequential solvents it was possible to separate two cardiolipin subspecies; one of them was preferentially hydrolysed by phospholipase C of Bacillus cereus, leading to inhibition of the proteolipid activity. Ca2+ complexed to cardiolipin stoichiometrically (1-1) inhibited the proteolipid activity. This effect could be due to a conformational change in the cardiolipin-protein association.

Animals↗