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PubMed1991

Regulation of phosphatidylglycerolphosphate synthase in Saccharomyces cerevisiae by factors affecting mitochondrial development.

Phosphatidylglycerolphosphate synthase (PGPS; CDP-diacylglycerol glycerol 3-phosphate 3-phosphatidyltransferase; EC 2.7.8.5) catalyzes the first step in the synthesis of cardiolipin, an acidic phospholipid found in the mitochondrial inner membrane. In the yeast Saccharomyces cerevisiae, PGPS expression is coordinately regulated with general phospholipid synthesis and is repressed when cells are grown in the presence of the phospholipid precursor inositol (M. L. Greenberg, S. Hubbell, and C. Lam, Mol. Cell. Biol. 8:4773-4779, 1988). In this study, we examined the regulation of PGPS in growth conditions affecting mitochondrial development (carbon source, growth stage, and oxygen availability) and in strains with genetic lesions affecting mitochondrial function. PGPS derepressed two- to threefold when cells were grown in a nonfermentable carbon source (glycerol-ethanol), and this derepression was independent of the presence of inositol. PGPS derepressed two- to fourfold as cells entered the stationary phase of growth. Stationary-phase derepression occurred in both glucose- and glycerol-ethanol-grown cells and was slightly greater in cells grown in the presence of inositol and choline. PGPS expression in mitochondria was not affected when cells were grown in the absence of oxygen. In mutants lacking mitochondrial DNA [( rho0] mutants), PGPS activity was 30 to 70% less than in isogenic [rho+] strains. PGPS activity in [rho0] strains was subject to inositol-mediated repression. PGPS activity in [rho0] cell extracts was derepressed twofold as the [rho0] cells entered the stationary phase of growth. No growth phase derepression was observed in mitochondrial extracts of the [rho0] cells. Relative cardiolipin content increased in glycerol-ethanol-grown cells but was not affected by growth stage or by growth in the presence of the phospholipid precursors inositol and choline. These results demonstrate that (i) PGPS expression is regulated by factors affecting mitochondrial development; (ii) regulation of PGPS by these factors is independent of cross-pathway control; and (iii) PGPS expression is never fully repressed, even during anaerobic growth.

Anaerobiosis↗
PubMed1998

D-Alanylcardiolipin, a major component of the unique lipid pattern of Vagococcus fluvialis.

Motile group N streptococci, classified as Vagococcus fluvialis, have been isolated from cows' udders, human and animal feces, river water, and seawater. They possess an unusual membrane lipid and fatty acid pattern. We isolated and characterized 13 polar lipids, 8 of them also found in other gram-positive bacteria: mono- and dihexosyldiacylglycerol, an acylated and a glycerophosphate-substituted derivative of the latter, cardiolipin, phosphatidylglycerol, D-alanylphosphatidylglycerol, and L-lysylphosphatidylglycerol. Besides them, we characterized two rare compounds, bis(acylglycero)phosphate and alpha-D-glucopyranosylcardiolipin, and two compounds so far not detected in nature, D-alanylbis(acylglycero)phosphate and D-alanylcardiolipin. The concomitant occurrence of four aminoacyl phospholipids in one organism is another unique finding. Substituted cardiolipins represent a novel lipid class: in vagococci, D-alanylcardiolipin is a major membrane lipid component, contributing 11 and 26 mol% of total lipids in the exponential and stationary phases of growth, respectively. The vagococcal lipids contain even-numbered straight-chain saturated and cis-monounsaturated fatty acids, but the cis-monoenic acids belong to the omega-9 series and not the omega-7 series, found in enterococci, lactococci, and streptococci.

Cardiolipins↗
PubMed2005

Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking alpha-synuclein.

The presynaptic protein alpha-synuclein, implicated in Parkinson disease (PD), binds phospholipids and has a role in brain fatty acid (FA) metabolism. In mice lacking alpha-synuclein (Snca-/-), total brain steady-state mass of the mitochondria-specific phospholipid, cardiolipin, is reduced 22% and its acyl side chains show a 51% increase in saturated FAs and a 25% reduction in essential n-6, but not n-3, polyunsaturated FAs. Additionally, 23% reduction in phosphatidylglycerol content, the immediate biosynthetic precursor of cardiolipin, was observed without alterations in the content of other brain phospholipids. Consistent with these changes, more ordered lipid head group and acyl chain packing with enhanced rotational motion of diphenylhexatriene (DPH) about its long axis were demonstrated in time-resolved DPH fluorescence lifetime experiments. These abnormalities in mitochondrial membrane properties were associated with a 15% reduction in linked complex I/III activity of the electron transport chain, without reductions in mitochondrial number, complex II/III activity, or individual complex I, II, III, or IV activity. Reduced complex I activity is thought to be a critical factor in the development of PD. Thus, altered membrane composition and structure and impaired complex I/III function in Snca-/- brain suggest a relationship between alpha-synuclein's role in brain lipid metabolism, mitochondrial function, and PD.

Animals↗
PubMed2006

Regulation of cytochrome C peroxidase activity by nitric oxide and laser irradiation.

Apoptosis can be induced by activation of so-called "death receptors" (extrinsic pathway) or multiple apoptotic factors (intrinsic pathway), which leads to release of cytochrome c from mitochondria. This event is considered to be a point of no return in apoptosis. One of the most important events in the development of apoptosis is the enhancement of cytochrome c peroxidase activity upon its interaction with cardiolipin, which modifies the active center of cytochrome c. In the present work, we have investigated the effects of nitric oxide on the cytochrome c peroxidase activity when cytochrome c is bound to cardiolipin or sodium dodecyl sulfate. We have observed that cytochrome c peroxidase activity, distinctly increased due to the presence of anionic lipids, is completely suppressed by nitric oxide. At the same time, nitrosyl complexes of cytochrome c, produced in the interaction with nitric oxide, demonstrated sensitivity to laser irradiation (441 nm) and were photolyzed during irradiation. This decomposition led to partial restoration of cytochrome c peroxidase activity. Finally, we conclude that nitric oxide and laser irradiation may serve as effective instruments for regulating the peroxidase activity of cytochrome c, and, probably, apoptosis.

Animals↗
PubMed1987

Anticardiolipin antibodies: isotype distribution and phospholipid specificity.

Quantitative isotype specific enzyme linked immunosorbent assay (ELISA) was used to determine the distribution of immunoglobulin isotypes and phospholipid specificities of anticardiolipin (anti-CL) antibodies in 40 patients with one or more of the following 'antiphospholipid (anti-PL) antibody associated clinical complications'--namely, thrombosis, fetal loss, thrombocytopenia. Twelve of 40 patients had IgG, IgM, and IgA anti-CL antibodies. Ten patients had IgG and IgM, five patients had IgG and IgA, and three patients had IgM and IgA anti-CL antibodies. There was no statistical association between any single isotype or any group of isotypes with thrombosis, fetal loss, or thrombocytopenia. The presence of IgG anti-CL antibodies in 36 of the 40 patients suggests that this isotype may be most important in determining clinical complications, but there were four patients without IgG anti-CL antibodies who also appeared susceptible to thrombosis, fetal loss, and thrombocytopenia. IgG, IgM, and IgA anti-CL antibodies bound the negatively charged phospholipids, phosphatidylserine and phosphatidylinositol, but not the zwitterionic phospholipid, phosphatidylcholine. There was no significant difference between binding to cardiolipin and binding to other negatively charged phospholipids, suggesting that the specificity of these antibodies is for negatively charged phospholipids in general rather than for cardiolipin in particular.

Antibody Specificity↗
PubMed1982

Modification of the system of screening for antisyphilis antibodies in a blood transfusion centre, featuring a miniaturisation of the Treponema pallidum haemagglutination assay.

A modified, miniaturised version of the Fujizoki Treponema pallidum haemagglutination assay (TPHA) is described. The method is fast, sensitive, specific, and very economical. During a test period of one year, use of the method gave rise to a 67% increase in confirmed positives among new donor sera and a 112.5% increase among the antenatal sera over the numbers that would have been detected using a cardiolipin test alone. With the new donor sera, the rate of confirmed positives detected during the test period was 150% greater than that of 1980, when a cardiolipin test alone was used (0.05 greater than p greater than 0.02 (chi 2 test)).

Antibodies, Bacterial↗
PubMed1985

Experimental infection of inbred guinea pigs with Treponema pallidum: development of lesions and formation of antibodies.

Inbred strain 2 and strain 13 guinea pigs were infected intradermally in the hind legs with different numbers of the virulent Nichols strain of Treponema pallidum. About 91% of the animals developed clearly visible lesions after being injected with 5 X 10(6) to 10 X 10(6) treponemes. T pallidum organisms could be isolated from skin lesions at various stages after infection. Infected animals were monitored for the production of specific treponemal and non-specific cardiolipin antibodies by the fluorescent treponemal antibody (FTA) and microhaemagglutination (MHA-TP) tests and the rapid plasma reagin (RPR) card test. Low levels of specific antibodies could be detected by both FTA and MHA-TP tests from three to four weeks after infection. Maximum titres of treponemal antibody generally occurred after week 6 and persisted for several more months. These peak titres ranged from 1/40 to 1/80 in the FTA test and 1/160 to 1/320 in the MHA-TP test. During the same period infected guinea pigs, unlike rabbits with syphilis, did not produce detectable quantities of antibodies against cardiolipin.

Animals↗
PubMed1978

Effect of respiratory deficiency and temperature on the mitochondrial lipid metabolism of Aspergillus niger.

A comparative study of the mitochondrial lipid composition of a wild strain (V 35) and a respiratory-deficient mutant (rd3) of Aspergillus niger grown at different temperatures (25, 30, 35, and 40 degrees C) has been performed. The lipid spectrum, though qualitatively similar, differs quantitatively in both cases. At the optimum growth temperature (30 degrees C) depletion in ergosterol (40%) and cardiolipin (52%) was observed. This probably indicates the formation of defective mitochondria in the mutant with a resultant impaired respiratory system. Complete depletion of cardiolipin species containing fatty acid (20:5omega3) in the respiratory-deficient mutant suggests a possible role of this lipid in mitochondriogenesis at least in A. niger. The effect of temperature is predominantly on the degree of unsaturation and sterol ester formation. The linoleic acid (18:2omega6) content decreases with a concomitant increase in oleic acid (18:1omega9) content as the growth temperature increases for both cell types. Some morphological changes and effects on the vegetative life cycle have been observed with variation in growth temperature in the wild type and also in the mutant form.

Aspergillus niger↗
PubMed1977

Selective enzymatic radioactive and spin labelling of phospholipids in biological membranes: application to study of temperature-induced changes of microsomal phosphatidylinositols and mitochondrial polyglycerophosphatides.

A new method for the covalent radioactive and spin labelling of lipids within isolated biological membranes has been described in detail and applied to studies of temperature-induced changes of microsomal and mitochondrial membranes. The method is based on the enzymatic use of radioactive substrates carrying covalently bound doxyl derivatives of stearic acid in the biosynthesis of phospholipids in isolated membranes. Radioactive-and spin-labelled lipids bound to the microsomal and mitochondrial membranes were then used as internal probes in monitoring temperature-induced changes of these membranes. Since the analysis of isolated radioactive-and spin-labelled lipids revealed the exact composition of membrane-bound labelled lipids, specific temperature-induced changes were correlated with specific lipids of examined membranes. Phosphatidylinositol of microsomal membranes and polyglycerophosphatides (phosphatidyl-glycerol and cardiolipin) of mitochondrial and inner mitochondrial membranes were found to be involved in the apparent formation of lipid clusters at around 20-30 degrees C. Cardiolipin was found to be involved in the fluidization of inner mitochondrial membranes. These findings are discussed in view of the present state of knowledge of the organization of lipids in biological membranes.

Animals↗
PubMed1991

Mitochondrial adaptations in denervated muscle: relationship to muscle performance.

We have studied mitochondrial adaptations in muscle subject to chronic denervation, and their relationship to muscle performance, using a model of unilateral sciatic nerve denervation in rats over periods of 2, 5, 8, 14, 21, 28, 35, and 42 days (n = 5-9 rats/day). Time to peak tension (TPT), one-half relaxation time (1/2RT), and endurance performance were evaluated during in situ stimulation of denervated and contralateral gastrocnemius-plantaris muscles. Denervation led to a 70% decline in muscle mass after 42 days. TPT and 1/2RT increased 17 and 30%, respectively, indicating a transformation toward slower muscle. The activities of the enzymes cytochrome-c oxidase (CYTOX), succinate dehydrogenase, and citrate synthase were decreased by 8-14 days, and by 42 days these were 34-58% of control. The mitochondrial phospholipid cardiolipin was reduced earlier, by 5 days, and gradually decreased to 37% of control. Thus phospholipid removal appears to precede the loss of enzyme activity during decreases in mitochondrial content. Endurance performance was reduced in parallel with decreases in enzyme activity and cardiolipin. Cytochrome c mRNA levels decreased to 52% of control by 5 days. Denervation resulted in coordinated changes in mRNA levels encoding the nuclear-derived CYTOX subunit VIc and the mitochondrially derived CYTOX subunit III. However, changes in CYTOX activity did not always parallel alterations in subunit mRNA levels. Thus transcriptional and translational mechanisms operate in regulating mitochondrial gene expression during denervation.

Animals↗
PubMed1997

Purine nucleotides and phospholipids in ischemic and reperfused rat skeletal muscle: effect of ascorbate.

The effect of intravenously administered ascorbate on the ischemic and reperfused rat skeletal muscle was investigated. Purine nucleotides and phospholipids in skeletal muscle from rats subjected to 4 h of ischemia followed by 1-h reperfusion were analyzed by high-performance liquid chromatography. In addition, ATP, phosphocreatine (PCr), Pi, and phosphomonoesters (PME) were analyzed by 31P-nuclear magnetic resonance at 202.4 MHz, and individual PME such as glucose-6-phosphate and IMP were quantified. PCr and ATP were exhausted after 4 h of ischemia and recovered poorly upon reperfusion in the soleus and tibialis muscle of untreated rats. Postischemic reperfusion resulted in significant loss of cardiolipin. Treatment with 55 mM ascorbate resulted in total restoration of PCr during reperfusion, and ATP recovered to 42% of control in the soleus. Recovery was improved in the tibialis as well, and the cardiolipin decrease was limited. A lower ascorbate concentration (5 mM) did not enhance postischemic recovery. Our findings show that a high dose of ascorbate improves the energetic state of rat skeletal muscle during postischemic reperfusion, probably due to its antioxidant function.

Animals↗
PubMed1997

Influence of aging on protein import into cardiac mitochondria.

This study was undertaken to determine whether age-related changes in the content and composition of cardiac mitochondria could be due, in part, to alterations in mitochondrial protein import. Precursor proteins malate dehydrogenase and ornithine carbamoyltransferase were synthesized by in vitro transcription and translation and were incubated with mitochondria isolated from the hearts of young (4-mo), old (22-mo), and senescent (28-mo) rats. Mitochondria from senescent animals exhibited a twofold higher import rate of both precursors into the matrix compartment compared with mitochondria from young and old animals. The expression of glucose regulated protein 75 and heat shock protein 60, two matrix chaperonins that are essential for import, was elevated in the mitochondria of both old and senescent animals before the observed changes in import. Import was equally affected in senescent and young heart mitochondria by inhibition of cardiolipin, a mitochondrial phospholipid involved in protein translocation. The results indicate that the altered mitochondrial phenotype evident in the aging myocardium cannot be accounted for by reduced rates of protein import. Furthermore, levels of cardiolipin and matrix chaperonins do not appear to be rate-limiting steps in the import process. These data suggest that the protein import step of mitochondrial assembly is subject to adaptations under pathophysiological conditions.

Aging↗
PubMed1999

Beta(2)-glycoprotein I promotes the binding of anionic phospholipid vesicles by macrophages.

Beta(2)-Glycoprotein I is a single-chain 50-kDa protein that circulates in plasma at a concentration of approximately 200 microg/mL. Its physiological role remains uncertain, but an important clue is the frequent presence of antibodies to this protein in patients with recurrent thrombosis. We have isolated beta(2)-glycoprotein I and examined its effect on the binding of phosphatidylserine (PS) vesicles by human monocyte-derived macrophages and by phorbol ester-stimulated THP-1 cells. beta(2)-Glycoprotein I stimulated the binding of PS vesicles by these cells in a concentration-dependent manner. Vesicles containing other anionic phospholipids, such as cardiolipin, phosphatidic acid, or cardiolipin, inhibited the binding, whereas PC vesicles had no effect. Platelet-derived microvesicles, which contain anionic phospholipid on the outer leaflet of their phospholipid bilayer, also inhibited beta(2)-glycoprotein I-dependent binding of anionic phospholipid vesicles. The binding is associated with incorporation of phospholipid in the cell membrane and internalization of beta(2)-glycoprotein I. These findings suggest a physiological function for beta(2)-glycoprotein I in the clearance of procoagulant anionic phospholipid-containing cell surfaces from the circulation.

Anions↗
PubMed2001

Anticardiolipin antibodies from patients with the antiphospholipid antibody syndrome recognize epitopes in both beta(2)-glycoprotein 1 and oxidized low-density lipoprotein.

BACKGROUND: We recently suggested that many anticardiolipin antibodies bind only to oxidized cardiolipin (OxCL) and/or to OxCL-beta(2)-glycoprotein 1 (beta(2)GP1) adducts but not to a "reduced" cardiolipin that is unable to undergo oxidation. To test this hypothesis, we investigated 24 sera, 4 protein A-purified IgG fractions, and 3 human monoclonal antibodies that were all isolated from patients with antiphospholipid antibody syndrome (APS); testing was also performed in 7 controls. Two monoclonal antibodies (IS3 and IS4) were selected for binding to CL and one was selected for binding to beta(2)GP1 (LJB8). METHODS AND RESULTS: By chemiluminescent immunoassay, all APS sera samples bound only to OxCL and not to reduced CL, and the binding was inhibited >95% by OxCL but not reduced CL. All purified IgG fractions bound to beta(2)GP1 but only when the beta(2)GP1 was plated on microtiter wells coated with OxCL. All 3 monoclonal antibodies bound only to OxCL. On Western blots, IS4 and LJB8 bound to beta(2)GP1 as well as to delipidated apoB of oxidized LDL but not to native apoB. IS3 also bound to oxidized apoB on Western blot. Covalent modification of beta(2)GP1 with oxidation products of CL made it more antigenic for APS serum samples, for purified IgG fractions, and for the monoclonal antibodies. CONCLUSIONS: These data support the hypothesis that oxidation of CL is needed to generate epitopes for many anticardiolipin antibodies and that some of these epitopes are covalent adducts of OxCL with beta(2)GP1 or apoB.

Antibodies, Anticardiolipin↗
PubMed1998

Genetics of apolipoprotein H (beta2-glycoprotein I) and anionic phospholipid binding.

Apolipoprotein H (apoH; also known as beta2-glycoprotein I), is an essential cofactor for the binding of certain antiphospholipid antibodies (APA) to anionic phospholipid. The gene coding for apoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect the binding of apoH to anionic phospholipids and consequently the production of APA. Our group has identified two common mutations at codons 306 (Cys-->Gly) and 316 (Trp-->Ser) in the fifth domain of apoH which affect the binding of apoH to anionic phospholipids (phosphatidylserine or cardiolipin). ApoH from serum samples homozygous for each of these mutations or compound heterozygotes for both mutations showed no binding with anionic phospholipids on ELISA. In vitro mutagenesis and transient expression of these mutations in COS-1 cells followed by cardiolipin binding studies confirmed that Gly306 and Ser316 are causative mutations. Our data indicate that the fifth domain of apoH is essential for anionic phospholipid binding and genetically determined variation in this domain can affect the production of apoH-dependent APA.

Alleles↗
PubMed2001

Oxidation of beta2-glycoprotein I (beta2GPI) by the hydroxyl radical alters phospholipid binding and modulates recognition by anti-beta2GPI autoantibodies.

We investigated whether beta2-glycoprotein I (beta2GPI), the key antigen in the antiphospholipid syndrome, is susceptible to oxidative modifications by the hydroxyl radical (*OH) that may influence its lipid-binding and antigenic properties. The effects on human and bovine beta2GPI of *OH free radicals generated by gamma-radiolysis of water with 137Cs were studied. Radiolytic *OH caused a dose-dependent loss of tryptophan, production of dityrosine and carbonyl groups. dimerization and/or extensive aggregation of beta2GPI. It ensued a reduction in affinity binding to cardiolipin liposomes and loss of beta2GPI-dependent autoantibody binding to immobilized cardiolipin. Patient anti-beta2GPI antibodies (n = 20) segregated into two groups based on the effect in the beta2GPI-ELISA of beta2GPI pretreatment with *OH: enhancement (group A, n = 10) or suppression (group B, n = 10) of IgG binding. The avidities of group A antibodies for fluid-phase beta2GPI were low but increased in a dose-dependent manner upon beta2GPI irradiation, in relation to protein crosslinking. Distinguishing features of group B antibodies included higher avidities for fluid-phase beta2GPI that was no longer recognized after *OH treatment, and negative anticardiolipin tests suggesting epitope location near the phospholipid binding site. The *OH scavengers thiourea and mannitol efficiently protected against all above changes. Therefore, oxidative modifications of beta2GPI via *OH attack of susceptible amino acids alter phospholipid binding, and modulate recognition by autoantibodies depending on their epitope specificities. These findings may be of clinical relevance for the generation and/or reactivity of anti-beta2GPI antibodies.

Animals↗
PubMed2005

Factors at diagnosis predict subsequent occurrence of seizures in systemic lupus erythematosus.

OBJECTIVE: To determine the factors associated with seizures in systemic lupus erythematosus (SLE). METHODS: One hundred ninety-five patients with SLE were followed at the University of Maryland Lupus Clinics from January 1992 until June 2004. Neuropsychiatric (NP) manifestations were defined according to the American College of Rheumatology nomenclature and case definitions for NP-SLE syndromes, and seizures were defined using the International Classification of Epileptic Seizures. At the end of the study period, 28 of the 195 (14%) patients with SLE had seizures (21 generalized convulsive, 7 partial) during their course of disease. Recurrent seizures or epilepsy occurred in 12 of 28 patients (43%). The baseline features of those patients with seizures and those without them were compared to determine their contribution to the occurrence of isolated seizures and epilepsy. RESULTS: Isolated seizures in SLE are common; epilepsy is less frequent but nonetheless important. Certain clinical features at baseline were independent predictors of seizures including disease activity, in particular psychosis, moderate- to high-titer serum anti-cardiolipin and anti-Smith antibodies, and damage accrual. Higher disease activity at baseline, concurrent multiple NP-SLE manifestations, prior strokes, and male gender were predictive of epilepsy. CONCLUSION: The risk of seizure and epilepsy in systemic lupus erythematosus (SLE) is increased in those patients with higher disease activity at baseline, prior neuropsychiatric SLE disease, and anti-cardiolipin and anti-Smith antibodies.

Adult↗
PubMed1991

Autoantibodies against all the phospholipids: a comparative systematic study with systemic lupus erythematosus and healthy sera.

The sera of systemic lupus erythematosus patients were tested by ELISA for the presence of autoantibodies against all the phospholipids: cardiolipin, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and phosphatidylserine. The quantity of phospholipid coated (in comparison with that initially deposited) on the microtitration plates was precisely evaluated in order to determine if the results (absorbance values) obtained for each phospholipid could be compared directly. The systemic lupus erythematosus sera tested gave positive results for all the phospholipids. The highest level of autoantibodies was observed with phosphatidic acid followed by phosphatidylserine, phosphatidylinositol, cardiolipin, phosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine. The sera seemed to contain antibodies directed either against all the 8 phospholipids tested or more specifically against one or two phospholipids. The results were compared with those obtained with 17 healthy sera. Much lower values were obtained for the sera of healthy subjects, the majority of which showed a weak binding, similar for all the phospholipids. These results suggest that the anti-phospholipid autoantibodies present in systemic lupus erythematosus sera are significantly higher than those of healthy subjects. It is concluded that in the investigation of anti-phospholipid antibodies, tests should be carried out for all the phospholipids.

Antibody Specificity↗