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PubMed2002

Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage.

The aim of this study was to investigate the influence of reactive oxygen species (ROS) on the activity of complex I and on the cardiolipin content in bovine heart submitochondrial particles (SMP). ROS were generated through the use of xanthine/xanthine oxidase (X/XO) system. Treatment of SMP with X/XO resulted in a large production of superoxide anion, detected by acetylated cytochrome c method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to ROS generation resulted in a marked loss of complex I activity and to parallel loss of mitochondrial cardiolipin content. Both these effects were completely abolished by SOD+catalase. Exogenous added cardiolipin was able to almost completely restore the ROS-induced loss of complex I activity. No restoration was obtained with other major phospholipid components of the mitochondrial membrane such as phosphatidylcholine and phosphatidylethanolamine, nor with peroxidized cardiolipin. These results demonstrate that ROS affect the mitochondrial complex I activity via oxidative damage 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 pathophysiological conditions characterized by an increase in the basal production of reactive oxygen species such as aging, ischemia/reperfusion and chronic degenerative diseases.

Aminoacridines↗

PubMed1987

Study of the adriamycin-cardiolipin complex structure using attenuated total reflection infrared spectroscopy.

Adriamycin plays a prominent role in the treatment of leukemia and solid tumors in man. The mode of interaction of adriamycin with its nuclear target, responsible for its therapeutic effect, is known [Berman, H. M., & Young, P.R. (1981) Annu. Rev. Biophys. Bioeng. 10, 87-114]. The planar anthracycline moiety of adriamycin intercalates between the base pairs whereas the sugar moiety fits into the DNA large groove. However, the cardiotoxicity of adriamycin places a limit on the total dose that may be given [Minow, R. A., Banjamin, R.S., & Gottlieb, J. A. (1975) Cancer Chemother. Rep. 6, 195-202]. Much evidence suggests that the mitochondrial membrane could be the target responsible for adriamycin cardiotoxicity. The formation of a very stable complex between adriamycin and cardiolipin, a phospholipid specific to the inner mitochondrial membrane, has been shown to inhibit several mitochondrial membrane enzymes whose activities depend on the presence of cardiolipin. Using attenuated total reflection infrared spectroscopy, we demonstrate here that, in the adriamycin-cardiolipin complex, both cardiolipin and adriamycin structures are modified as compared with the pure substances. Dichroism values indicate a slight reorientation of the cardiolipin molecule toward a normal to the plane of the bilayer whereas adriamycin, which shows no ordering in a pure phase, is highly ordered in the complex, the anthracycline moiety titled at about 40 degrees with respect to the normal to the plane of the bilayer. The partial disappearance of NH3+ characteristic bands indicates the involvement of the positively charged amino group of adriamycin in the complex formation.

Ammonia↗

PubMed1981

Phase Equilibria in binary mixtures of dimyristoylphosphatidylcholine and cardiolipin.

Paramagnetic resonance spectra of the spin-label 2,2,6,6-tetramethylpiperidinyl-l-oxy have been used to study phase separations in binary mixtures of dimyristoyl-phosphatidylcholine and cardiolipin. Two different samples of cardiolipin were used: (i) One sample contained calcium ions at a mole ratio of calcium:cardiolipin = 1:2; the experimental data support the view that cardiolipin is present in the bilayer membrane as calcium ion linked dimers, (CL)2 Ca2+. (ii) A calcium-free sodium cardiolipin sample yielded remarkable spin-label partition data that were quite different from those obtained in the presence of Ca2+. In both cases the spin-label data provide evidence for compound formation and for fluid-fluid immiscibility in the bilayer membrane.

Calcium↗

PubMed2005

Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction.

Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate, diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linking altered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomics and multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial inner membrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 +/- 0.3 nmol/mg of protein in control hearts to 3.1 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Moreover, the direct metabolic precursor of cardiolipin, phosphatidylglycerol, was also substantially depleted (2.5 +/- 0.2 nmol/mg of protein in control hearts vs 1.3 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Similarly, glycerol 3-phosphate, necessary for the penultimate step in phosphatidylglycerol production, decreased by 58% in diabetic myocardium (from 4.9 +/- 0.9 to 2.2 +/- 0.3 nmol/mg of protein; n = 4). Since Barth's syndrome (a disorder of cardiolipin metabolism) induces mitochondrial dysfunction and cardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, these results provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabetic myocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultant hemodynamic compromise.

Animals↗

PubMedDate not supplied

Shape and size of giant unilamellar phospholipid vesicles containing cardiolipin.

The effect of cardiolipin content on the shape and size of giant palmitoyloleylphosphatidylcholine/cardiolipin vesicles was studied. Unilamellar vesicles were prepared in sugar solution by the method of electroformation, from mixtures containing up to 50% weight ratio of cardiolipin. At room temperature the vesicles containing cardiolipin exhibited abrupt changes in the curvature of the vesicle contour indicating regions of phase separation. The deviations from the spherical shape were larger if vesicles were made from mixtures with a higher content of cardiolipin. Numerous vesicles with soft fluctuating walls were observed. The estimated size of the vesicles containing cardiolipin was found to be smaller than the size of pure palmitoyloleylphosphatidylcholine vesicles.

Cardiolipins↗

PubMed1998

Cardiolipins and mitochondrial proton-selective leakage.

The proton-selective leak (State 4 respiratory rate) but not delta psi, in mitochondria from thyroid-sensitive tissues, responds to in vivo stimuli in unique correlation with changes in cardiolipins, saturated and mono-unsaturated (extended) fatty acyl contents, cardiolipins/phospholipids ratios, and/or membrane outer-sidedness. Liver mitochondrial State 4 respiration, basal in fasted rats, contributes little to resting metabolic rate in fed rats, where State 3 depresses delta psi. In a proposed model, an essential inner-membrane outer-surface proton antenna collects protons and donates them, via a water-shuttle, to transmembrane porters: transient water-molecule-chains between extended phospholipid acyls; protonophores, and uncoupling proteins. Only cardiolipin microdomains can donate, from an anomalously-dissociating phosphate group in each headgroup; unadapted cardiolipins have few conducting water chains. Thyroid states regulate each cardiolipin property, and are permissive, via the proton antenna, for proton leaks, including those through adapted and possibly constitutive BAT and ectopic uncoupling proteins. Slow leakage in liposomes may reflect insufficient cardiolipin proton antennas.

Animals↗

PubMed2005

Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.

Programmed death (apoptosis) is turned on in damaged or unwanted cells to secure their clean and safe self-elimination. The initial apoptotic events are coordinated in mitochondria, whereby several proapoptotic factors, including cytochrome c, are released into the cytosol to trigger caspase cascades. The release mechanisms include interactions of B-cell/lymphoma 2 family proteins with a mitochondria-specific phospholipid, cardiolipin, to cause permeabilization of the outer mitochondrial membrane. Using oxidative lipidomics, we showed that cardiolipin is the only phospholipid in mitochondria that undergoes early oxidation during apoptosis. The oxidation is catalyzed by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. In a previously undescribed step in apoptosis, we showed that oxidized cardiolipin is required for the release of proapoptotic factors. These results provide insight into the role of reactive oxygen species in triggering the cell-death pathway and describe an early role for cytochrome c before caspase activation.

Animals↗

PubMed2006

Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria.

In eukaryotic cells, CLS (cardiolipin synthase) is involved in the final step of cardiolipin synthesis by catalysing the transfer of a phosphatidyl residue from CDP-DAG (diacylglycerol) to PG (phosphatidylglycerol). Despite an important role of cardiolipin in regulating mitochondrial function, a gene encoding the mammalian CLS has not been identified so far. We report in the present study the identification and characterization of a human cDNA encoding the first mammalian CLS [hCLS1 (human CLS1)]. The predicted hCLS1 peptide sequence shares significant homology with the yeast and plant CLS proteins. The recombinant hCLS1 enzyme expressed in COS-7 cells catalysed efficiently the synthesis of cardiolipin in vitro using CDP-DAG and PG as substrates. Furthermore, overexpression of hCLS1 cDNA in COS-7 cells resulted in a significant increase in cardiolipin synthesis in intact COS-7 cells without any significant effects on the activity of the endogenous phosphatidylglycerophosphate synthase of the transfected COS-7 cells. Immunohistochemical analysis demonstrated that the recombinant hCLS1 protein was localized to the mitochondria when transiently expressed in COS-7 cells, which was further corroborated by results from subcellular fractionation analyses of the recombinant hCLS1 protein. Northern-blot analysis showed that the hCLS1 gene was predominantly expressed in tissues that require high levels of mitochondrial activities for energy metabolism, with the highest expression in skeletal and cardiac muscles. High levels of hCLS1 expression were also detected in liver, pancreas, kidney and small intestine, implying a functional role of hCLS1 in these tissues.

Amino Acid Sequence↗

PubMed1993

Kinetic mechanism of activation by cardiolipin (diphosphatidylglycerol) of the rat liver multicatalytic proteinase.

The effect of phospholipids on the trypsin-like, chymotrypsin-like and peptidylglutamyl-peptide-hydrolysing activities of the so-called latent form of the rat liver multicatalytic proteinase was studied, assaying them with the following substrates: N-Cbz-ARR-4MNA (N-Cbz, N-benzyloxycarbonyl; 4MNA, 4-methoxy-beta-naphthylamide), N-Suc-LLVY-MCA (N-Suc, N-succinyl; MCA, methylcoumarin) and N-Cbz-LLE-beta-NA (beta-NA, beta-naphthylamide) respectively (amino acids are shown as their one-letter symbol). For the most part neither lysophospholipids nor phospholipids at 20 micrograms/ml have any effect on the activity of the enzyme (assayed at 50 microM peptide), except for phosphatidylserine, which activates 2-fold the hydrolysis of N-Suc-LLVY-MCA, and phosphatidylinositol, which inhibits by 20% the hydrolysis of N-Cbz-LLE-beta-NA. By contrast, cardiolipin (diphosphatidylglycerol) is a strong activator of the hydrolysis of N-Suc-LLVY-MCA (60-fold) and N-Cbz-LLE-beta-NA (30-fold), with half-maximal activation at concentrations of 0.15 micrograms/ml and 1.5 micrograms/ml respectively. The activation of N-Suc-LLVY-MCA hydrolysis is due to an increase of the affinity of the enzyme for the peptide and to an increase in the Vmax. (30-fold). The activation of N-Cbz-LLE-beta-NA hydrolysis is explained by suppressing the co-operativity for this substrate, producing hyperbolic kinetics with a Km of 60 microM and a 15-fold increase in the Vmax. of the enzyme. This activation by cardiolipin was completely suppressed by micromolar concentrations of fluophenazine, a drug known to inhibit other phospholipid-regulated process. Cardiolipin activation and the known activation by SDS are additive, either at suboptimal or optimal concentrations of both activators. Cardiolipin also activates the in vitro degradation of some proteins from metabolically labelled total cellular extracts by the latent multicatalytic proteinase. These results clearly show that cardiolipin is a natural positive modulator of the peptidase and proteolytic activities of the multicatalytic proteinase, probably acting through a binding site different from that of SDS.

Amino Acid Sequence↗

PubMed1999

Anti-cardiolipin antibodies and circulating immune complexes in type 1 diabetes mellitus: increased prevalence and relation to vascular complications.

Anti-cardiolipin antibodies, oxidatively modified low-density lipoproteins (oxLDL) and circulating immune complexes are humoral factors that have been linked to vascular damage. To analyse their possible role in the vascular complications in type 1 diabetes mellitus, we investigated patients with and without vascular complications (retinopathy, nephropathy, polyneuropathy, foot ulcers). The patients were matched for age, sex and duration of diabetes. The patients were also compared with 102 healthy individuals. Anti-cardiolipin antibodies of IgG and IgA type were more common in patients compared with healthy individuals. There was no difference between patients with and without vascular complications. There was no increased prevalence of IgM anti-cardiolipin antibodies, but the levels of these antibodies were higher in patients with vascular complications compared with patients without complications and controls. Eighty-three percent of patients had circulating immune complexes in comparison with 5% of healthy individuals. Such complexes were more common in patients with complications. Both the prevalence and the levels of immune complexes were higher in patients with null alleles of complement factor C4. Patients with vascular complications had higher prevalence of C4A than of C4B null alleles. Anti-cardiolipin antibodies were present in higher relative concentrations in immune complex form than in serum in all six patients analysed. There was no increased prevalence of antibodies against oxidatively modified LDL in the patients. The higher prevalence and levels of anti-cardiolipin antibodies and circulating immune complexes in patients with vascular complications suggests that these humoral factors might be involved in the vascular complications of type 1 diabetes mellitus.

Adult↗

PubMed2002

Intracellular distribution of the fluorescent dye nonyl acridine orange responds to the mitochondrial membrane potential: implications for assays of cardiolipin and mitochondrial mass.

Cardiolipin, a polyunsaturated acidic phospholipid, is found exclusively in bacterial and mitochondrial membranes where it is intimately associated with the enzyme complexes of the respiratory chain. Cardiolipin structure and concentration are central to the function of these enzyme complexes and damage to the phospholipid may have consequences for mitochondrial function. The fluorescent dye, 10 nonyl acridine orange (NAO), has been shown to bind cardiolipin in vitro and is frequently used as a stain in living cells to assay cardiolipin content. Additionally, NAO staining has been used to measure the mitochondrial content of cells as dye binding to mitochondria is reportedly independent of the membrane potential. We used confocal microscopy to examine the properties of NAO in cortical astrocytes, neonatal cardiomyocytes and in isolated brain mitochondria. We show that NAO, a lipophilic cation, stained mitochondria selectively. However, the accumulation of the dye was clearly dependent upon the mitochondrial membrane potential and depolarisation of mitochondria induced a redistribution of dye. Moreover, depolarisation of mitochondria prior to NAO staining also resulted in a reduced NAO signal. These observations demonstrate that loading and retention of NAO is dependant upon membrane potential, and that the dye cannot be used as an assay of either cardiolipin or mitochondrial mass in living cells.

Acridine Orange↗

PubMed1978

Cardiolipin: a stereospecifically spin-labeled analogue and its specific enzymic hydrolysis.

The spin-labeled cardiolipin 1-(3-sn-phosphatidyl)-3-[1-acyl-2-(16-doxylstearoyl)glycero(3)phosphol]-sn-glycerol has been prepared. The stereoselective synthesis makes use of the monolysocardiolipin 1-(3-sn-phosphatidyl)-3-[1-acyl-2-lyso-sn-glycero(3)phospho]-sn-glycerol, available from the stereospecific hydrolysis of cardiolipin by phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) of Trimeresurus flavoviridis. The results of treatment of the spin-labeled cardiolipin with the cardiolipin-specific phospholipase D (phosphatidylcholine phosphatidohydrolase, EC 3.1.4.4) (Hemophilus parainfluenzae) of known specificity and with phospholipase C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3) of Bacillus cereus are consistent with the assigned structure. The spin-labeled cardiolipin is further characterized and the unique features of this diastereomer are discussed in the context of the unusual stereochemistry of the natural phospholipid.

Cardiolipins↗

PubMed2001

Decreased cardiolipin synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis.

Apoptosis has been identified recently as a component of many cardiac pathologies. However, the potential triggers of programmed cell death in the heart and the involvement of specific metabolic pathway(s) are less well characterized. Detachment of cytochrome c from the mitochondrial inner membrane is a necessary first step for cytochrome c release into the cytosol and initiation of apoptosis. The saturated long chain fatty acid, palmitate, induces apoptosis in rat neonatal cardiomyocytes and diminishes content of the mitochondrial anionic phospholipid, cardiolipin. These changes are accompanied by 1) acyl chain saturation of phosphatidic acid and phosphatidylglycerol, 2) large increases in the levels of these two phospholipids, and 3) a decline in cardiolipin synthesis. Although cardiolipin synthase activity is unchanged, saturated phosphatidylglycerol is a poor substrate for this enzyme. Under these conditions, decreased cardiolipin synthesis and release of cytochrome c are directly and significantly correlated. The results suggest that phosphatidylglycerol saturation and subsequent decreases in cardiolipin affect the association of cytochrome c with the inner mitochondrial membrane, directly influencing the pathway to cytochrome c release and subsequent apoptosis.

Animals↗

PubMed1995

Role of the N- and C-terminal domains of bovine beta 2-glycoprotein I in its interaction with cardiolipin.

beta 2-Glycoprotein I (beta 2-GPI) is a cofactor in the recognition of the phospholipid antigen cardiolipin by anti-cardiolipin antibodies in autoimmune diseases such as systemic lupus erythematosus. We examined the interactions of various forms of bovine beta 2-GPI, such as its intact form, desialylated form (Asialo-beta 2-GPI), N-terminal domain (Domain I), and modified forms of beta 2-GPI and Asialo-beta 2-GPI with nicks in their C-terminal domains, with phospholipid liposomes under different conditions of pH and ionic strength. We found that at neutral pH and low ionic strength, beta 2-GPI became bound to liposome membranes containing cardiolipin, phosphatidylglycerol, phosphatidylserine, phosphatidylserine, phosphatidic acid, or phosphatidylinositol, but not phosphatidylcholine alone. The number of phospholipids involved in the binding seemed to depend on the head group structure of the negatively charged phospholipids, but the dissociation constant did not, being about 10(-8) M, except that for the interaction with phosphatidylinositol, which was one order of magnitude lower. We also found that Domain I and Asialo-beta 2-GPI bound to liposome membranes containing negatively charged phospholipids, and that in the interaction with cardiolipin, their dissociation constants were about 10(-6) and 10(-8) M, respectively. At neutral pH and both low and high ionic strengths, the affinities of the nicked forms of beta 2-GPI and Asialo-beta 2-GPI for cardiolipin were both lower than those of their intact forms but similar to that of Domain I.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Human cardiolipin as the antigen in an ELISA to detect anticardiolipin antibodies.

Human cardiolipin was purified from cadaver heart tissue and used as the antigen in an enzyme-linked immunoassay (ELISA) for anticardiolipin antibodies. The correlation between assays using human and bovine cardiolipin was r = 0.90. Of the lupus anticoagulant positive patients 88% had antibodies to the human antigen and 75% had antibodies to the bovine antigen. Six of 45 samples contained antibodies which only reacted with the human antigen. All six samples remained positive when retested with a different human cardiolipin preparation and were negative when tested against a preparation of sheep cardiolipin. These studies suggest that there was increased specificity when human cardiolipin was used as the phospholipid antigen.

Animals↗

PubMed2003

Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria.

Several lines of evidence indicate that mitochondria-mediated reactive oxygen species (ROS) generation is a major source of oxidative stress in the cell. Release of cytochrome c from mitochondria is a central event in apoptosis induction and appears to be mediated by ROS. Dissociation of cytochrome c from the IMM, where it is bound to cardiolipin, represents a necessary first step for cytochrome c release. In the present study, the role of ROS and cardiolipin in the release of cytochrome c from rat liver mitochondria was investigated. ROS were produced by mitochondria oxidizing succinate in the nonphosphorylating state. Cytochrome c was quantitated by a new, very sensitive and rapid reverse-phase HPLC method. We found that succinate-supported ROS production resulted in a release of cytochrome c from mitochondria and a parallel loss of cardiolipin content. These effects were directly and significantly correlated and also abolished by ADP, which prevents succinate-mediated ROS production. The ROS-induced cytochrome c release was independent from MPT and appears to involve VDAC. It is suggested that mitochondrial-induced ROS production promotes cytochrome c release from mitochondria by a two-steps process, consisting of the dissociation of this protein from cardiolipin, followed by permeabilization of the outer membrane, probably by interaction with VDAC. The data may help clarify the molecular mechanism underlying the release of cytochrome c from the mitochondria to the cytosol and the role of ROS and cardiolipin in this release.

Animals↗

PubMed1988

Identification and primary structure of the cardiolipin-binding domain of mitochondrial creatine kinase.

It was recently shown that the mitochondrial isozyme of heart creatine kinase binds to cardiolipin on the outer half of the inner membrane [Müller, M., et al. (1985) J. Biol. Chem. 260, 3839-3843]. The enzyme has now been extracted and purified to homogeneity from rat heart mitochondria, and cleaved with CNBr. The fragments have been separated on an FPLC system using a Mono Q HR 5/5 column. Only one of these binds to cardiolipin-containing liposomes and has thus been identified as the cardiolipin-binding domain of the enzyme. Its amino acid sequence has been determined. The fragment contains 25 amino acids and corresponds to the N-terminal region of the protein. The binding of the fragment of cardiolipin-containing liposomes was inhibited by adriamycin. Another and larger CNBr fragment could be specifically labelled with periodate-oxidized (di-aldehyde) ATP and has thus been identified as the ATP-binding domain. Chemical modification of the basic amino acids Lys and Arg of the enzyme abolished its binding to cardiolipin.

Adenosine Triphosphate↗

PubMed1975

Phospholipid composition and cardiolipin synthesis in fermentative and nonfermentative marine bacteria.

Twenty biochemically distinct isolates of marine bacteria, comprising a collection of gram-negative, motile, straight and curved rod-shaped organisms, were separated into fermentative and nonfermentative groups. The isolates were analyzed fro phospholipid composition and the activities of the enzymes, cardiolipin synthetase, and a phosphilipase were determined. The phospholipid compositions of all isolates were generally similar. Phosphatidylethanolamine and phosphatidylglycerol were the major phospholipid classes detected. The absence of cardiolipin in most of the nonfermentative isolates was the most striking observation noted. This was verified chromatographically and by the absence of cardiolipin synthetase activity. In isolates which had cardiolipin, it apparently was synthesized by the condensation of two molecules of phosphatidylglycerol, a mechanism similar to that observed in terrestrial bacteria. Possible correlations between the presence of cardiolipin and Mg-2+ requirements for growth are discussed.

Bacteria↗