1. Structure and Composition
Cardiolipin is the trivial but universally used name for a lipid that should be correctly termed 'diphosphatidylglycerol' or more precisely 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol. It is a unique phospholipid with in essence a dimeric structure, having four acyl groups and potentially carrying two negative charges. The tetra-linoleoyl molecular species, important in heart mitochondria, is illustrated.
It is found almost exclusively in certain membranes of bacteria (plasma membrane and hydrogenosomes) and of mitochondria of eukaryotes, i.e. those membranes whose function is to generate an electrochemical potential for substrate transport and ATP synthesis. The trivial name 'cardiolipin' is derived from the fact that it was first found in animal hearts, where it is especially abundant, but it can be found in mitochondria of all animal tissues and indeed of the eukaryotic kingdom. For example, it amounts to about 10% of the phospholipids of bovine heart muscle, and 20% of the phospholipids of the mitochondrial membrane in this organ. Indeed, it has been termed the 'signature lipid' of the mitochondrion in that its presence in the membranes of an organelle identifies that organelle as a mitochondrion.
Even with four identical acyl residues, cardiolipin has two chemically distinct phosphatidyl moieties, as two chiral centres exist, one in each outer glycerol group, i.e. one is in a pro-R and the other in a pro-S position with respect to the central carbon atom of the glycerol bridge. These could in theory give rise to diastereomers, although natural cardiolipin has the R/R configuration. In consequence, the two phosphate groups have different chemical environments, and they produce distinct 31P-NMR resonances. They are designated 1'-phosphate and 3'-phosphate with respect to the central glycerol. Each of them contains one acidic proton, but they have very different levels of acidity. Until recently, figures of pK1 = 2.8 and pK2 ~7.5 were accepted, but a newer study suggests a pK1 of 2.15, similar to that of phosphoric acid, while pK2 is only about one unit greater. The weaker acidity of the second phosphate is believed to be a result of formation of a stable intramolecular hydrogen bond with the central 2'-hydroxyl group. In fact, there is a suggestion that under normal physiological conditions, the molecule may carry only one negative charge. Molecular models of cardiolipin show that in aqueous dispersions its phosphates can form a tight bicyclic resonance structure with the central hydroxyl group, producing an acid-anion and giving an especially compact structure in which one of the protons is trapped. This resonance structure is especially stable when the four fatty acid constituents are identical so the molecule is symmetrical.
Because of this unique structure, cardiolipin is able to form micellar, lamellar, and hexagonal states in aqueous dispersions, depending on pH and ionic strength. It is believed to exist mainly in a bilayer state in natural membranes, with its two phosphatidylglycerol moieties oriented perpendicular to the bilayer surface and the central glycerol group oriented at the water/membrane interface and parallel to it. However, there may remain a tendency of cardiolipin to form transient non-bilayer domains, which could have a profound influence on its function in vital cellular processes. The ability to form hexagonal phases is believed to be responsible for its location in the inner mitochondrial membrane at contact sites with the outer mitochondrial membrane. For example, the four linoleate residues in heart cardiolipin tend to spread laterally in a bilayer causing it to thin; together with the compact head group, this tends to formation of a hexagonal phase. In contrast, the mainly palmitate/vaccenate residues in cardiolipin from E. coli favour bilayer formation.
As the head-group glycerol of cardiolipin is shared by two phosphatidate moieties, its mobility is severely restricted, reducing its capacity for either intra- or intermolecular interactions with other phospholipid head groups. Also, the secondary hydroxyl group of the central glycerol moiety is the sole source of hydrogen-bonding donor groups available for such interactions, so that bonding to other lipids is unlikely. It should be recognized that as the two phosphate groups are chirally distinct, there exist opportunities for differential activities or interactions of each under both chiral and achiral conditions.
As there are four fatty acyl groups in cardiolipin, the potential for complexity in the distribution within molecular species is enormous. However, the compositions can be remarkably simple, very different from those of other phospholipids, and in animals they are resistant to dietary manipulation. For example, in most animal tissues, cardiolipin contains almost exclusively 18 carbon fatty acids, and 80% of this is typically linoleic acid (18:2(n-6)). This appears to be true of higher plants also. Amongst animal tissues, testis cardiolipin is an exception in that it contains mainly palmitic acid, while cardiolipin in the brain contains more fatty acids including arachidonic and docosahexaenoic acids. In addition to tetra-acyl species, some bacteria contain mono- and dialk-1-enyl forms (plasmalogens).
Yeast cardiolipin can differ in having mainly 16:1 and 18:1 fatty acids, while the bacterial lipid such as that in Escherichia coli contains saturated and monoenoic fatty acids with 14 to18 carbons. In some marine species, cardiolipin contains only docosa- or tetracosahexaenoic acids (22:6 or 24:6), while lymphoblast cardiolipin contains only monoenoic fatty acids. Thus, a common feature of this lipid in a variety of very different organisms is a relatively simple fatty acid and molecular species composition, leading to a high degree of structural symmetry.
Analysis of the molecular species of cardiolipin, including the positional distributions on the various glycerol moieties, has been a technically daunting task, but it has been accomplished for many species and data for bovine heart and rat liver are listed in Table 1.
Table 1. The main molecular species of mammalian cardiolipin
|Source||Molecular species*||Amount (mol%)|
|Fatty acid 1A||Fatty acid 2A||Fatty acid 1B||Fatty acid 2B|
|* Fatty acyl residues are designated as shown in the formula above.
From Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem., 212, 727-735 (1993).
Until relatively recently, it was thought that cardiolipin was associated exclusively with the mitochondrial inner membrane, where it represents about 25% of the total phospholipids in bovine heart mitochondria, for example. It is now know to occur in the mitochondrial outer membrane also if only at a level of about 4%. However, this may be significant as it appears to predominate at sites connecting the outer membrane with the inner, where its unique physical properties may be important.
The highly specific location of cardiolipin is used as an argument in favour of the hypothesis that mitochondria are derived from prokaryotes, which lived inside a eukaryotic progenitor cell in symbiosis. If this did indeed occur, the function of cardiolipin has changed during evolution, as mitochondria require a constant level of cardiolipin to function correctly, while prokaryotes only appear to require it in specific circumstances.
2. Biosynthesis and Metabolism
The biosynthetic pathway to cardiolipin is similar to that of some other phospholipids in that it passes through the common intermediates, phosphatidic acid and then cytidine diphosphate diacylglycerol (see our web pages on phosphatidylglycerol). However, the final step is a unique reaction, which is very different in prokaryotes and eukaryotes. In the latter, it is the only phospholipid that is not synthesised on the cytosolic side of the endoplasmic reticulum but in the mitochondrion.
In prokaryotes such as bacteria, diphosphatidylglycerol synthase catalyses a transfer of the phosphatidyl moiety of one phosphatidylglycerol to the free 3'-hydroxyl group of another, with the elimination of one molecule of glycerol, via the action of two structurally related enzymes, which are part of the phospholipase D superfamily. In effect, transphosphatidylation occurs with one phosphatidylglycerol acting as a donor and the other an acceptor of a phosphatidyl moiety. The enzymes can operate in reverse under some physiological conditions to remove cardiolipin. The biosynthesis of cardiolipin is regulated via that of phosphatidylglycerol. Surprisingly, cardiolipin synthesis occurs by the prokaryote pathway in the protozoan parasite, Trypanosoma brucei.
A second mechanism has been found in the bacterium Escherichia coli in which cardiolipin is formed by condensation of phosphatidylglycerol and phosphatidylethanolamine with elimination of ethanolamine, via the action of a third related enzyme.
With eukaryotes (yeasts, plants and animals), the first committed step in step in the biosynthesis of cardiolipin is the formation of phosphatidylglycerolphosphate, a key intermediate in the biosynthesis of phosphatidylglycerol (as described in the web page on phosphatidylglycerol). The cardiolipin (or diphosphatidylglycerol) synthase, a phosphatidyl transferase, then links phosphatidylglycerol to diacylglycerol phosphate from the activated phosphatidyl moiety cytidine diphosphate diacylglycerol, with elimination of cytidine monophosphate (CMP). The enzymes from all species examined in detail require certain divalent cations (Mg2+, Mn2+ or Co2+) together with a high pH (8 to 9). In rat liver, the cardiolipin synthase resides in the inner mitochondrial membrane, while in yeast it is part of a large protein complex. The catalytic centre of cardiolipin synthase is exposed to the matrix side of the inner membrane.
As eukaryotic cardiolipin synthase is a mitochondrial enzyme and mitochondria are believed to be phylogenetic derivatives of ancient prokaryotes, it appears strange that there has been such a change in mechanism. In eukaryotes, cardiolipin is the only phospholipid synthesised in the mitochondrion, and it remains there for the life of the cell. Surprisingly, actinomycetes use the eukaryote biosynthetic system.
The ultimate fatty acid composition of cardiolipin in eukaryotes is attained by remodelling. This can be achieved by the coenzyme A (CoA)-dependent deacylation-reacylation cycle known as the 'Lands cycle' (after W.E.M. (Bill) Lands), though it is now believed that the main route is via CoA-independent transacylation between different phospholipids in which an enzyme termed ‘tafazzin’ plays a major part. This is necessary as the precursor phospholipid is very different in composition from that apparently required in the final product if it is to function correctly.
The first step in remodelling of cardiolipin involves the removal of a single acyl chain with formation of monolysocardiolipin by a calcium-independent phospholipase A2. It hydrolyses newly synthesised cardiolipin with a strong substrate preference for palmitoyl residues. In heart and yeast mitochondria, tafazzin is known to transfer linoleate groups highly selectively from phosphatidylcholine to monolysocardiolipin, promoting molecular symmetry among the molecular species of fully acylated cardiolipin (and with formation of lysophosphatidylcholine). The reaction does not require a coenzyme A ester as an intermediate, and it is reversible. This is believed to be the first CoA-independent phospholipid transacylase to have been identified, and it may be involved in remodelling of other phospholipid classes. The reaction is thus quite different from the cycle of acylation and deacylation involved in the remodelling of the more conventional phospholipids. Unlike the latter in which only position sn-2 is modified, all four positions in cardiolipin are affected. When the remodelling reaction proceeds by the cyclic mechanism illustrated, only a trace level of either lysophosphatidylcholine or monolysocardiolipin need be present. In addition, there is evidence that the reaction of taffazin is responsive to the phase state of the membrane, selecting molecular species of cardiolipin that favour membrane curvature.
From a mathematical model based on the assumption that different molecular species have different free energies, it has been concluded that specific acyl-distributions in cardiolipin could arise from phospholipid transacylations in the tafazzin domain, even if tafazzin itself does not have substrate specificity. On the other hand, this model may be an oversimplification in that two further enzymes have the ability to attach an acyl chain to monolysocardiolipin, i.e. monolysocardiolipin acyltransferase-1 and acyl-CoA:lysocardiolipin acyltransferase-1. The first of these especially has a high specificity for linoleate and has the potential to be a major contributor to the production of the mature cardiolipin.
In yeast, tafazzin is located in outer leaflet of the inner membrane so cardiolipin must be translocated by means of a scramblase or other transporter from the inner leaflet of this membrane for remodelling to occur. Similarly, the final product must be transported by appropriate mechanisms to its final membrane destination.
In addition to the biogenesis of new cardiolipin, this remodelling process may be utilized to repair oxidatively damaged cardiolipin or to change the molecular form of existing cardiolipin to suit a specific mitochondrial function.
Catabolism of cardiolipin may occur by the action of phospholipase A2 to remove fatty acyl groups, possibly after oxidation as part of the process of apoptosis (see below). There is also a specific mitochondrial phospholipase D, which hydrolyses cardiolipin to phosphatidic acid (and phosphatidylglycerol) and in so doing promotes the fusion of mitochondria. This may be especially important under conditions of oxidative stress. The rate of hydrolysis by all phospholipases is significantly higher in the 3'-phosphatidyl moiety.
As cardiolipin is the specific lipid component of mitochondria, its biological function in this organelle is clearly crucial. It is located mainly on the inner membrane of mitochondria, where it interacts with a large number of mitochondrial proteins. This interaction effects functional activation of certain enzymes, especially those involved in oxidative phosphorylation and photophosphorylation, which result in ATP production. In animals, the respiratory chain consists of four enzymes (NADH dehydrogenase, succinate dehydrogenase, cytochrome bc1 complex, and cytochrome c oxidase), which are now believed to be organized in large complexes, designated complexes I to IV and constituting a supramolecular network. Cardiolipin has been identified as an integral component in crystals of mitochondrial complex III, complex IV and the ADP-ATP-carrier, and it is known to be essential for the stability of the quaternary protein structure of the last. Similarly in yeast, the related enzymes appear to form part of a single functional unit, components of which contain tightly bound cardiolipin. This is an essential component of the interface between the complex and its membrane environment or between subunits within the complex. Removal of cardiolipin leads to breakup of the complex and loss of functionality.
Another function for cardiolipin in relation to energy metabolism is that it anchors two kinases, mitochondrial creatine kinase and nucleoside diphosphate kinase, to the inner and possibly the outer mitochondrial membranes where they come in contact. In this instance, and with the ADP-ATP- and phosphate-carrier proteins, it may facilitate the transport of solutes between the intra-membrane and matrix spaces of mitochondria.
The physical chemistry of the interaction between cardiolipin and enzymes is the key to understanding this function. Cardiolipin has a strong binding capacity for many structurally unrelated proteins, so its structure must be adapted to differing protein surfaces. This interaction has been studied intensively for the cytochrome bc1 complex of the respiratory chain, which couples electron transfer between ubiquinol and cytochrome c to the translocation of protons across the lipid bilayer. One cardiolipin molecule is bound close to the site of ubiquinone reduction and is believed to ensure the stability of the catalytic site as well as being involved in proton uptake. In general, the head group of cardiolipin and certain amino acid residues interact strongly via electrostatic forces, hydrogen bonds, and water molecules, while the acyl chains retain their flexibility and interact through van der Waals forces with the protein surface at a number of sites. However, we do not yet know why or indeed if the highly specific fatty acid and molecular species compositions are necessary for these functions.
Cardiolipin has been implicated in the process of apoptosis (programmed cell death) in animal cells through its interactions with a variety of death-inducing proteins, including cytochrome c. The enzyme is believed to act as a peroxidase, which reacts quite specifically with cardiolipin but not with other more abundant phospholipids, causing oxidation and then hydrolysis of the product cardiolipin hydroperoxides. The consequence is that the cytochrome c is released into the inter-membrane space, while the oxidized cardiolipin is translocated to the outer mitochondrial membrane and participates in the formation of the mitochondrial permeability transition pore that facilitates egress of pro-apoptopic factors from mitochondria into the cytosol where they trigger apoptosis. During this process, cardiolipin is also involved in the anchoring, translocation, and embedding of caspase, a key protein in the process of apoptosis, in the mitochondrial membrane, and thereby causes further release of apoptotic factors into the cytosol. Specific nontypical molecular species of cardiolipin with a high content of arachidonic and docosahexaenoic acid may be involved in the process. As a result, the cellular concentration of cardiolipin decreases rapidly while some monolysocardiolipin may accumulate.
Cardiolipin is believed to be an important cofactor for cholesterol translocation from the outer to the inner mitochondrial membrane, and in steroidogenic tissues, it activates mitochondrial cholesterol side-chain cleavage and is a potent stimulator of steroidogenesis. Cardiolipin may also have a specific role in the import of proteins into mitochondria, and it can behave as a molecular chaperone to promote folding of mitochondrial proteins. It binds in a highly specific way to the DNA in eukaryotic chromatin (the material of which chromosomes are composed), and indeed all of this lipid in chromatin is bound to DNA, where both have a common 'interphosphate' structural motive. Thus, cardiolipin appears to have a functional role in the regulation of gene expression. As a component of the plasma lipoproteins, it is believed to have an anticoagulant function.
In higher plants and photosynthetic bacteria, cardiolipin is an integral constituent of the photosystem II complexes, which are also involved in oxidative processes, where it may be required for the maintenance of structural and functional properties. Similarly, in eubacteria, it has a role in oxidative phosphorylation, but can be replaced by other phospholipids in selected mutants at least. The cytoplasmic membranes of bacteria are believed to contain microdomains of cardiolipin (and of phosphatidylethanolamine), which assemble spontaneously because of the intrinsic physical properties of the lipid. These microdomains seem be located where there is intense phospholipid biosynthesis and may be relevant to other cellular processes, including cell division and sporulation.
Cardiolipin is an integral component of several prokaryotic enzyme systems, including those involved in cell division, energy metabolism and membrane transport. Its distinctive physical properties are essential for osmoregulation in bacteria such as E. coli.
4. Cardiolipin in Disease
Barth syndrome, a human disease state (an infantile cardiomyopathy) linked to the X-chromosome, is associated with marked abnormalities in the composition of cardiolipin, i.e. a decrease in tetralinoleoyl molecular species and an accumulation of monolysocardiolipin. There is evidence that the metabolic defect involves the phospholipid acyltransferase (‘tafazzin’) that under normal circumstances remodels cardiolipin by a specific transference of linoleate (see above). The consequence may be a reduction in the efficiency of oxidative phosphorylation in mitochondria or an increase in the permeability of the mitochondrial membranes. Similar phenomena have been observed in yeast mutants that lack the corresponding acyltransferase. Determination of the relative amounts of cardiolipin and lysocardiolipin in blood aids diagnosis of the disease.
In addition, reductions in the concentrations of cardiolipin or changes in its composition in heart mitochondria have been implicated in many different human diseases states, including heart failure, diabetes and cancer, although it is not clear whether these effects are symptoms or the cause. For example, there is a dramatic decline in the content of myocardial cardiolipin at the onset of diabetes, and this is accompanied by extensive remodelling with the production of molecular species enriched in docosahexaenoic acid. Although oxidation of cardiolipin is part of the normal process of apoptosis, there is evidence that the proximity of this lipid to highly reactive oxygen species can lead to excessive peroxidation and oxidative stress, for example in the ischemic heart and skeletal muscle or during aging. Malfunctions of cardiolipin metabolism in brain mitochondria have been implicated in Alzheimer’s disease and Parkinson’s disease.
The bacteria responsible for syphilis produce antibodies to cardiolipin. Although the reasons for this are not properly understood, cardiolipin is widely used an antigen in tests for the disease. Indeed, it was this property that lead to the first isolation of cardiolipin by Mary Pangborn in 1942, followed by the establishment of its structure by LeCocq and Ballou in 1964. The presence of antibodies to cardiolipin in plasma of patients with various diseases in which tissue damage occurs is considered to be a danger signal to the immune system. T cells responsive to cardiolipin or oxidized cardiolipin may have a function in immune surveillance during infection and tissue injury, while antibodies to cardiolipin are used in diagnostic tests after unexplained venous or arterial thrombotic episodes or recurrent miscarriages.
5. Related Lipids
Animals and higher plants appear to contain only cardiolipin per se, but structural analogues, such as phosphatidylglycerophosphoglycerol, D-glucopyranosylcardiolipin, D-alanylcardiolipin, L-lysylcardiolipin and phosphatidylglycerol acetal of plasmenyl diphosphatidylglycerol, have been found in both gram-positive and gram-negative bacteria. For example, lysyl-cardiolipin is a major constituent of the membranes of Listeria species and can represent up to 30% of the total phospholipids. In these lipids, the alanyl, lysyl and glucosyl residues are linked to the hydroxyl-2' on the central glycerol moiety. The amino-acid containing lipids are obviously related to the complex lipoamino acids derived from phosphatidylglycerol, and they are synthesised by analogous enzymes.
In the glucosylcardiolipin from Geobacillus stearothermophilus, the main fatty acids present have iso-and anteiso-methyl branches (15:0 to 17:0), while fatty acids with a terminal cyclohexyl group are the main components in the lipid from A. acidoterrestris. There is also an O-acyl glycosylated cardiolipin in the thermophilic bacterium Alicyclobacillus acidoterrestris.
In Halobacterium salinarum (Archaea), osmotic shock induces formation of an even more complex lipid consisting of sulfo-triglycosyl-diether esterified to the phosphate group of phosphatidic acid, which has been termed 'glycocardiolipin'. However, use of the term ‘cardiolipin’ in this instance seems something of a misnomer as a glucose unit takes the place of the central glycerol. However, some of the Archaea contain true cardiolipin analogues.
Cardiolipin elutes close to phosphatidylglycerol and phosphatidic acid in many chromatographic systems, but it can be resolved with care. Modern liquid chromatography-mass spectrometry and 'shotgun lipidomics' techniques are proving to be sensitive and specific. However, such methods do not distinguish between the two chiral glycerol moieties, so detailed analyses of molecular species and positional distributions are still difficult technical problems. The papers by Schlame et al. cited below are invaluable guides. A method involving high-performance liquid chromatography linked to electrospray mass spectrometry has been developed to separated cardiolipin and monolysocardiolipin as an aid to the diagnosis of Barth syndrome.
- Christie, W.W. and Han, X. Lipid Analysis - Isolation, Separation, Identification and Lipidomic Analysis (4th edition), 446 pages (Oily Press, Bridgwater, U.K. and Woodhead Publishing Ltd, Cambridge, U.K.) (2010) - Woodhead Publishing Ltd.
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- Corcelli, A. The cardiolipin analogues of Archaea. Biochim. Biophys. Acta, 1788, 2101-2106 (2009) (DOI: 10.1016/j.bbamem.2009.05.010).
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- Lewis, R.N.A.H. and McElhaney, R.N. The physicochemical properties of cardiolipin bilayers and cardiolipin-containing lipid membranes. Biochim. Biophys. Acta, 1788, 2069-2079 (2009) (DOI: 10.1016/j.bbamem.2009.03.014).
- Li, G., Chen, S., Thompson, M.N. and Greenberg, M.L. New insights into the regulation of cardiolipin biosynthesis in yeast: Implications for Barth syndrome. Biochim. Biophys. Acta, 1771, 432-441 (2007) (DOI: 10.1016/j.bbalip.2006.06.007).
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- Peter-Katalinic, J. and Fischer, W. α-Glucopyranosyl-, D-alanyl-and L-lysylcardiolipin from gram-positive bacteria: analysis by fast atom bombardment mass spectrometry. J. Lipid Res., 39, 2286-229 (1998) (DOI: 10.1194/jlr.R700018-JLR200).
- Schlame, M. Cardiolipin remodeling and the function of tafazzin. Biochim. Biophys. Acta, 1831, 582-588 (2013) (DOI: 10.1016/j.bbalip.2012.11.007).
- Schlame, M. and Ren, M. The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim. Biophys. Acta, 1788, 2080-2083 (2009) (DOI: 10.1016/j.bbamem.2009.04.019).
- Schlame, M. and Ren, M. Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Letts., 580, 5450-5455 (2006) (DOI: 10.1016/j.febslet.2006.07.022).
- Schlame, M., Ren, M., Xu, Y., Greenberg, M.L. and Haller, I. Molecular symmetry in mitochondrial cardiolipins. Chem. Phys. Lipids, 138, 38-49 (2005) (DOI: 10.1016/j.chemphyslip.2005.08.002).
- Schug, Z.T. and Gottlieb, E. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim. Biophys. Acta, 1788, 2022-2031 (2009) (DOI: 10.1016/j.bbamem.2009.05.004).
Updated July 1, 2014