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Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol, "''sn''" designating
stereospecific numbering Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes in eukaryotic cells. They are a type of lipid, of which its composition affects membrane structure and properties. Tw ...
) is an important component of the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
. The name "cardiolipin" is derived from the fact that it was first found in animal hearts. It was first isolated from the beef heart in the early 1940s by Mary C. Pangborn. In mammalian cells, but also in plant cells, cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane, where it is essential for the optimal function of numerous
enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
that are involved in mitochondrial energy metabolism.


Structure

Cardiolipin (CL) is a kind of diphosphatidylglycerol lipid. Two phosphatidic acid moieties connect with a
glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
backbone in the center to form a dimeric structure. So it has four alkyl groups and potentially carries two negative charges. As there are four distinct alkyl chains in cardiolipin, the potential for complexity of this molecule species is enormous. However, in most animal tissues, cardiolipin contains 18-carbon fatty alkyl chains with 2 unsaturated bonds on each of them. It has been proposed that the (18:2)4 acyl chain configuration is an important structural requirement for the high affinity of CL to inner membrane proteins in mammalian mitochondria. However, studies with isolated enzyme preparations indicate that its importance may vary depending on the protein examined. In vitro experiments have shown that CL has high affinity for curved membrane regions. Since there are two phosphates in the molecule, each of them can bond with one proton. Although it has a symmetric structure, ionizing one phosphate happens at a very different levels of acidity than ionizing both: pK1 = 3 and pK2 > 7.5. So under normal physiological conditions (wherein pH is around 7), the molecule may carry only one negative charge. The hydroxyl groups (–OH and –O−) on phosphate would form a stable intramolecular hydrogen bond with the centered glycerol's hydroxyl group, thus forming a bicyclic resonance structure. This structure traps one proton, which is quite helpful for
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
. As the head group forms such compact bicycle structure, the head group area is quite small relative to the big tail region consisting of 4 acyl chains. Based on this special structure, the fluorescent mitochondrial indicator, nonyl acridine orange (NAO) was introduced in 1982, and was later found to target mitochondria by binding to CL. NAO has a very large head and small tail structure which can compensate with cardiolipin's small head and large tail structure, and arrange in a highly ordered way. Several studies were published utilizing NAO both as a quantitative mitochondrial indicator and an indicator of CL content in mitochondria. However, NAO is influenced by membrane potential and/or the spatial arrangement of CL, so it's not proper to use NAO for CL or mitochondria quantitative studies of intact respiring mitochondria. But NAO still represents a simple method of assessing CL content. Image:Cardiolipin bicyclic structure.svg, Cardiolipin bicyclic structure Image:Nonyl acridine orange.svg, Structure of NAO Image:NAOandCL.jpg, NAO & CL arranged in a highly ordered way


Methods to quantify and detect cardiolipin

The detection, quantification, and localisation of CL species is a valuable tool to investigate mitochondrial dysfunction and the pathophysiological mechanisms underpinning several human disorders. CL is measured using liquid chromatography, usually combined with
mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...
, mass spectrometry imaging, shotgun lipidomics,
ion mobility spectrometry Ion mobility spectrometry (IMS) It is a method of conducting analytical research that separates and identifies ionized molecules present in the gas phase based on the mobility of the molecules in a carrier buffer gas. Even though it is used exte ...
, fluorometry, and radiolabelling. Therefore, the choice of the analytical method depends on the experimental question, level of detail, and sensitivity required.


Metabolism and catabolism


Metabolism


Eukaryotic pathway

In eukaryotes such as yeasts, plants and animals, the synthesis processes are believed to happen in mitochondria. The first step is the acylation of glycerol-3-phosphate by a glycerol-3-phosphate
acyltransferase Acyltransferase is a type of transferase enzyme that acts upon acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen ...
. Then acylglycerol-3-phosphate can be once more acylated to form a phosphatidic acid (PA). With the help of the enzyme CDP-DAG synthase (CDS) ( phosphatidate cytidylyltransferase), PA is converted into
cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1-glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid that is ...
diphosphate-diacylglycerol (CDP-DAG). The following step is conversion of CDP-DAG to phosphatidylglycerol phosphate (PGP) by the enzyme PGP synthase, followed by
dephosphorylation In biochemistry, dephosphorylation is the removal of a phosphate () group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate e ...
by PTPMT1 to form PG. Finally, a molecule of CDP-DAG is bound to PG to form one molecule of cardiolipin, catalyzed by the mitochondria-localized enzyme cardiolipin synthase (CLS).


Prokaryotic pathway

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 an enzyme related to
phospholipase D Phospholipase D (PLD) (EC 3.1.4.4; also known as lipophosphodiesterase II, lecithinase D, choline phosphatase; systematic name: phosphatidylcholine phosphatidohydrolase) is an anesthetic-sensitive and mechanosensitive enzyme of the phospholipa ...
. The enzyme can operate in reverse under some physiological conditions to remove cardiolipin.


Catabolism

Catabolism of cardiolipin may happen by the catalysis of
phospholipase A2 The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycero ...
(PLA) to remove fatty acyl groups.
Phospholipase D Phospholipase D (PLD) (EC 3.1.4.4; also known as lipophosphodiesterase II, lecithinase D, choline phosphatase; systematic name: phosphatidylcholine phosphatidohydrolase) is an anesthetic-sensitive and mechanosensitive enzyme of the phospholipa ...
(PLD) in the mitochondrion hydrolyses cardiolipin to phosphatidic acid.


Functions


Regulates aggregate structures

Because of cardiolipin's unique structure, a change in pH and the presence of
divalent In chemistry, the valence (US spelling) or valency (British spelling) of an atom is a measure of its combining capacity with other atoms when it forms chemical compounds or molecules. Valence is generally understood to be the number of chemica ...
cations can induce a structural change. CL shows a great variety of forms of aggregates. It is found that in the presence of Ca2+ or other divalent cations, CL can be induced to have a lamellar-to-
hexagonal In geometry, a hexagon (from Greek , , meaning "six", and , , meaning "corner, angle") is a six-sided polygon. The total of the internal angles of any simple (non-self-intersecting) hexagon is 720°. Regular hexagon A regular hexagon is d ...
(La-HII)
phase transition In physics, chemistry, and other related fields like biology, a phase transition (or phase change) is the physical process of transition between one state of a medium and another. Commonly the term is used to refer to changes among the basic Sta ...
. And it is believed to have a close connection with
membrane fusion In membrane biology, fusion is the process by which two initially distinct lipid bilayers merge their hydrophobic cores, resulting in one interconnected structure. If this fusion proceeds completely through both leaflets of both bilayers, an aqueou ...
.


Facilitates the quaternary structure

The enzyme
cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes. It is the last enzyme in the Cellular respir ...
, also known as Complex IV, is a large
transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...
complex found in mitochondria and bacteria. It is the last enzyme in the respiratory
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
located in the inner mitochondrial or bacterial membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. Complex IV has been shown to require two associated CL molecules in order to maintain its full enzymatic function. Cytochrome bc1 (Complex III) also needs cardiolipin to maintain its quaternary structure and functional role. Complex V of the
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
machinery also displays high binding affinity for CL, binding four molecules of CL per molecule of complex V.


Triggers apoptosis

Cardiolipin distribution to the outer mitochondrial membrane would lead to apoptosis of the cells, as evidenced by cytochrome c (cyt c) release, Caspase-8 activation, MOMP induction and NLRP3 inflammasome activation. During
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, cyt c is released from the intermembrane spaces of mitochondria into the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. Cyt c can then bind to the IP3 receptor on
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
, stimulating calcium release, which then reacts back to cause the release of cyt c. When the calcium concentration reaches a toxic level, this causes cell death. Cytochrome c is thought to play a role in apoptosis via the release of apoptotic factors from the
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
. A cardiolipin-specific oxygenase produces CL
hydroperoxide Hydroperoxides or peroxols are Chemical compound, compounds of the form ROOH, where R stands for any group, typically Organic compound, organic, which contain the hydroperoxy functional group (). Hydroperoxide also refers to the hydroperoxide anio ...
s which can result in the conformation change of the lipid. The oxidized CL transfers from the inner membrane to the outer membrane, and then helps to form a permeable pore which releases cyt c.


Serves as proton trap for oxidative phosphorylation

During the
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
process catalyzed by Complex IV, large quantities of protons are transferred from one side of the membrane to another side causing a large pH change. CL is suggested to function as a proton trap within the mitochondrial membranes, thereby strictly localizing the proton pool and minimizing the changes in pH in the mitochondrial intermembrane space. This function is due to CL's unique structure. As stated above, CL can trap a proton within the bicyclic structure while carrying a negative charge. Thus, this bicyclic structure can serve as an electron buffer pool to release or absorb protons to maintain the pH near the membranes.


Other functions

*
Cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
translocation from outer to the inner mitochondrial membrane *Activates mitochondrial cholesterol side-chain cleavage *Import protein into mitochondrial matrix *
Anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...
function *Modulates α-synuclein - malfunction of this process is thought to be a cause of Parkinson's disease.


Clinical significance

Increasing evidence links aberrant CL metabolism and content to human disease. Human conditions include neurological disorders, cancer, and cardiovascular and metabolic disorders (''a full list can be found at''). As the number of human diseases with CL profile abnormalities has exponentially grown, the use of qualitative and quantitative diagnostics has emerged as a necessity.


Metabolic diseases


Barth syndrome

Barth syndrome is a rare genetic disorder that was recognised in the 1970s to cause infantile death. It has a mutation in the gene coding for
tafazzin Tafazzin is a protein that in humans is encoded by the ''TAFAZZIN'' gene. Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid- lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acylt ...
, an enzyme involved in the
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
of cardiolipin. Tafazzin is an indispensable enzyme to synthesize cardiolipin in eukaryotes involved in the remodeling of CL acyl chains by transferring
linoleic acid Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid. Linoleic acid is a polyunsat ...
from PC to monolysocardiolipin. Mutation of tafazzin would cause insufficient cardiolipin remodeling. However, it appears that cells compensate and ATP production is similar or higher than normal cells. Females
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
for the trait are unaffected. Sufferers of this condition have mitochondria that are abnormal.
Cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...
and general weakness is common to these patients.


Combined malonic and methylmalonic aciduria (CMAMMA)

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, there is an altered composition of complex lipids as a result of impaired
mitochondrial fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two '' de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) and mitochondrial ...
(mtFAS), so for example the content of cardiolipins is strongly increased.


Tangier disease

Tangier disease is also linked to CL abnormalities. Tangier disease is characterized by very low
blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
levels of HDL cholesterol, accumulation of cholesteryl esters in tissues, and an increased risk for developing
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
. Unlike Barth syndrome, Tangier disease is mainly caused by abnormal enhanced production of CL. Studies show that there are three to fivefold increase of CL level in Tangier disease. Because increased CL levels would enhance cholesterol oxidation, and then the formation of
oxysterol An oxysterol is a derivative of cholesterol obtained by Redox, oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, ...
s would consequently increase cholesterol efflux. This process could function as an escape mechanism to remove excess cholesterol from the cell.


Parkinson's disease and Alzheimer's disease

Oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
and
lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
are believed to be contributing factors leading to neuronal loss and mitochondrial dysfunction in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...
in
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, and may play an early role in the pathogenesis of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. It is reported that CL content in the brain decreases with aging, and a recent study on rat brain shows it results from lipid peroxidation in mitochondria exposed to free radical stress. Another study shows that the CL biosynthesis pathway may be selectively impaired, causing 20% reduction and composition change of the CL content. It is also associated with a 15% reduction in linked complex I/III activity of the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
, which is thought to be a critical factor in the development of Parkinson's disease.


Nonalcoholic fatty liver disease and heart failure

Recently, it is reported that in
non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...
and
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
, decreased CL levels and change in acyl chain composition are also observed in the mitochondrial dysfunction. However, the role of CL in aging and ischemia/reperfusion is still controversial.


Diabetes

Heart disease is twice as common in people with diabetes. In diabetics, cardiovascular complications occur at an earlier age and often result in premature death, making heart disease the major killer of diabetic people. Cardiolipin has been found to be deficient in the heart at the earliest stages of diabetes, possibly due to a lipid-digesting enzyme that becomes more active in diabetic heart muscle.


Syphilis

Cardiolipin from a cow heart is used as an antigen in the Wassermann test for
syphilis Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
. Anti-cardiolipin antibodies can also be increased in numerous other conditions, including systemic lupus erythematosus, malaria and tuberculosis, so this test is not specific.


HIV-1

Human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
-1 (HIV-1) has infected more than 60 million people worldwide. HIV-1 envelope glycoprotein contains at least four sites for neutralizing antibodies. Among these sites, the membrane-proximal region (MPR) is particularly attractive as an antibody target because it facilitates viral entry into T cells and is highly conserved among viral strains. However, it is found that two antibodies directed against 2F5, 4E10 in MPR react with self-antigens, including cardiolipin. Thus, it's difficult for such antibodies to be elicited by vaccination.


Cancer

It was first proposed by
Otto Heinrich Warburg Otto Heinrich Warburg (, ; 8 October 1883 – 1 August 1970) was a German physiologist, medical doctor, and Nobel laureate. He served as an officer in the elite Uhlan (cavalry regiment) during the First World War, and was awarded the Iron Cross ...
that cancer originated from irreversible injury to mitochondrial respiration, but the structural basis for this injury has remained elusive. Since cardiolipin is an important phospholipid found almost exclusively in the inner mitochondrial membrane and very essential in maintaining mitochondrial function, it is suggested that abnormalities in CL can impair mitochondrial function and bioenergetics. A study published in 2008 on mouse brain tumors supporting Warburg's cancer theory shows major abnormalities in CL content or composition in all tumors.


Antiphospholipid syndrome

Patients with
anti-cardiolipin antibodies Anti-cardiolipin antibodies (ACA) are antibodies often directed against cardiolipin and found in several diseases, including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathi ...
(
Antiphospholipid syndrome Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-relate ...
) can have recurrent thrombotic events even early in their mid- to late-teen years. These events can occur in vessels in which thrombosis may be relatively uncommon, such as the hepatic or renal veins. These antibodies are usually picked up in young women with recurrent spontaneous abortions. In anti-cardiolipin-mediated autoimmune disease, there is a dependency on the apolipoprotein H for recognition.


Additional anti-cardiolipin diseases


Chronic fatigue syndrome

Chronic fatigue syndrome Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling Chronic condition, chronic illness. People with ME/CFS experience profound fatigue that does not go away with rest, as well as sleep issues and problems with memory ...
is debilitating illness of unknown cause that often follows an acute viral infection. According to one research study, 95% of CFS patients have anti-cardiolipin antibodies.


See also

* Phosphatidylglycerol


References


External links

*
Cardiolipin (Diphosphatidylglycerol)
{{Autoantigens Phospholipids Membrane biology