Cardiolipin
Encyclopedia
Structure
Phosphatidylglycerol
Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant.The general structure of phosphatidylglycerol consists of a L-glycerol 3-phosphate backbone ester-bonded to either saturated or unsaturated fatty acids on carbons 1 and 2. The head group substituent glycerol is bonded...
lipid. Two phosphatidylglycerols connect with a glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
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.
Since there are two phosphates in the molecule, each of them can catch 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
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
.
As the head group forms such compact bicycle structure, the head group area is quite small relative to the big tail region consist 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 tail large head 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, it is found that NAO was 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.
Metabolism and catabolism
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 acyltransferaseAcyltransferase
Acyltransferase is a type of transferase enzyme that acts upon acyl groups.Examples include:* Glyceronephosphate O-acyltransferase* Lecithin-cholesterol acyltransferase...
. Then acylglycerol-3-phosphate can be acylated to form a phosphatidic acid (PA). With the help of the enzyme CDP-DAG synthase (phosphatidate cytidylyltransferase
Phosphatidate cytidylyltransferase
Phosphatidate cytidylyltransferase is the enzyme that catalyzes the synthesis of CDP-diacylglycerol from cytidine triphosphate and phosphatidate....
), PA is converted into cytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
diphosphate-diacylglycerol (CDP-DAG). The following step is conversion of CDP-DAG to phosphatidylglycerol
Phosphatidylglycerol
Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant.The general structure of phosphatidylglycerol consists of a L-glycerol 3-phosphate backbone ester-bonded to either saturated or unsaturated fatty acids on carbons 1 and 2. The head group substituent glycerol is bonded...
phosphate (PGP) by the enzyme PGP synthase, followed by dephosphorylation
Dephosphorylation
Dephosphorylation is the essential process of removing phosphate groups from an organic compound by hydrolysis. Its opposite is phosphorylation...
by PTPMT1 to form PG. Finally, a molecule of CDP-DAG is bind 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 DPhospholipase D
Phospholipase D is an enzyme which is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid , releasing the soluble choline headgroup into the cytosol...
. The enzyme can operate in reverse under some physiological conditions to remove cardiolipin.
Catabolism
Catabolism of cardiolipin may happen by the catalysis of phospholipase A2Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
(PLA) to remove fatty acyl groups. Phospholipase D (PLD) in the mitochondrion hydrolyses cardiolipin to phosphatidic acid.
Regulates aggregate structures
Divalent
In chemistry, a divalent ion or molecule has a valence of two and thus can form two bonds with other ions or molecules. An older term for divalent is bivalent....
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 (La-HII) phase transition. And it is believed to have a close connection with membrane fusion.
Helps to build quaternary structure
The enzyme cytochrome c oxidaseCytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
or Complex IV is a large transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
complex found in bacteria and the mitochondrion. It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the 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
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...
and to maintains its functional role. Complex V of the oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
machinery also displays high binding affinity for CL, binding four molecules of CL per molecule of complex V.
Triggers apoptosis
During apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
(cyt c) is released from the intermembrane spaces of mitochondria
into the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. Cyt c can then bind to the IP3 receptor on ER, 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 cardiolipin-specific oxygenase
Oxygenase
An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14....
produces CL hydroperoxides 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 phosphorylationOxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
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
- CholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
translocation from outer to the inner membrane of mitochondrial - Activates mitochondrial cholesterol side-chain cleavage
- Import protein into mitochondrial matrix
- AnticoagulantAnticoagulantAn anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
function
Barth syndrome
Barth syndromeBarth syndrome
Barth syndrome , also known as 3-Methylglutaconic aciduria type II, is a X-linked genetic disorder.-Presentation:Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy , neutropenia Barth syndrome (BTHS), also known as 3-Methylglutaconic...
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
Tafazzin is a protein that in humans is encoded by the TAZ gene. Tafazzin is highly expressed in cardiac and skeletal muscle. It is involved in the metabolism of cardiolipin....
, an enzyme involved in the biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
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
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
from PC to monolyso-CL. Mutation of tafazzin would cause not enough cardiolipin synthesis and thus cause not enough ATP production.
Girls heterozygous for the trait are unaffected. Sufferers of this condition have mitochondria that are abnormal, and they cannot sustain adequate production of ATP. Cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
and general weakness is common to these patients. Cardiolipin treats the symptoms of Barth syndrome and prevents infections.
Parkinson's disease and Alzheimer’s disease
Oxidative stressOxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
and lipid peroxidation are believed to be important contributing factors leading to neuronal loss and mitochondrial dysfunction in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
in Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, and may play an early role in the pathogenesis of Alzheimer’s disease. It is reported that CL content in the brain would decrease with aging. and a recently study on rat brain shows it’s resulted from lipid peroxidation in mitochondria exposed to free radical stress. Another study also shows that CL biosynthesis pathway of CL may be selectively impaired and cause 20% reduction and composition change of CL content. And it’s also associated with a 15% reduction in linked complex I/III activity of the electron transport chain, which though 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 diseaseNon-alcoholic fatty liver disease
Non-alcoholic fatty liver disease is one cause of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states...
and heart failure， 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.
Tangier disease
Tangier diseaseTangier disease
Tangier disease is a rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein , often referred to as "good cholesterol," in the bloodstream.-Diagnosis:...
is also linked to CL abnormalities. Tangier disease is characterized by very low blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels of high-density lipoprotein cholesterol, accumulation of cholesteryl esters in tissues and an increased risk for developing cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. 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
Oxysterol
Oxysterols are oxidized derivatives of cholesterol, which are important in many biological processes, including cholesterol homeostasis, sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation.Some examples of oxysterols include:*...
s would consequently increase cholesterol efflux. This process could function as an escape mechanism to remove excess cholesterol from the cell.
Diabetes
Heart disease hits people with diabetes twice as often as people without diabetes. In those with diabetes, cardiovascular complications occur at an earlier age and often result in premature death, making heart disease the major killer of diabetic people. Cardiolipin has recently 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.Antiphospholipid syndrome
Patients with anti-cardiolipin antibodiesAnti-cardiolipin antibodies
Anti-cardiolipin antibodies are antibodies often directed against cardiolipin and found in several diseases including syphilis, antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behçet's syndrome, idiopathic spontaneous abortion, and systemic lupus erythematosus. They...
(Antiphospholipid syndrome
Antiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome , often also Hughes syndrome, is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids that provokes blood clots in both arteries and veins as well as pregnancy-related complications such as...
) 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
Apolipoprotein H
Apolipoprotein H , previously known as , is a multifunctional apolipoprotein. One of its functions is to bind cardiolipin. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure...
for recognition.
Syphilis
Cardiolipin from a cow heart is used as an antigen in the Wassermann testWassermann test
The Wassermann test or Wassermann reaction is an antibody test for syphilis, named after the bacteriologist August Paul von Wassermann, based on complement-fixation.-Method:...
for syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
. 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-1 (HIV-1) has infected more than 60 million people worldwide. Developing effective antibodies for HIV-1 becomes a hotspot in scientific research. 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 WarburgOtto Heinrich Warburg
Otto Heinrich Warburg , son of physicist Emil Warburg, was a German physiologist, medical doctor and Nobel laureate. He served as an officer in the elite Uhlan during the First World War and won the Iron Cross for bravery. Warburg was one of the twentieth century's leading biochemists...
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.