The cardiolipin, also known as diphosphatidylglycerol, is a lipid glicerofosfolípidos family and the group of poliglicerofosfolípidos. It is found in the mitochondrial membrane of eukaryotic organisms, in the plasma membrane of many bacteria, and also in some archaea.
It was discovered by Pangborn in 1942 from the analysis of the membrane lipids of the heart tissue of a bovine. Its structure was proposed in 1956 and chemical synthesis took place about 10 years later.
Structure of Cardiolipin (Source: Edgar181 via Wikimedia Commons)
Some authors consider that its presence is restricted to ATP-producing membranes, such as in the case of mitochondria in eukaryotes, plasma membranes in bacteria, and hydrogensomes (mitochondrial-like organelles) in certain protists.
The fact that cardiolipin is found in the mitochondria and in the plasma membrane of bacteria has been used to reinforce the bases of the endosymbiotic theory, which states that mitochondria arose in the progenitor cells of eukaryotes by phagocytosis of a bacterium, which then it became dependent on the cell and vice versa.
Its biosynthetic pathway in animals was described between 1970 and 1972 and later it was shown that it is the same pathway that occurs in plants, yeasts, fungi and invertebrates. It is not a very abundant lipid, but cells require it to function properly.
The importance of this phospholipid for the mitochondria and, therefore, for cellular metabolism, is evident when the malfunction of the metabolic pathways associated with it produces a human pathology known as Barth's syndrome (cardio-skeletal myopathy).
Structure
Cardiolipin or diphosphatidylglycerol is made up of two molecules of phosphatidic acid (the simplest phospholipid) linked together through a glycerol molecule.
Phosphatidic acid, one of the common intermediates in the biosynthetic pathways of other phospholipids, consists of a glycerol 3-phosphate molecule, to which two fatty acid chains are esterified at the positions of carbons 1 and 2, so it is also known as 1,2-diacylglycerol 3-phosphate.
Therefore, cardiolipin is composed of three glycerol molecules: a central glycerol, attached to a phosphate group at carbon 1, another phosphate group at carbon 3, and a hydroxyl group at carbon 2; and two "side" glycerols.
The two "side" glycerol molecules are attached to the central molecule by "glycerol bridges" through their carbons at position 3. At the carbons at positions 1 and 2, two fatty acid chains of length and saturation are esterified. variable.
Cardiolipin is a lipid that may or may not form bilayers, depending on the presence or absence of divalent cations. This is related to the fact that it is a symmetric molecule, which makes it important in membranes that are responsible for energy transduction processes.
Like the other lipids of the group of polyglycerophospholipids, cardiolipin has several hydroxyl groups that can serve for the binding of fatty acids. Therefore, it has multiple positional stereoisomers.
Your fatty acids
Different studies have determined that the fatty acids attached to the side glycerol molecules of cardiolipin are typically unsaturated, but the degree of unsaturation has not been determined.
So, such fatty acids can be 14-22 carbons in length and 0-6 double bonds. This and the fact that cardiolipin has four linked fatty acid molecules, implies that there can be multiple variables and combinations of this phospholipid.
Synthesis
Cardiolipin biosynthesis, as might be expected, begins with the synthesis of phosphatidic acid or 1,2-diacylglycerol 3-phosphate from glycerol 3-phosphate and fatty acids. This process occurs in the mitochondria of eukaryotes and in the plasma membrane of bacteria.
Synthesis in eukaryotes
After being formed, phosphatidic acid reacts with a high-energy molecule analogous to ATP: CTP. Then an intermediate, also of high energy, known as phosphatidyl-CMP is formed. The activated phosphatidyl group is transferred to the hydroxyl group at the C1 position of the central glycerol molecule that serves as the backbone.
This process results in a molecule called phosphatidylglycerophosphate, which is hydrolyzed to yield phosphatidylglycerol. This receives another phosphatidyl group activated from another phosphatidyl-CMP molecule, a reaction catalyzed by a phosphatidyltransferase also known as cardiolipin synthase.
The enzyme cardiolipin synthase resides in the inner mitochondrial membrane and appears to form a large complex, at least in yeast. Its gene is expressed in large quantities in tissues rich in mitochondria such as the heart, liver and skeletal muscle of vertebrates.
The regulation of its activity depends, to a large extent, on the same transcription factors and endocrine factors that modulate mitochondrial biogenesis.
Once synthesized in the inner mitochondrial membrane, cardiolipin must be translocated towards the outer mitochondrial membrane so that a series of topological processes take place in the membrane and other structural elements of the same are accommodated.
Synthesis in prokaryotes
The cardiolipin content in bacteria can be highly variable and depends mainly on the physiological state of the cells: it is usually less abundant in the exponential growth phase and more abundant when there is reduction of it (in the stationary phase, for example).
Its biosynthetic pathway can be triggered by different stressful stimuli such as energy deficits or osmotic stress.
Until the formation of phosphatidylglycerol, the process in eukaryotes and prokaryotes is equivalent, but in prokaryotes, phosphatidylglycerol receives, by transesterification, a phosphatidyl group from another phosphatidylglycerol molecule. This reaction is catalyzed by a phospholipase D-type enzyme also known as cardiolipin synthase.
This reaction is known as the “transphosphatidylation” reaction (from the English “transphosphatidylation”), where one of the phosphatidylglycerols acts as a donor of the phosphatidyl group and the other as an acceptor.
Features
The physical characteristics of cardiolipin molecules apparently allow certain interactions that play important roles in the structural organization of the membranes where they are found.
Among these functions are the discrimination of some membrane domains, the interaction or "crossover" with transmembrane proteins or their subdomains, among others.
Thanks to its physicochemical characteristics, cardiolipin is recognized as a lipid that does not form a bilayer, but whose function may be to stabilize and “accommodate” transmembrane proteins in lipid bilayers.
Its electrical characteristics, in particular, give it functions in the proton transfer processes that take place in the mitochondria.
Although cells can survive without this phospholipid, some studies have determined that it is required for their optimal functioning.
References
- Harayama, T., & Riezman, H. (2018). Understanding the diversity of membrane lipid composition. Nature Reviews Molecular Cell Biology, 19 (5), 281–296.
- Luckey, M. (2008). Membrane structural biology: with biochemical and biophysical foundations. Cambridge University Press.
- Murray, R., Bender, D., Botham, K., Kennelly, P., Rodwell, V., & Weil, P. (2009). Harper's Illustrated Biochemistry (28th ed.). McGraw-Hill Medical.
- van Meer, G., Voelker, DR, & Feigenson, GW (2008). Membrane lipids: where they are and how they behave. Nature Reviews, 9, 112-124.
- Vance, JE, & Vance, DE (2008). Biochemistry of lipids, lipoproteins and membranes. In New Comprehensive Biochemistry Vol. 36 (4th ed.). Elsevier.