# Cardiolipin
**Cardiolipin** (CL, diphosphatidylglycerol) is a dimeric phospholipid made of two phosphatidic acid residues linked by a glycerol bridge, and it is the phospholipid specific to mitochondrial membranes in all eukaryotes[1](https://pubmed.ncbi.nlm.nih.gov/24769127/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). Although a minor component, accounting for 10 to 20 percent of the total phospholipid content of mitochondria, it plays a central role in the molecular organization and function of the cristae, the folded structures of the inner mitochondrial membrane[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). Because it is confined to mitochondria, cardiolipin can be used to identify and quantify mitochondria in subcellular fractions[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
| Key fact | Detail |
|---|---|
| Structure | Dimeric phospholipid: two phosphatidic acid residues joined by a glycerol bridge, giving four acyl chains and two negatively charged phosphates[1](https://pubmed.ncbi.nlm.nih.gov/24769127/) |
| Location | Synthesized and localized in the inner mitochondrial membrane; a universal component of mitochondria in all eukaryotes[1](https://pubmed.ncbi.nlm.nih.gov/24769127/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) |
| Abundance | 10–20% of total mitochondrial phospholipid content[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) |
| Biosynthesis | CDP-diacylglycerol pathway on the matrix face of the inner membrane; final step catalyzed by cardiolipin synthase (Crd1 in yeast)[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) |
| Remodeling | Nascent CL is remodeled by the transacylase tafazzin; the dominant mature species in the mammalian heart is tetralinoleoyl cardiolipin (TLCL)[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/) |
| Protein partners | High-affinity binding to respiratory complexes I, III, IV, and V, the ADP-ATP carrier, cytochrome c, and creatine kinase[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC2757492/) |
| Disease link | Mutations in the TAZ gene (tafazzin) cause Barth syndrome; the elevated monolysocardiolipin-to-cardiolipin ratio in blood is diagnostic[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) • [5](https://pubmed.ncbi.nlm.nih.gov/33415565/) |
| Turnover | Half-life several-fold longer than other phospholipids; no measurable CL turnover in Drosophila over 9 days[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) |
## Structure and physicochemical properties
The dimeric architecture distinguishes cardiolipin from all common membrane phospholipids. Two phosphatidic acid residues are linked by a central glycerol, so the molecule carries four fatty acyl chains and a small, motion-restricted head group bearing two negatively charged phosphates[1](https://pubmed.ncbi.nlm.nih.gov/24769127/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). This combination of a large hydrophobic acyl moiety and an unshielded, doubly charged head group gives cardiolipin a tendency to cluster and to form strong non-covalent bonds with proteins[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
Cardiolipin is also not a single molecule. Remodeling of its acyl chains produces an enormous diversity of acyl chain combinations and therefore many possible molecular species[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/). In tissues with high energy turnover the pattern is narrow, often dominated by one or two unsaturated acyl groups, while mammalian brain shows a much more diverse CL pattern[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
## Biosynthesis
The biosynthetic pathway, established in the 1970s, takes place on the matrix face of the inner mitochondrial membrane[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). [Phosphatidic acid](https://www.edgepedia.org/phosphatidic-acid) is formed from glycerol-3-phosphate and activated fatty acids on the outer mitochondrial membrane and in the endoplasmic reticulum, then transferred across the intermembrane space by lipid transport complexes (Ups1/Mdm35 in yeast, PRELID1/TRIAP1 in humans)[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6586490/). On the matrix side, the pathway proceeds through four steps: Tam41 generates CDP-diacylglycerol; Pgs1 transfers a phosphatidyl group to glycerol-3-phosphate to form phosphatidylglycerophosphate; Gep4 in yeast or PTPMT1 in mammals removes the terminal phosphate to give phosphatidylglycerol; and cardiolipin synthase (Crd1) condenses phosphatidylglycerol with CDP-diacylglycerol to form cardiolipin[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
The pathway is regulated by PGC-1, the transcription factor that controls [mitochondrial biogenesis](https://www.edgepedia.org/mitochondrial-biogenesis), and ATP citrate lyase activation has been proposed to stimulate cardiolipin formation[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
## Remodeling to mature cardiolipin
Nascent cardiolipin undergoes post-synthetic exchange of acyl groups, known as remodeling, before reaching its mature form in the inner membrane[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/). The best-characterized remodeling enzyme is tafazzin, a transacylase that transfers an acyl chain from a donor phospholipid to monolysocardiolipin (MLCL), regenerating intact cardiolipin[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/) • [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3259273/). Other acyltransferases, MLCLAT1 and ALCAT1, may also participate[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/).
Tafazzin itself shows little intrinsic acyl-chain specificity; it acts as a vehicle that lets fatty acids exchange between phospholipid molecules, and its output depends on the surrounding membrane environment such as curvature and protein density[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) • [3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/). Transgenic experiments support this: human tafazzin replicates the Drosophila-type cardiolipin pattern in flies and the yeast-type pattern in yeast, patterns that differ from each other and from human cardiolipin[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). Remodeled cardiolipin generally contains more unsaturated acyl chains; the dominant mature species in the mammalian heart is tetralinoleoyl cardiolipin, which carries four linoleic acid chains[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/). A notable exception is extramitochondrial tetrapalmitoyl cardiolipin[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/).
## Role in mitochondrial membranes and function
Cardiolipin interacts by non-covalent bonds with a long list of proteins, a behavior compared to that of molecular chaperones. High-affinity binders include respiratory complexes I, III, IV, and V, the mitochondrial carrier family (ADP-ATP carrier, phosphate carrier, uncoupling protein), and the peripheral membrane proteins cytochrome c and creatine kinase[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC2757492/). Studies in isolated mitochondria indicate that most, if not all, cardiolipin is protein-associated, leaving virtually none free in the bulk lipid phase[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
Crystal structures show specific binding sites. In the ADP/ATP translocase a cardiolipin sits between two adjacent transmembrane helices, apparently adding stability; in cytochrome c oxidase a cardiolipin spans two monomeric complexes and helps stabilize the dimer; and in the cytochrome bc1 complex a bound cardiolipin near a proton uptake pathway may participate in proton translocation[8](https://www.pnas.org/content/pnas/113/31/8687.full.pdf).
Beyond individual complexes, cardiolipin promotes the assembly of oxidative phosphorylation complexes into supercomplexes and is found at high concentration within them[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). It is also required for membrane structure, membrane fusion and fission, protein import, and apoptosis[9](https://academic.oup.com/advances/article-pdf/9/3/247/24813600/nmy007.pdf).
## Turnover and signaling
The half-life of cardiolipin is several-fold longer than that of other phospholipids, a property first observed in rats labeled with 32P phosphate or 2H2O and later confirmed in cell cultures and flies[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). In [Drosophila](https://www.edgepedia.org/drosophila), which live about 60 days, no measurable cardiolipin turnover occurs over a 9-day period even though other phospholipids turn over readily[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). This stability reflects mutual stabilization: cardiolipin promotes protein supercomplex assembly, and the resulting large assemblies protect cardiolipin from degradation[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
Despite this stability, cardiolipin can be chemically modified and re-localized in ways tied to mitophagy and apoptosis. The intermembrane-space protein NDPK-D can transfer cardiolipin from the inner to the outer mitochondrial membrane, where cytosolic factors trigger mitophagy; if the translocated cardiolipin is also oxidized, it may trigger apoptosis[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
## Barth syndrome
Mutations in the human tafazzin gene (TAZ) cause [Barth syndrome](https://www.edgepedia.org/barth-syndrome), a rare X-linked multisystemic disorder presenting with cardiomyopathy, skeletal muscle weakness, fatigue, neutropenia, and abnormal growth[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) • [5](https://pubmed.ncbi.nlm.nih.gov/33415565/). It was the first human disease recognized in which the primary causative factor is an alteration in cardiolipin remodeling[10](https://pubmed.ncbi.nlm.nih.gov/16442164/). Patients have low cardiolipin levels, aberrant cardiolipin species composition, and accumulation of monolysocardiolipin, a lipid not detectable in normal tissues; tetralinoleoyl-CL, the predominant species in normal heart, is virtually absent from patient cells[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/).
The elevated MLCL-to-CL ratio in blood, measured in platelets, leukocytes, or blood spots, has become an important diagnostic marker, and clinical severity correlates with this ratio[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC6586490/). Yeast experiments indicate that the deleterious effects of defective tafazzin arise from cardiolipin deficiency or MLCL accumulation rather than from abnormal cardiolipin molecular species as such[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/). Investigated therapeutic approaches include lipid replacement therapy, PPAR agonists, tafazzin gene replacement, mitochondria-targeted antioxidants and peptides, and resveratrol[5](https://pubmed.ncbi.nlm.nih.gov/33415565/).
## Evolutionary distribution
Cardiolipin occurs in both mitochondrial inner membranes and bacterial membranes, and its presence in both has been cited as evidence for the endosymbiotic origin of mitochondria[11](https://link.springer.com/article/10.1186/1471-2148-12-32). The synthesis chemistry differs, however. Bacteria make cardiolipin by a reversible transesterification between two phosphatidylglycerol molecules catalyzed by a phospholipase D-type synthase (CLS_pld), while eukaryotes use an irreversible reaction between phosphatidylglycerol and CDP-diacylglycerol catalyzed by a CDP-alcohol phosphatidyltransferase-type synthase (CLS_cap)[11](https://link.springer.com/article/10.1186/1471-2148-12-32). Phylogenetic analysis indicates that eukaryotic CLS_cap is closest to that of alpha-proteobacteria, consistent with acquisition through mitochondrial endosymbiosis, whereas eukaryotic CLS_pld lineages share a common ancestor not closely tied to any extant bacterial group[11](https://link.springer.com/article/10.1186/1471-2148-12-32). Only eukaryotes remodel nascent cardiolipin into a mature form; bacteria have no such maturation process[11](https://link.springer.com/article/10.1186/1471-2148-12-32). No cardiolipin has been found in archaea[11](https://link.springer.com/article/10.1186/1471-2148-12-32).
## History
Cardiolipin was first isolated from beef heart in the early 1940s, which accounts for its name[12](https://journals.physiology.org/doi/10.1152/ajpcell.00243.2006).
## References
1. [Metabolism and function of mitochondrial cardiolipin, PubMed](https://pubmed.ncbi.nlm.nih.gov/24769127/)
2. [Schlame M, Greenberg ML. Biosynthesis, remodeling and turnover of mitochondrial cardiolipin, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5125896/)
3. [The critical role of cardiolipin in metazoan differentiation, development, and maturation, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10238668/)
4. [The role of cardiolipin in the structural organization of mitochondrial membranes, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2757492/)
5. [Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets, PubMed](https://pubmed.ncbi.nlm.nih.gov/33415565/)
6. [Mitochondrial dysfunctions in Barth syndrome, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6586490/)
7. [The Complexity of Cardiolipin in Health and Disease, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3259273/)
8. [Role of Cardiolipin in Mitochondrial function, PNAS](https://www.pnas.org/content/pnas/113/31/8687.full.pdf)
9. [Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function, Advances in Nutrition](https://academic.oup.com/advances/article-pdf/9/3/247/24813600/nmy007.pdf)
10. [Cardiolipin metabolism and Barth Syndrome, PubMed](https://pubmed.ncbi.nlm.nih.gov/16442164/)
11. [The evolution of cardiolipin biosynthesis and maturation pathways and its implications for the evolution of eukaryotes, BMC Evolutionary Biology](https://link.springer.com/article/10.1186/1471-2148-12-32)
12. [Role of cardiolipin alterations in mitochondrial dysfunction and disease, American Journal of Physiology-Cell Physiology](https://journals.physiology.org/doi/10.1152/ajpcell.00243.2006)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Lipid and fatty acid metabolism › Glycerophospholipid and sphingolipid metabolism › Glycerophospholipid biosynthesis*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license