1. Cardiolipin
Xi Huang
Feb 3, 2009

2. Cardiolipin Structure Biosynthesis and metabolism Function
Cardiolipin in disease

3. Structure of Cardiolipin
Diphosphatidylglycerol
1,3-bis(sn-3’-phosphatidyl)-sn-glycerol
It’s usually found in certain membrane of bacteria and of mitochondria.
It amounts to about 10% of the phospholipids of bovine heart muscle, and 20% of the phospholipids of the mitochondrial membrane in this organ

4. Structure of Cardiolipin
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Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002)

5. Acid-anion bicyclic resonance structure One of the protons is trapped
Acyl chain - 18:2
In heart mitochondria
NAO
pK1≈3, pK2＞7.5
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
Acid-anion bicyclic resonance structure
One of the protons is trapped
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Thomas H. Hainesa;
, Norbert A. Dencherb. (2002) FEBS Letters

6. Biosynthesis and metabolism
Prokaryotic mechanism
Eukaryotic mechanism

7. Biosynthesis and metabolism
PLA2
PLD
Phospholipase A2 remove fatty acyl group. Phospholipase D hydrolyses cardiolipin to phosphatidic acid

8. Build quaternary structure
4 Fe 2+ -cytochrome c + 8 H+in + O2 → 4 Fe3+-cytochrome c + 2 H2O + 4 H+out
Cytochrome c oxidase (Complex IV)need to form a dimer to catalysis the reaction.
Cardiolipin help to connect the subunits with the complex
Cytochrome bc1(Complex III) also need cardiolipin to maintain its quaternary structure
In general, the head group of cardiolipin and certain amino acid residues interact strongly
via electrostatic forces, hydrogen bonds
while the acyl chains retain their
flexibility and interact through van-der-Waals forces with the protein surface at a number of sites

9. Serve as proton trap for oxidative phosphorylation
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Thomas H. Hainesa;
, Norbert A. Dencherb. (2002) FEBS Letters

10. Trigger apoptosis
Cytochrome c released into cytosol  react with IP3 receptor on ER
 release calcium
 large release of cytochrome c
Cytochrome c is also an intermediate in apoptosis
we showed that oxidized cardiolipin is required for the release of proapoptotic factors
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Natalia A. Belikova, Yury A. Vladimirov, at el. (2006) Biochemistry. 45,

11. Other Functions
cholesterol translocation from outer to the inner membrane of mitochondrial
activates mitochondrial cholesterol side-chain cleavage
Import protein into mitochondrial
anti-coagulant function
…..

12. Disease Barth syndrome Diabetes  higher heart attack rate
mutation in the gene coding for tafazzin  can’t synthesis enough cardiolipin  not enough ATP production
Diabetes  higher heart attack rate
diabetes  more active lipid-digesting enzyme  quicker catabolism of cardiolipin  heart attack
Alzheimer’s disease and Parkinson’s disease
Malfunction of cardiolipin metabolism in brain mitochondria

13. Difficulties in neutralizing HIV-1 envelope
Two antibodies directed against MPR, 2F5, 4E10, react with self-antigens, including cardiolipin
Such antibodies would not be easily elicited by vaccination.
It has recently been proposed that antibodies to HIV cannot be easily made by humans because certain HIV antigens too closely resemble cardiolipin. Thus, anti-HIV antibodies would not be made by the immune system because they can induce autoimmune disease
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Gary J. Nabel. (2005) Science. 308,

14. Reference
Thomas H. Hainesa, Norbert A. Dencherb. (2002) FEBS Lett. 528, 35-39
Gary J. Nabel. (2005) Science. 308,
Antonio Ortiz, J. Antoinette Killian, et al. (1999) Biophysical Journal. 77, 2003–2014
Mei Zhang, Eugenia Mileykovskaya and William Dowhan. (2002) J. Biol. Chem. 277, 43553–43556
Natalia A. Belikova, Yury A. Vladimirov, et al. (2006) Biochemistry. 45,
Valerian E Kagan, et al. (2005) Nat. Chem. Biol. 1,
Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002)