Cardiolipin

Xi Huang

Feb 3, 2009

Cardiolipin

Structure Biosynthesis and metabolism Function Cardiolipin in disease

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

Structure of Cardiolipin

Structure of Cardiolipin

____________________________________________________________________________Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002) 528 35-39

Acyl chain - 18:2In heart mitochondria

pK1≈3, pK2＞ 7.5

Acid-anion bicyclic resonance structureOne of the protons is trapped

____________________________________________________________________________Thomas H. Hainesa;, Norbert A. Dencherb. (2002) FEBS Letters 528 35-39

N

10-N-Nonyl acridine

NAO

Biosynthesis and metabolism

Eukaryotic mechanism

Prokaryotic mechanism

Biosynthesis and metabolism

PLA2

PLA2

PLA2

PLA2

PLA2

PLA2

PLD

PLD

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

Serve as proton trap for oxidative phosphorylation

____________________________________________________________________________Thomas H. Hainesa;, Norbert A. Dencherb. (2002) FEBS Letters 528 35-39

Trigger apoptosis

____________________________________________________________________________Natalia A. Belikova, Yury A. Vladimirov, at el. (2006) Biochemistry. 45, 4998-5009

Cytochrome c released into cytosol react with IP3 receptor on ER release calcium large release of cytochrome c

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

…..

Disease

Barth syndromemutation 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 cardiol

ipin heart attack

Alzheimer’s disease and Parkinson’s disease Malfunction of cardiolipin metabolism in brain mitochondria

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.

____________________________________________________________________________Gary J. Nabel. (2005) Science. 308, 1878-1879

Reference

Thomas H. Hainesa, Norbert A. Dencherb. (2002) FEBS Lett. 528, 35-39 Gary J. Nabel. (2005) Science. 308, 1878-1879 Antonio Ortiz, J. Antoinette Killian, et al. (1999) Biophysical Journal. 77, 200

3–2014 Mei Zhang, Eugenia Mileykovskaya and William Dowhan. (2002) J. Biol. Ch

em. 277, 43553–43556 Natalia A. Belikova, Yury A. Vladimirov, et al. (2006) Biochemistry. 45, 4998-

5009 Valerian E Kagan, et al. (2005) Nat. Chem. Biol. 1, 223-232 Schlame, M., Brody, S. and Hostetler, K.Y. Eur. J. Biochem (2002) 528 35-3

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