Possible role of the Complex III - bound cardiolipin
dimer in initiation of mitochondrial lipid peroxidation
D.A. Cherepanov
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky Av. 31, Moscow
The bottleneck of chain free-radical oxidation of lipid membranes is the hydrogen atom transfer
in the course of radical propagation reaction
LOO˙ +LH → LOOH + L˙ (1)
It is a slow process, for polyunsaturated linoleate acid its rate constant is as small as 60 M-1s-1.
The mitochondrial membrane contains a large amount of native antioxidant ubiquinone, the
rate constant of its action
LOO˙ + UQH2 → LOOH + UQH˙ (2)
is as high as 3x105 M-1s-1. Because the
concentration of ubiquinone in mitochondrial membrane is comparable with the concentration
of polyunsaturated lipid chains, ubiquinone protects the peroxidation of lipids with high efficiency.
The main source of polyunsaturated hydrocarbon chains in the inner mitochondrial membrane
is cardiolipin (CL), one molecule of CL carries usually four linoleate chains (eight unsaturated
bonds). A large fraction of CL in the inner mitochondrial membrane is not free but tightly bound
to various proteins. We analyzed molecular structures of membrane protein complexes containing
CL, namely, ADP/ATP carrier, II complex (succinate dehydrogenase), III complex (cytochrome
bc1 complex), IV complex (cytochrome c oxidase), and formate dehydrogenase. In all cases, with
the exception of III complex, CL is bound at the protein/membrane interface where it is easily
reached for the direct interaction with ubiquinone in the lipid phase. The exception is the structure
of III complex, where the CL binding site is deeply buried into proteins in the vicinity of the Qi site.
In the structure of bovine cytochrome bc1 complex (1PP9), the site contains two CL molecules
and one molecule of phosphatidilcholine, whereas in the structure of yeast enzyme (3CX5), the
site contains one CL molecule and one molecule of phosphatidilcholine. An essential difference
in the two structures is the accessibility of the interior of CL binding sites for the external lipid
phase. In the case of bovine enzyme, the binding site is completely covered by protein and represents
a well, where the bound CL is protected from the direct interaction with the lipid phase. To the
contrary, in the structure of yeast enzyme, the binding site is open and CL is reached for the
interaction with ubiquinone diffusing in the lipid phase.
Cytochrome bc1 complex is a major producer of superoxide radical in the mitochondrial
membrane, the radicals are generated at the Qi site just in the vicinity of the CL binding site.
Some features of the CL binding site in the bovine enzyme point out that it might function as
an initiator of the mitochondrial membrane oxidation: (1) eight linoleate chains are tightly packed
in the site so that the local concentration of polyunsaturated bonds is an order of magnitude higher
than that in the lipid phase on the average (increased oxidation rate); (2) the chains of bound CL
could not directly interact with ubiquinone coming from the lipid phase (decreased antioxidant
protection). As a consequence, appearance of the first peroxide radical in the CL binding site
would result in a fast oxidation of all eight linoleate chains to their peroxide derivatives. It is
noteworthy, that in yeast mitochondria such function of the CL binding site is apparently missing,
that correlates with the absence of polyunsaturated acids in yeast membranes.
Oxidation of CL in the binding site of the bc1 complex might induce some conformational
changes, which could increase the superoxide production by III complex. In such a case
peroxidation of CL in III complex is the primary trigger of apoptotic cascade coordinated by mitochondria.
Homo Sapiens Liberatus Workshop, Moscow State University, May 2010