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REVIEW: Molecular Mechanisms of Apoptosis. Structure of Cytochrome c–Cardiolipin Complex

Yu. A. Vladimirov1,2*, E. V. Proskurnina1, and A. V. Alekseev2

1Lomonosov Moscow State University, Faculty of Basic Medicine, Lomonosovsky pr. 31/5, 117192 Moscow, Russia; fax: +7 (499) 147-5508; E-mail: yuvlad@mail.ru

2Shubnikov Institute of Crystallography, Russian Academy of Sciences, Leninsky pr. 59, 119333 Moscow, Russia; fax: +7 (499) 135-1011; E-mail: yuvlad@mail.ru

* To whom correspondence should be addressed.

Received May 6, 2013; Revision received June 16, 2013
One of the functions of cytochrome c in living cells is the initiation of apoptosis by catalyzing lipid peroxidation in the inner mitochondrial membrane, which involves cytochrome c bound with acidic lipids, especially cardiolipin. In this paper the results of studies of cytochrome c–cardiolipin complex structure carried out by different authors mainly on unilamellar cardiolipin-containing phospholipid liposomes are critically analyzed. The principal conclusion from the published papers is that cytochrome c–cardiolipin complex is formed by attachment of a cytochrome c molecule to the membrane surface via electrostatic interactions and the subsequent penetration of one of the fatty-acid cardiolipin chains into the protein globule, this being associated with hydrophobic interactions that break the >Fe·⋅·S(Met80) coordinate bond and giving rise to appearance of cytochrome c peroxidase activity. Nevertheless, according to data obtained in our laboratory, cytochrome c and cardiolipin form spherical nanoparticles in which protein is surrounded by a monolayer of cardiolipin molecules. Under the action of cooperative forces, the protein in the globule expands greatly in volume, its conformation is modified, and the protein becomes a peroxidase. In extended membranes, such as giant monolayer liposomes, and very likely in biological membranes, the formation of nanospheres of cytochrome c–cardiolipin complex causes fusion of membrane sections and dramatic chaotization of the whole membrane structure. The subsequent disintegration of the outer mitochondrial membrane is accompanied by cytochrome c release from the mitochondria and triggering of a cascade of programmed cell death reactions.
KEY WORDS: apoptosis, cytochrome c, cardiolipin, peroxidase activity

DOI: 10.1134/S0006297913100027