Cytochrome c Interaction with Cardiolipin Plays a Key Role in Cell Apoptosis: Implications for Human Diseases

In the cell cytochrome, c performs different functions depending on the environment in which it acts; therefore, it has been classified as a multifunction protein. When anchored to the outer side of the inner mitochondrial membrane, native cytochrome c acts as a Schweitzer-StennerSchweitzer-Stenner that transfers electrons from cytochrome c reductase to cytochrome c oxidase in the respiratory chain. On the other hand, to interact with cardiolipin (one of the phospholipids making up the mitochondrial membrane) and form the cytochrome c/cardiolipin complex in the apoptotic process, the protein reorganizes its structure into a non-native state characterized by different asymmetry. The formation of the cytochrome c/cardiolipin complex is a fundamental step of the apoptotic pathway, since the structural rearrangement induces peroxidase activity in cytochrome c, the subsequent permeabilization of the membrane, and the release of the free protein into the cytoplasm, where cytochrome c activates the apoptotic process. Apoptosis is closely related to the pathogenesis of neoplastic, neurodegenerative and cardiovascular diseases; in this contest, the biosynthesis and remodeling of cardiolipin are crucial for the regulation of the apoptotic process. Since the role of cytochrome c as a promoter of apoptosis strictly depends on the non-native conformation(s) that the protein acquires when bound to the cardiolipin and such event leads to cytochrome c traslocation into the cytosol, the structural and functional properties of the cytochrome c/cardiolipin complex in cell fate will be the focus of the present review.