Cytochrome c - cardiolipin interaction leads to the cytochrome c modification and degradation via formation of cardiolipin hydroperoxides

Recently, the complex of cytochrome c (cyt c), a small heme mitochondrial protein, with mitochondria specific lipid cardiolipin (CL) was linked to the control of apoptotic cell death. Under apoptotic conditions cyt c - CL complex exhibits peroxidase activity, leading to the formation of CL- hydroperoxides. CL-hydroperoxides promote cyt c release to the cytoplasm, where cyt c participates in apoptosis pathway. However, not much known about the modifications of cyt c as a part of cyt c - CL complex. In the present work, the systematic study on the peroxidase activity of CL-cyt c complex in CL-containing liposomes was performed. CL-hydroperoxides stimulate cyt c peroxidase activity in the absence of hydrogen peroxide. Furthermore, in the presence of oxygen, CL-hydroperoxides are generated as the products of the CL - cyt c peroxidase reaction. During peroxidase cycle cyt c amino acid residues are modified by reactive unsaturated aldehydes including 4-hydroxy- and 4-oxo-nonenal, derived from CL- peroxidation. This leads to the consecutive cyt c inactivation and heme degradation accompanied by the release of free iron. The current study on CL-driven cyt c degradation and iron release probably plays an important role in the mitochondrial pathway of apoptosis induction.