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

Abstract

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.

Effect of COVID-19 mRNA Vaccine on Human Lung Carcinoma Cells In Vitro by Means of Raman Spectroscopy and Imaging

“…The peroxidase activity decreases the Raman signal at 1584 cm –1 of cytochrome c because the oxidized Fe 3+ cytochrome c in mitochondria upon interactions with cardiolipin monitors the transformation of Fe 3+ cytochrome c into iron-oxo (ferryl) intermediates called Compound I and Compound II, which are (unprotonated) Fe IV O or (protonated) Fe IV –OH. − …”

Ligand-Based Regulation of Dynamics and Reactivity of Hemoproteins

“…In particular, CL–cytc acquires the peroxidase activity that is critical for CL redistribution across the intermembrane space [ 114 ]. This is crucial for mitochondrial biology since CL in the inner membrane maintains the protein complexes’ structure and function, while its oxidation and subsequent redistribution on the outer membrane allows cytc to be released in the cytosol, thus triggering the apoptotic process [ 121 ]. As reported for CO and O 2 , nitric oxide (NO) also binds to the heme, causing conformational changes and allosteric regulation of the activity [ 56 , 122 , 123 , 124 ].…”

“…With nitric oxide playing a key role in disease resistance in plants, such as Arabidopsis thaliana , ferric At –Nb was hypothesized to be involved in wounding and pathogenic infections by transporting and rapidly releasing NO at the infection site, therefore, contributing to the generation of reactive oxygen species (ROS) as NO may reduce O 2 to superoxide radicals that can dismute to H 2 O 2 [ 27 , 120 , 121 ]. The inability of At –Nb to establish stable complexes with O 2 , CO, or NO in the presence of air excludes possible roles in O 2 storage or transport.…”

Novel triphenylphosphonium amphiphilic conjugates of glycerolipid type: synthesis, cytotoxic and antibacterial activity, and targeted cancer cell delivery

“…25 The presence of unsaturated fatty acids in its composition and its proximity to the redox centers of complexes I and III of the respiratory chain in mitochondria provide CL oxidation during active operation of ETC. 22 Cell sensitivity to apoptosis is controlled by delivering non-oxidizable precursors (oleic, stearic, palmitic) or easily oxidizable polyunsaturated fatty acids (such as docosapenta- and docosahexaenoic acids) to mitochondria. These acids can be integrated into the CL structure.…”

“…[18][19][20][21] The mitochondrial process of apoptosis is associated with the biosynthesis and remodeling of cardiolipin (CL), in particular, with changes in the composition of fatty acid residues, which is important for antitumor therapy and also for the pathogenesis of neoplastic, neurodegenerative and cardiovascular diseases. 22 Cardiolipin (CL) is a unique type of dimeric lipid synthesized exclusively de novo in eukaryotes in the mitochondrial inner membrane. 23,24 The CL fatty acid composition affects biophysical membrane properties and this is critical for mitochondrial bioenergetics and cell function.…”