Cytochrome c/cardiolipin relations in mitochondria: a kiss of death

Abstract

Recently, phospholipid peroxidation products gained a reputation as key regulatory molecules and participants in oxidative signaling pathways. During apoptosis, a mitochondria-specific phospholipid, cardiolipin (CL), interacts with cytochrome c (cyt c) to form a peroxidase complex that catalyzes CL oxidation; this process plays a pivotal role in the mitochondrial stage of the execution of the cell death program. This review is focused on redox mechanisms and essential structural features of cyt c's conversion into a CL-specific peroxidase that represent an interesting and maybe still unique example of a functionally significant ligand change in hemoproteins. Furthermore, specific characteristics of CL in mitochondria -its asymmetric trans-membrane distribution and mechanisms of collapse, regulation of its synthesis, remodeling and fatty acid composition -are given significant consideration. Finally, new concepts in drug discovery based on the design of mitochondria-targeted inhibitors of cyt c/CL peroxidase and CL peroxidation with antiapoptotic effects are presented.

The effects of ATP and sodium chloride on the cytochrome c–cardiolipin interaction: The contrasting behavior of the horse heart and yeast proteins

“…The unbound cyt c participates in eT and actively prevents oxidative stress, while membrane-bound cyt c is mainly involved in cell death. To initiate the apoptotic process the protein acquires peroxidase activity, an event which favors protein dissociation from the mitochondrial membrane [9,39,40] and the subsequent release of cyt c into the cytosol. Among the phospholipids constituting the mitochondrial membrane, CL is known to bind the hemoprotein [41].…”

“…CL-bound cyt c shows tertiary structural rearrangements, which include alteration of the heme pocket region and detachment of M80 from the sixth coordination position of the heme iron [3][4][5][6]. The CL-specific peroxidase action acquired by membrane-bound cyt c in the early stages of apoptosis, which initiates the protein pro-apoptotic activity, is critical for cells; CL peroxidation induces cyt c release into the cytosol and favors the accumulation of products releasing pro-apoptotic factors [7][8][9][10]. This explains why considerable effort has been made over recent years to clarify the mechanisms governing the cyt c-CL interaction and the (cyt c-CL) complex stability.…”

Myxococcus CsgA, Drosophila Sniffer, and human HSD10 are cardiolipin phospholipases

“…In a separate function, CytC can also bind CL and induces a disordered structure that has presented a challenge to study but has also led to an appreciation that these changes provoke the transition from electron carrier to peroxidase (Muenzner and Pletneva 2014). Once bound to CytC, the polyunsaturated fatty acids of CL are oxidized in the presence of hydrogen peroxide (Kagan et al 2005(Kagan et al , 2009). …”

Cardiolipin drives cytochrome c proapoptotic and antiapoptotic actions

“…Data reported so far indicate that CL-hhcytc could act as either a proapoptotic or an antiapoptotic factor, depending on the conditions under which it operates. In particular, CL-hhcytc functions as a proapoptotic factor catalyzing the peroxidative reduction of H 2 O 2 , which leads to CL peroxidation (31,34). In contrast, CL-hhcytc exerts an antiapoptotic action facilitating the isomerization of peroxynitrite to nitrate with the consequent scavenging of reactive nitrogen species (29).…”

“…This supported by several evidences, such as the observation that the oxidative degradation of CL occurs in the p53-induced apoptosis (33) and that CL hydroperoxides show a decreased affinity for hhcytc with respect to CL (4,31). CL oxidation leads to structural changes of hhcytc, such as partial protein unfolding, weak axial binding to the heme iron, and enhanced access of the heme catalytic site to small molecules (e.g., hydrogen peroxide), which result in a modification of the hhcytc catalytic properties, transforming it into a peroxidase (8,34).…”