Cytochrome c/cardiolipin relations in mitochondria: a kiss of death.
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 transmembrane distribution and mechanisms of collapse, the 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.
Kagan
Valerian E
VE
Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA. kagan@pitt.edu
Bayir
Hülya A
HA
Belikova
Natalia A
NA
Kapralov
Olexandr
O
Tyurina
Yulia Y
YY
Tyurin
Vladimir A
VA
Jiang
Jianfei
J
Stoyanovsky
Detcho A
DA
Wipf
Peter
P
Kochanek
Patrick M
PM
Greenberger
Joel S
JS
Pitt
Bruce
B
Shvedova
Anna A
AA
Borisenko
Grigory
G
D000818:Animals; D017209:Apoptosis; D002308:Cardiolipins / Q000502:physiology*; D045304:Cytochromes c / Q000502:physiology*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress; D011485:Protein Binding; D015398:Signal Transduction
D002308:Cardiolipins; D045304:Cytochromes c