title: Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: antioxidant function in mitochondria.
abstract: Cytochrome c (cyt c), a mitochondrial intermembrane electron shuttle between complexes III and IV, can, upon binding with an anionic phospholipid, cardiolipin (CL), act as a peroxidase that catalyzes cardiolipin oxidation. H(2)O(2) was considered as a source of oxidative equivalents for this reaction, which is essential for programmed cell death. Here we report that peroxidase cyt c/CL complexes can utilize free fatty acid hydroperoxides (FFA-OOH) at exceptionally high rates that are approximately 3 orders of magnitude higher than for H(2)O(2). Similarly, peroxidase activity of murine liver mitochondria was high with FFA-OOH. Using EPR spin trapping and LC-MS techniques, we have demonstrated that cyt c/CL complexes split FFA-OOH predominantly via a heterolytic mechanism, yielding hydroxy-fatty acids, whereas H(2)O(2) (and tert-butyl hydroperoxide, t-BuOOH) undergo homolytic cleavage. Computer simulations have revealed that Arg(38) and His(33) are important for the heterolytic mechanism at potential FFA-OOH binding sites of cyt c (but not for H(2)O(2) or t-BuOOH). Regulation of FFA-OOH metabolism may be an important function of cyt c that is associated with elimination of toxic FFA-OOH and synthesis of physiologically active hydroxy-fatty acids in mitochondria.
authors.affiliation: Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219-3130, USA.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Belikova
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: Grigory
authors.initials: G
authors.lastname: Borisenko
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tyurin
authors.forename: Alejandro K
authors.initials: AK
authors.lastname: Samhan Arias
authors.forename: Naveena
authors.initials: N
authors.lastname: Yanamala
authors.forename: Paul Georg
authors.initials: PG
authors.lastname: Furtmüller
authors.forename: Judith
authors.initials: J
authors.lastname: Klein-Seetharaman
authors.forename: Christian
authors.initials: C
authors.lastname: Obinger
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D031215:Armoracia / Q000201:enzymology; D002308:Cardiolipins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000201:enzymology*; D008958:Models, Molecular; D051189:Murinae; D010084:Oxidation-Reduction; D011485:Protein Binding
chemical_list: D000975:Antioxidants; D002308:Cardiolipins; D005227:Fatty Acids; D045304:Cytochromes c; D006861:Hydrogen Peroxide