TY  - JOUR
AU  - Belikova, N.A.
AU  - Tyurina, Y.Y.
AU  - Borisenko, G.
AU  - Tyurin, V.
AU  - Samhan Arias, A.K.
AU  - Yanamala, N.
AU  - Furtmüller, P.G.
AU  - Klein-Seetharaman, J.
AU  - Obinger, C.
AU  - Kagan, V.E.
TI  - Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: antioxidant function in mitochondria
JO  - Journal of the American Chemical Society
VL  - 131
SN  - 0002-7863
CY  - Washington, DC
PB  - American Chemical Society
M1  - PreJuSER-7755
SP  - 11288 - 11289
PY  - 2009
N1  - This work was supported by grants from the NIH (U19-AI068021, HL70755, R03TW007320, 2RO1LM007994-05), the NSF (CC0449117), the PittGrid, and la Junta de Extremadura, Orden 2008050288 (A.K.S.A.).
AB  - 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.
KW  - Animals
KW  - Antioxidants: metabolism
KW  - Armoracia: enzymology
KW  - Cardiolipins: metabolism
KW  - Cytochromes c: metabolism
KW  - Fatty Acids: metabolism
KW  - Hydrogen Peroxide: metabolism
KW  - Mitochondria, Liver: enzymology
KW  - Models, Molecular
KW  - Murinae
KW  - Oxidation-Reduction
KW  - Protein Binding
KW  - Antioxidants (NLM Chemicals)
KW  - Cardiolipins (NLM Chemicals)
KW  - Fatty Acids (NLM Chemicals)
KW  - Hydrogen Peroxide (NLM Chemicals)
KW  - Cytochromes c (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:19627079
UR  - <Go to ISI:>//WOS:000269379200009
DO  - DOI:10.1021/ja904343c
UR  - https://juser.fz-juelich.de/record/7755
ER  -