TY - JOUR
T1 - Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes
T2 - Antioxidant function in mitochondria
AU - Belikova, Natalia A.
AU - Tyurina, Yulia Y.
AU - Borisenko, Grigory
AU - Tyurin, Vladimir
AU - Samhan Arias, Alejandro K.
AU - Yanamala, Naveena
AU - Furtmüller, Paul Georg
AU - Klein-Seetharaman, Judith
AU - Obinger, Christian
AU - Kagan, Valerian E.
PY - 2009/8/19
Y1 - 2009/8/19
N2 - (Chemical Equation Presented) 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. H2O2 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 ∼3 orders of magnitude higher than for H2O2. 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 H2O2 (and tert-butyl hydroperoxide, t-BuOOH) undergo homolytic cleavage. Computer simulations have revealed that Arg38 and His33 are important for the heterolytic mechanism at potential FFA-OOH binding sites of cyt c (but not for H2O2 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.
AB - (Chemical Equation Presented) 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. H2O2 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 ∼3 orders of magnitude higher than for H2O2. 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 H2O2 (and tert-butyl hydroperoxide, t-BuOOH) undergo homolytic cleavage. Computer simulations have revealed that Arg38 and His33 are important for the heterolytic mechanism at potential FFA-OOH binding sites of cyt c (but not for H2O2 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.
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U2 - 10.1021/ja904343c
DO - 10.1021/ja904343c
M3 - Article
C2 - 19627079
AN - SCOPUS:68849090289
SN - 0002-7863
VL - 131
SP - 11288
EP - 11289
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 32
ER -