Heterolytic reduction of fatty acid hydroperoxides by cytochrome c/cardiolipin complexes: Antioxidant function in mitochondria

Natalia A. Belikova, Yulia Y. Tyurina, Grigory Borisenko, Vladimir Tyurin, Alejandro K. Samhan Arias, Naveena Yanamala, Paul Georg Furtmüller, Judith Klein-Seetharaman, Christian Obinger, Valerian E. Kagan

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

(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.

Original languageEnglish (US)
Pages (from-to)11288-11289
Number of pages2
JournalJournal of the American Chemical Society
Volume131
Issue number32
DOIs
StatePublished - Aug 19 2009
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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