Heterolytic Reduction of Fatty Acid Hydroperoxides by Cytochrome c/Cardiolipin Complexes: Antioxidant Function in Mitochondria

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• 作者：Natalia A. Belikova ; Yulia Y. Tyurina ; Grigory Borisenko ; Vladimir Tyurin ; Alejandro K. Samhan Arias ; Naveena Yanamala ; Paul Georg Furtmller ; Judith Klein-Seetharaman ; Christian Obinger ; Valerian E. Ka
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：August 19, 2009
• 年：2009
• 卷：131
• 期：32
• 页码：11288-11289
• 全文大小：163K
• 年卷期：v.131,no.32(August 19, 2009)
• ISSN：1520-5126

文摘

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.