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Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.

ABSTRACT: We report herein that oxidation of a mitochondria-specific phospholipid tetralinoleoyl cardiolipin (L(4)CL) by cytochrome c and H(2)O(2) leads to the formation of 4-hydroxy-2-nonenal (4-HNE) via a novel chemical mechanism that involves cross-chain peroxyl radical addition and decomposition. As one of the most bioactive lipid electrophiles, 4-HNE possesses diverse biological activities ranging from modulation of multiple signal transduction pathways to the induction of intrinsic apoptosis. However, where and how 4-HNE is formed in vivo are much less understood. Recently a novel chemical mechanism has been proposed that involves intermolecular dimerization of fatty acids by peroxyl bond formation; but the biological relevance of this mechanism is unknown because a majority of the fatty acids are esterified in phospholipids in the cellular membrane. We hypothesize that oxidation of cardiolipins, especially L(4)CL, may lead to the formation of 4-HNE via this novel mechanism. We employed L(4)CL and dilinoleoylphosphatidylcholine (DLPC) as model compounds to test this hypothesis. Indeed, in experiments designed to assess the intramolecular mechanism, more 4-HNE is formed from L(4)CL and DLPC oxidation than 1-palmitoyl-2-linoleoylphosphatydylcholine. The key products and intermediates that are consistent with this proposed mechanism of 4-HNE formation have been identified using liquid chromatography-mass spectrometry. Identical products from cardiolipin oxidation were identified in vivo in rat liver tissue after carbon tetrachloride treatment. Our studies provide the first evidence in vitro and in vivo for the formation 4-HNE from cardiolipin oxidation via cross-chain peroxyl radical addition and decomposition, which may have implications in apoptosis and other biological activities of 4-HNE.

SUBMITTER: Liu W

PROVIDER: S-EPMC3014443 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.

Liu Wei W Porter Ned A NA Schneider Claus C Brash Alan R AR Yin Huiyong H

Free radical biology & medicine 20101101 1

We report herein that oxidation of a mitochondria-specific phospholipid tetralinoleoyl cardiolipin (L(4)CL) by cytochrome c and H(2)O(2) leads to the formation of 4-hydroxy-2-nonenal (4-HNE) via a novel chemical mechanism that involves cross-chain peroxyl radical addition and decomposition. As one of the most bioactive lipid electrophiles, 4-HNE possesses diverse biological activities ranging from modulation of multiple signal transduction pathways to the induction of intrinsic apoptosis. Howeve ...[more]

PMID: 21047551

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Project description:BackgroundFibrous chrysotile has been the most commonly applied asbestos mineral in a range of technical applications. However, it is toxic and carcinogenic upon inhalation. The chemical reactivity of chrysotile fiber surfaces contributes to its adverse health effects by catalyzing the formation of highly reactive hydroxyl radicals (HO•) from H2O2. In this Haber-Weiss cycle, Fe on the fiber surface acts as a catalyst: Fe3+ decomposes H2O2 to reductants that reduce surface Fe3+ to Fe2+, which is back-oxidized by H2O2 (Fenton-oxidation) to yield HO•. Chrysotile contains three structural Fe species: ferrous and ferric octahedral Fe and ferric tetrahedral Fe (Fe3+tet). Also, external Fe may adsorb or precipitate onto fiber surfaces. The goal of this study was to identify the Fe species on chrysotile surfaces that catalyze H2O2 decomposition and HO• generation.ResultsWe demonstrate that at the physiological pH 7.4 Fe3+tet on chrysotile surfaces substantially contributes to H2O2 decomposition and is the key structural Fe species catalyzing HO• generation. After depleting Fe from fiber surfaces, a remnant fiber-related H2O2 decomposition mode was identified, which may involve magnetite impurities, remnant Fe or substituted redox-active transition metals other than Fe. Fe (hydr)oxide precipitates on chrysotile surfaces also contributed to H2O2 decomposition, but were per mole Fe substantially less efficient than surface Fe3+tet. Fe added to chrysotile fibers increased HO• generation only when it became incorporated and tetrahedrally coordinated into vacancy sites in the Si layer.ConclusionsOur results suggest that at the physiological pH 7.4, oxidative stress caused by chrysotile fibers largely results from radicals produced in the Haber-Weiss cycle that is catalyzed by Fe3+tet. The catalytic role of Fe3+tet in radical generation may also apply to other pathogenic silicates in which Fe3+tet is substituted, e.g. quartz, amphiboles and zeolites. However, even if these pathogenic minerals do not contain Fe, our results suggest that the mere presence of vacancy sites may pose a risk, as incorporation of external Fe into a tetrahedral coordination environment can lead to HO• generation.

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Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.

Publications

Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.

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