Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.
Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.
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DOI：
10.1016/j.freeradbiomed.2010.10.709
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发表时间：
2011-01-01
影响因子：
7.4
通讯作者：
Yin, Huiyong
中科院分区：
文献类型：
--
作者：
Liu, Wei;Porter, Ned A.;Schneider, Claus;Brash, Alan R.;Yin, Huiyong
关键词：
本文报道了线粒体特异性磷脂四氢杨酸油酰心磷脂(L4CL)被细胞色素c和H_2O_2氧化生成4-羟基-2-壬烯醛(4-HNE)的新的化学机制，包括跨链过氧基的加成和分解。4-HNE作为最具生物活性的脂类亲电活性物质之一，具有多种生物活性，从调节多种信号转导途径到诱导内源性细胞凋亡。然而，4-HNE在体内是在哪里以及如何形成的还知之甚少。最近提出了一种新的化学机制，涉及通过过氧键的形成使脂肪酸发生分子间二聚反应，但该机制的生物学意义尚不清楚，因为大多数脂肪酸是在细胞膜的磷脂中酯化的。我们推测，心磷脂的氧化，特别是L4CL，可能通过这一新的机制导致4-HNE的形成。我们使用L4CL和二亚油酰基磷脂酰胆碱(DLPC)作为模型化合物来验证这一假说。事实上，在旨在评估分子内机制的实验中，L4CL和DLPC氧化生成的4-HNE比1-棕榈酰基-2-亚油酰基磷脂酰胆碱(PLPC)更多。用液质联用(LC-MS)方法鉴定了与4-HNE生成机理相一致的关键产物和中间体。在四氯化碳处理后的大鼠肝组织中，鉴定出相同的心磷脂氧化产物。我们的研究首次在体外和体内证明了心磷脂通过跨链过氧化基自由基加成和分解生成4-HNE，这可能与4-HNE的细胞凋亡和其他生物学活性有关。
We report herein that oxidation of a mitochondria-specific phospholipid tetralinoleoyl cardiolipin (L4CL) by cytochrome c and H2O2 leads to the formation of 4-hydroxy-2-nonenal (4-HNE) via a novel chemical mechanism which 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 is much less understood. Recently a novel chemical mechanism has been proposed that involves inter-molecular 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 L4CL, may lead to the formation of 4-HNE via this novel mechanism. We employed L4CL and di-linoleoyl-phosphatidylcholine (DLPC) as model compounds to test this hypothesis. Indeed, in experiments designed to assess the intramolecular mechanism, more 4-HNE is formed from L4CL and DLPC oxidation than 1-palmitoyl-2-linoleoyl-phosphatydylcholine (PLPC). The key products and intermediates that are consistent with this proposed mechanism of 4-HNE formation have been identified using liquid chromatography – mass spectrometry (LC-MS) methods. 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.
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影响因子：
7.4
作者：
Liang, Hanyu;Ran, Qitao;Jang, Youngmok Charles;Holstein, Deborah;Lechleiter, James;McDonald-Marsh, Tiffany;Musatov, Andrej;Song, Wook;Van Remmen, Holly;Richardson, Arlan
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通讯作者：
Borisenko, GG
影响因子：
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作者：
Doorn, JA;Hurley, TD;Petersen, DR
通讯作者：
Petersen, DR