Targeting lipoic acid to mitochondria:: Synthesis and characterization of a triphenylphosphonium-conjugated α-lipoyl derivative
Targeting lipoic acid to mitochondria:: Synthesis and characterization of a triphenylphosphonium-conjugated α-lipoyl derivative
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DOI：
10.1016/j.freeradbiomed.2007.02.033
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发表时间：
2007-06-15
影响因子：
7.4
通讯作者：
Murphy, Michael P.
中科院分区：
文献类型：
--
作者：
Brown, Stephanie E.;Ross, Meredith F.;Murphy, Michael P.
硫辛酸（LA）是一种广泛使用的抗氧化剂，可保护线粒体免受体内氧化损伤。这种保护大部分被认为是由于 LA 还原为二氢硫辛酸 (LAH(2))。这种还原在体内由硫氧还蛋白、硫氧还蛋白还原酶(TrxR)和硫辛酸酰胺脱氢酶催化。我们假设，将 LA 特异性靶向线粒体（大多数细胞活性氧产生的场所）将使其成为更有效的抗氧化剂。为此，我们通过将硫辛酸连接到亲脂性三苯基鏻阳离子上，制成了一种新型分子 MitoLipoic 酸。 MitoL 在膜电位的驱动下在线粒体内快速积累数百倍。 MitoL 被硫氧还蛋白和硫辛酸酰胺脱氢酶还原为活性抗氧化剂二氢MitoLipoic 酸，但不被TrxR 还原。在分离的线粒体或细胞中，MitoL 仅轻微减少（5-10%），而相反，LA 大幅减少。这种差异主要是由于 LA 与 TrxR 发生反应，而 MitoL 则不会发生这种反应。此外，在细胞中MitoL被定量转化为S-甲基化产物。由于缺乏还原作用，MitoL 不能保护线粒体或细胞免受一系列氧化应激。这些结果表明，LA 在体内的保护作用可能需要其还原为 LAH2，并且这种还原很大程度上是由 TrxR 介导的。 (c) 2007 Elsevier Inc. 保留所有权利。
Lipoic acid (LA) is a widely used antioxidant that protects mitochondria from oxidative damage in vivo. Much of this protection is thought to be due to the reduction of LA to dihydrolipoic acid (LAH(2)). This reduction is catalyzed in vivo by thioredoxin, tbioredoxin reductase (TrxR), and lipoamide dehydrogenase. We hypothesized that specifically targeting LA to mitochondria, the site of most cellular reactive oxygen species production, would make it a more effective antioxidant. To do this, we made a novel molecule, MitoLipoic acid, by attaching lipoic acid to the lipophilic triphenylphosphonium cation. MitoL was accumulated rapidly within mitochondria several-hundred fold driven by the membrane potential. MitoL was reduced to the active antioxidant dihydroMitoLipoic acid by thioredoxin and by lipoamide dehydrogenase but not by TrxR. In isolated mitochondria or cells MitoL was only slightly reduced (5-10%), while, in contrast, LA was extensively reduced. This difference was largely due to the reaction of LA with TrxR, which did not occur for MitoL. Furthermore, in cells MitoL was quantitatively converted to an S-methylated product. As a consequence of its lack of reduction, MitoL was not protective for mitochondria or cells against a range of oxidative stresses. These results suggest that the protective action of LA in vivo may require its reduction to LAH2 and that this reduction is largely mediated by TrxR. (c) 2007 Elsevier Inc. All rights reserved.