Complex I and cytochrome c are molecular targets of flavonoids that inhibit hydrogen peroxide production by mitochondria
Complex I and cytochrome c are molecular targets of flavonoids that inhibit hydrogen peroxide production by mitochondria
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DOI：
10.1016/j.bbabio.2011.09.022
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发表时间：
2011-12-01
影响因子：
4.3
通讯作者：
Gutierrez-Merino, Carlos
中科院分区：
文献类型：
--
作者：
Lagoa, Ricardo;Graziani, Ilaria;Gutierrez-Merino, Carlos
类黄酮可以保护细胞免受不同的损伤，导致线粒体介导的细胞死亡，流行病学数据显示，其中一些化合物可以减缓与氧化应激和线粒体相关的疾病的进展！功能障碍。本研究筛选了5种黄酮类化合物的主要亚类，发现它们对大鼠脑和心脏线粒体产生H2O2有不同的影响。槲皮素、山奈酚和表儿茶素是两种组织线粒体产生H2O2的有效抑制剂（IC50约为1-2 μ M），即使线粒体抑制剂鱼藤酮和抗霉素a刺激了H2O2的产生速率，尽管氧消耗速率不受这些类黄酮浓度高达10 μ M的影响，槲皮素、山奈酚和芹菜素抑制复合物I的活性，而高达100 μ M的表儿茶素产生的抑制作用不到20%。这种抑制的程度取决于培养基中辅酶Q的浓度，这表明黄酮类化合物和泛醌之间竞争复合物中的紧密结合位点。相比之下，这些类黄酮并没有显著抑制复合物II和III的活性，也没有影响复合物IV的氧化还原状态。然而，我们发现表儿茶素、槲皮素和山奈酚能够化学定量地降低纯化的细胞色素c。我们的研究结果表明，线粒体可能是类黄酮介导的主要靶点，至少在一定程度上，它们对氧化应激和线粒体功能障碍相关病理的预防作用。(C) 2011 Elsevier B.V.版权所有
Flavonoids can protect cells from different insults that lead to mitochondria-mediated cell death, and epidemiological data show that some of these compounds attenuate the progression of diseases associated with oxidative stress and mitochondria! dysfunction. In this work, a screening of 5 flavonoids representing major subclasses showed that they display different effects on H2O2 production by mitochondria isolated from rat brain and heart. Quercetin, kaempferol and epicatechin are potent inhibitors of H2O2 production by mitochondria from both tissues (IC50 approximate to 1-2 mu M), even when H2O2 production rate was stimulated by the mitochondrial inhibitors rotenone and antimycin A. Although the rate of oxygen consumption was unaffected by concentrations up to 10 mu M of these flavonoids, quercetin, kaempferol and apigenin inhibited complex I activity, while up to 100 mu M epicatechin produced less than 20% inhibition. The extent of this inhibition was found to be dependent on the concentration of coenzyme Q in the medium, suggesting competition between the flavonoids and ubiquinone for close binding sites in the complex. In contrast, these flavonoids did not significantly inhibit the activity of complexes II and III, and did not affect the redox state of complex IV. However, we have found that epicatechin, quercetin and kaempferol are able to stoichiometrically reduce purified cytochrome c. Our results reveal that mitochondria are a plausible main target of flavonoids mediating, at least in part, their reported preventive actions against oxidative stress and mitochondrial dysfunction-associated pathologies. (C) 2011 Elsevier B.V. All rights reserved.