Role of mitochondria in oxidative stress and aging
Role of mitochondria in oxidative stress and aging
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DOI：
10.1111/j.1749-6632.2002.tb02094.x
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Ventura, B
中科院分区：
文献类型：
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作者：
Lenaz, G;Bovina, C;Ventura, B
线粒体呼吸链是活性氧（ROS）的强大来源，被认为是许多疾病和衰老的病原体。我们已经研究了复合物I在超氧自由基产生中的作用，并通过复合物I的特异性抑制剂的组合使用发现，复合物中的氧的单电子供体是位于三种不同类型的辅酶Q（CoQ）竞争者结合的位点之前的氧化还原中心，其被鉴定为Fe-S簇，最可能是N2，或可能是对所有上述抑制剂不敏感的泛半醌中间体。短链辅酶Q类似物增强超氧化物的形成，大概是通过介导电子从N2转移到氧气。临床上使用的辅酶Q类似物艾地苯醌特别有效，引起了对其作为药物安全性的怀疑。衰老的线粒体理论认为ROS诱导的线粒体DNA体细胞突变是能量下降的主要原因;在大鼠肝线粒体中，复合物I似乎受衰老的影响最大，并成为电子转移的强烈速率限制。线粒体能量学在人类血小板老化时也会紊乱，如巴斯德效应降低（呼吸抑制剂增加乳酸产生）所示。细胞通过抗氧化剂对抗氧化应激：辅酶Q是唯一可以生物合成的亲脂性抗氧化剂。然而，外源性辅酶Q通过细胞还原酶将其转化为还原的抗氧化剂形式来保护细胞免受氧化应激。质膜氧化还原酶和DT-心肌黄酶是两个这样的系统：同样，它们在氧化应激条件下过表达。
The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production and found by combined use of specific inhibitors of Complex I that the one-electron donor in the Complex to oxygen is a redox center located prior to the sites where three different types of coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain coenzyme Q analogues enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analogue idebenone is particularly effective, raising doubts about its safety as a drug. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by ROS as the primary cause of energy decline; in rat liver mitochondria, Complex I appears to be most affected by aging and to become strongly rate limiting for electron transfer. Mitochondrial energetics is also deranged in human platelets upon aging, as demonstrated by the decreased Pasteur effect (enhancement of lactate production by respiratory inhibitors). Cells counteract oxidative stress by antioxidants: CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems: likewise, they are overexpressed under oxidative stress conditions.