Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan.
Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan.
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DOI：
10.1016/j.cmet.2016.03.009
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发表时间：
2016-04-12
期刊：
影响因子：
29
通讯作者：
Sanz A
中科院分区：
文献类型：
--
作者：
Scialò F;Sriram A;Fernández-Ayala D;Gubina N;Lõhmus M;Nelson G;Logan A;Cooper HM;Navas P;Enríquez JA;Murphy MP;Sanz A
长期以来，活性氧（ROS）产生的增加一直被认为是衰老的原因。然而，最近的研究表明 ROS 是重要的第二信使。在这里，我们表明，ROS 的产生位点对其明显的双重性质有重大贡献。我们报告称，随着线粒体功能的恶化，ROS 会随着年龄的增长而增加。然而，我们还证明，特别是通过呼吸复合物 I 反向电子传递来增加 ROS 的产生，可以延长果蝇的寿命。反向电子传递挽救了严重氧化应激诱导的发病机制，凸显了 ROS 产生位点在信号传导中的重要性。此外，通过敲除 PINK1 来防止泛醌还原，会缩短寿命并加速衰老；通过增加反向电子传输来挽救的表型。这些结果表明，ROS 信号的来源对于确定其对细胞生理学的影响至关重要，并证实操纵泛醌氧化还原状态是延缓衰老的有效策略。线粒体 ROS 在衰老过程中在果蝇大脑中积累 诱导体内反向电子传递 (RET) 增加线粒体 ROS RET 通过 ROS 介导的机制延长果蝇寿命 RET 改善帕金森病模型中的线粒体功能 特别是通过复合物 I 增加线粒体 ROS (mtROS)，改善健康并延长寿命。 Scialò 等人。研究表明，mtROS 的产生位点决定了它们的作用，并且通过线粒体复合物 I 的反向电子传输来增加 mtROS 可以延缓果蝇的衰老和与年龄相关的疾病的发生。
Increased production of reactive oxygen species (ROS) has long been considered a cause of aging. However, recent studies have implicated ROS as essential secondary messengers. Here we show that the site of ROS production significantly contributes to their apparent dual nature. We report that ROS increase with age as mitochondrial function deteriorates. However, we also demonstrate that increasing ROS production specifically through respiratory complex I reverse electron transport extends Drosophila lifespan. Reverse electron transport rescued pathogenesis induced by severe oxidative stress, highlighting the importance of the site of ROS production in signaling. Furthermore, preventing ubiquinone reduction, through knockdown of PINK1, shortens lifespan and accelerates aging; phenotypes that are rescued by increasing reverse electron transport. These results illustrate that the source of a ROS signal is vital in determining its effects on cellular physiology and establish that manipulation of ubiquinone redox state is a valid strategy to delay aging. Mitochondrial ROS accumulate in the fly brain during aging Inducing reverse electron transport (RET) in vivo increases mitochondrial ROS RET extends fly lifespan through a ROS-mediated mechanism RET improves mitochondrial function in a model of Parkinson’s disease Increasing mitochondrial ROS (mtROS) specifically through complex I improves health and extends lifespan. Scialò et al. show that the site at which mtROS are produced determines their effects and increasing mtROS specifically via reverse electron transport through mitochondrial complex I delays aging and the onset of age-related diseases in flies.