Raffaello Anna, Rizzuto Rosario
Department of Biomedical Sciences, University of Padova, Padova, Italy.
Biochim Biophys Acta. 2011 Jan;1813(1):260-8. doi: 10.1016/j.bbamcr.2010.10.007. Epub 2010 Oct 13.
Production of reactive oxygen species (ROS) is a tightly regulated process, and increased levels of ROS within mitochondria are the principal trigger not only for mitochondrial dysfunctions but, more in general, for the diseases associated with aging, thus representing a powerful signaling molecules. One of the key regulators of ROS production, mitochondrial dysfunction, and aging is the 66-kDa isoform of the growth factor adapter shc (p66(shc)) that is activated by stress and generates ROS within the mitochondria, driving cells to apoptosis. Accordingly, p66(shc) knockout animals are one of the best characterized genetic model of longevity. On the other hand, caloric restriction is the only non-genetic mechanism that is shown to increase life span. Several studies have revealed a complex network of signaling pathways modulated by nutrients, such as IGF-1, TOR, sirtuins, AMP kinase, and PGC-1α that are connected and converge to inhibit oxidative stresses within the mitochondria. Animal models in which components of these signaling pathways are induced or silenced present a general phenotype characterized by the deceleration of the aging process. This review will summarize the main findings in the process that link mitochondria to longevity and the connections between the different signaling molecules involved in this intriguing relationship.
活性氧（ROS）的产生是一个受到严格调控的过程，线粒体中ROS水平的升高不仅是线粒体功能障碍的主要触发因素，更普遍地说，是与衰老相关疾病的主要触发因素，因此ROS是一种强大的信号分子。生长因子衔接蛋白shc的66 kDa异构体（p66(shc)）是ROS产生、线粒体功能障碍和衰老的关键调节因子之一，它在应激状态下被激活，在线粒体内产生活性氧，促使细胞凋亡。因此，p66(shc)基因敲除动物是寿命最长的最佳遗传模型之一。另一方面，热量限制是唯一被证明能延长寿命的非遗传机制。多项研究揭示了一个由营养物质调节的复杂信号通路网络，如胰岛素样生长因子-1（IGF-1）、雷帕霉素靶蛋白（TOR）、沉默调节蛋白、腺苷酸活化蛋白激酶（AMP激酶）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α），这些信号通路相互连接并汇聚，以抑制线粒体内的氧化应激。诱导或沉默这些信号通路组成部分的动物模型呈现出一种以衰老过程减速为特征的一般表型。本综述将总结线粒体与长寿之间联系过程中的主要发现，以及参与这种有趣关系的不同信号分子之间的联系。
