Gong Changxia, Li Chengwei, Qi Xiaoqing, Song Zhiyin, Wu Jianguo, Hughes Michael E, Li Xiaodong
a State Key Laboratory of Virology, College of Life Sciences, Wuhan University , Wuhan, Hubei Province , P.R. China and.
b Department of Biology , University of Missouri-St. Louis . St. Louis, MO , USA.
Chronobiol Int. 2015;32(9):1254-63. doi: 10.3109/07420528.2015.1085388. Epub 2015 Oct 29.
The circadian clock regulates many cellular processes, notably including the cell cycle, metabolism and aging. Mitochondria play essential roles in metabolism and are the major sites of reactive oxygen species (ROS) production in the cell. The clock regulates mitochondrial functions by driving daily changes in NAD(+) levels and Sirt3 activity. In addition to this central route, in the present study, we find that the expression of some mitochondrial genes is also rhythmic in the liver, and that there rhythms are disrupted by the Clock(Δ19) mutation in young mice, suggesting that they are regulated by the core circadian oscillator. Related to this observation, we also find that the regulation of oxidative stress is rhythmic in the liver. Since mitochondria and ROS play important roles in aging, and mitochondrial functions are also disturbed by aging, these related observations prompt the compelling hypothesis that circadian oscillators influence aging by regulating ROS in mitochondria. During aging, the expression rhythms of some mitochondrial genes were altered in the liver and the temporal regulation over the dynamics of mitochondrial oxidative stress was disrupted. However, the expression of clock genes was not affected. Our results suggested that mitochondrial functions are combinatorially regulated by the clock and other age-dependent mechanism(s), and that aging disrupts mitochondrial rhythms through mechanisms downstream of the clock.
生物钟调节许多细胞过程，尤其包括细胞周期、新陈代谢和衰老。线粒体在新陈代谢中发挥着重要作用，是细胞内活性氧（ROS）产生的主要场所。生物钟通过驱动NAD(+)水平和Sirt3活性的每日变化来调节线粒体功能。除了这条核心途径外，在本研究中，我们发现一些线粒体基因的表达在肝脏中也具有节律性，并且这些节律在年轻小鼠中因Clock(Δ19)突变而被破坏，这表明它们受核心生物钟振荡器调节。与此观察结果相关，我们还发现肝脏中氧化应激的调节具有节律性。由于线粒体和ROS在衰老过程中发挥重要作用，并且线粒体功能也会因衰老而受到干扰，这些相关观察结果促使我们提出一个引人注目的假设，即生物钟振荡器通过调节线粒体中的ROS来影响衰老。在衰老过程中，肝脏中一些线粒体基因的表达节律发生改变，并且对线粒体氧化应激动态的时间调节被破坏。然而，生物钟基因的表达并未受到影响。我们的结果表明，线粒体功能受到生物钟和其他年龄依赖性机制的联合调节，并且衰老通过生物钟下游的机制破坏线粒体节律。
