Hsieh Ching-Chyuan, Papaconstantinou John
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555-0643, USA.
FASEB J. 2006 Feb;20(2):259-68. doi: 10.1096/fj.05-4376com.
We have proposed that the age-associated increase of reactive oxygen species (ROS) by electron transport chain (ETC) dysfunction may cause the elevated basal level of p38 MAPK stress response pathway activity. However, the mechanism by which ROS activates this pathway is not clear. Here we propose that activation of the p38 MAPK pathway by complex I (CI) generated ROS, in response to rotenone (ROT) treatment, is based on the ability of reduced Trx to bind to and inhibit ASK 1 and its release from the complex upon oxidation. This balance of free vs. bound ASK1 regulates the level of p38 MAPK pathway activity. To support this mechanism we demonstrate that the production of ROS by ROT treated AML12 hepatocyte cells dissociates the Trx-ASK1 complex, thereby increasing p38 MAPK pathway activity. This mechanism is supported by the ability of N-acetyl cysteine (NAC) to prevent dissociation of Trx-ASK1 and activation of the p38 MAPK pathway. We also demonstrated that the ratio of ASK1/Trx-ASK1 increases in aged mouse livers and that this correlates with the increased basal activity of the p38 MAPK pathway. The longevity of Snell dwarf mice has been attributed to their resistance to oxidative stress. A comparison of the levels of Trx-ASK1 in young and aged dwarfs showed a higher abundance of the complex than in their age-matched controls. These results, which are indicative of a decreased level of oxidative stress, suggest that increased ROS production in aged liver may alter the ratio of ASK1 and Trx-ASK1, thereby increasing the age-associated basal level of p38 MAPK pathway activity.
我们提出，电子传递链（ETC）功能障碍导致的活性氧（ROS）随年龄增长而增加，可能会导致p38丝裂原活化蛋白激酶（MAPK）应激反应途径活性的基础水平升高。然而，ROS激活该途径的机制尚不清楚。在此，我们提出，响应鱼藤酮（ROT）处理，由复合物I（CI）产生的ROS激活p38 MAPK途径，是基于还原型硫氧还蛋白（Trx）结合并抑制凋亡信号调节激酶1（ASK 1）的能力，以及氧化时其从复合物中释放的能力。游离型与结合型ASK1的这种平衡调节p38 MAPK途径活性的水平。为支持这一机制，我们证明，ROT处理的AML12肝细胞产生的ROS使Trx-ASK1复合物解离，从而增加p38 MAPK途径活性。N-乙酰半胱氨酸（NAC）能够防止Trx-ASK1解离并激活p38 MAPK途径，这支持了这一机制。我们还证明，衰老小鼠肝脏中ASK1/Trx-ASK1的比率增加，且这与p38 MAPK途径基础活性的增加相关。斯内尔侏儒小鼠的长寿归因于它们对氧化应激的抗性。对年轻和老年侏儒小鼠中Trx-ASK1水平的比较显示，该复合物的丰度高于其年龄匹配的对照。这些结果表明氧化应激水平降低，提示老年肝脏中ROS产生增加可能会改变ASK1和Trx-ASK1的比率，从而增加与年龄相关的p38 MAPK途径活性基础水平。
