Hsieh Ching-Chyuan, Papaconstantinou John
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Aging (Albany NY). 2009 Jul 31;1(9):784-802. doi: 10.18632/aging.100077.
Activation of p38 MAPK by ROS involves dissociation of an inactive, reduced thioredoxin-ASK1 complex [(SH)(2)Trx-ASK1]. Release of ASK1 activates its kinase activity thus stimulating the p38 MAPK pathway. The level of p38 MAPK activity is, therefore, regulated by the balance of free vs. bound ASK1. Longevity of Ames dwarf mice is attributed to their resistance to oxidative stress. The levels of (SH)(2) Trx-ASK1 are more abundant in young and old dwarf mice compared to their age-matched controls suggesting that the levels of this complex may play a role in their resistance to oxidative stress. In these studies we demonstrate that dermal fibroblasts from these long-lived mice exhibit (a) higher levels of (SH)(2)Trx-ASK1 that correlate with their resistance to ROS generated by inhibitors of electron transport chain complexes CI (rotenone), CII (3-nitropropionic acid), CIII, (antimycin A), and H(2)O(2)-mediated activation of p38 MAPK, and (b) maintain their in vivo resistance to ROS generated by 3NPA. We propose that elevated levels of (SH)(2)Trx-ASK1 play a role in conferring resistance to mitochondrial generated oxidative stress and decreased endogenous ROS which are characteristics of longevity determination.
活性氧（ROS）对p38丝裂原活化蛋白激酶（MAPK）的激活涉及无活性的、还原型硫氧还蛋白-凋亡信号调节激酶1复合物[（SH）₂Trx-ASK1]的解离。ASK1的释放激活其激酶活性，从而刺激p38 MAPK信号通路。因此，p38 MAPK的活性水平由游离ASK1与结合ASK1的平衡来调节。艾姆斯侏儒小鼠的长寿归因于它们对氧化应激的抗性。与年龄匹配的对照相比，年轻和年老的侏儒小鼠中（SH）₂Trx-ASK1的水平更为丰富，这表明该复合物的水平可能在它们对氧化应激的抗性中发挥作用。在这些研究中，我们证明来自这些长寿小鼠的皮肤成纤维细胞表现出：（a）更高水平的（SH）₂Trx-ASK1，这与它们对电子传递链复合物CI（鱼藤酮）、CII（3-硝基丙酸）、CIII（抗霉素A）抑制剂以及H₂O₂介导的p38 MAPK激活所产生的ROS的抗性相关；（b）维持其对3NPA产生的ROS的体内抗性。我们提出，升高的（SH）₂Trx-ASK1水平在赋予对线粒体产生的氧化应激的抗性以及降低内源性ROS方面发挥作用，而这是寿命决定的特征。
