Zhang Shu, Ding Jian-Hua, Zhou Fang, Wang Zhi-Yuan, Zhou Xi-Qiao, Hu Gang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, Peoples Republic of China.
J Neurosci Res. 2009 Apr;87(5):1230-9. doi: 10.1002/jnr.21931.
In addition to the established role of the mitochondrion in energy metabolism, regulation of cell death has been regarded as a major function of this organelle. Our previous studies have demonstrated that iptakalim (IPT), a novel ATP-sensitive potassium channel (K(ATP) channel) opener, protects against 1-methyl-4-phenyl-pyridinium ion (MPP+)-induced astrocyte apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. The present study aimed to investigate whether IPT can protect astrocyte mitochondria against MPP+-induced mitochondrial dysfunction. We showed that treatment with IPT could ameliorate the inhibitory effect of MPP+ on mitochondrial respiration and ATP production by using mitochondrial complex I-supported substrates. IPT could also inhibit the increased production of mitochondrial reactive oxygen species (ROS) and the release of cytochrome c from mitochondria induced by MPP+. However, mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5-HD) could partly abolish all of the above effects of IPT. Because mitochondrial complex dysfunction impairs mitochondrial respiration and ATP production, a further experiment was undertaken to study the effects of IPT on the activity of mitochondrial complex (COX) I and COX IV. It was found that IPT inhibited the decrease in mitochondrial COX I and COX IV activity induced by MPP+, but 5-HD failed to abolish these effects. Taken together, these findings suggest that IPT may protect astrocyte mitochondrial function by regulating complex activity in addition to opening mitoK(ATP) channels.
除了线粒体在能量代谢中已确立的作用外，细胞死亡的调控也被视为该细胞器的一项主要功能。我们之前的研究表明，新型ATP敏感性钾通道（K(ATP)通道）开放剂艾替卡林（IPT）通过线粒体和丝裂原活化蛋白激酶信号通路，保护星形胶质细胞免受1-甲基-4-苯基吡啶离子（MPP+）诱导的凋亡。本研究旨在探讨IPT是否能保护星形胶质细胞线粒体免受MPP+诱导的线粒体功能障碍。我们发现，通过使用线粒体复合体I支持的底物，IPT处理可改善MPP+对线粒体呼吸和ATP生成的抑制作用。IPT还可抑制MPP+诱导的线粒体活性氧（ROS）生成增加以及细胞色素c从线粒体的释放。然而，线粒体ATP敏感性钾（mitoK(ATP)）通道阻滞剂5-羟基癸酸（5-HD）可部分消除IPT的上述所有作用。由于线粒体复合体功能障碍会损害线粒体呼吸和ATP生成，因此进一步开展实验研究IPT对线粒体复合体（COX）I和COX IV活性的影响。结果发现，IPT可抑制MPP+诱导的线粒体COX I和COX IV活性降低，但5-HD无法消除这些作用。综上所述，这些发现表明，IPT除了开放mitoK(ATP)通道外，还可能通过调节复合体活性来保护星形胶质细胞的线粒体功能。
