Nobiletin, a polymethoxylated flavonoid found in citrus, has been studied because of its modulatory functions in cellular signaling cascades, and effects to prevent mitochondrial calcium overload and neuronal cell death. Particularly, we previously reported that nobiletin induced changes in the mitochondrial membrane potential through K⁺ channel regulation, suggesting that nobiletin might exert neuroprotective effects via regulating mitochondrial functions associated with the electron transport chain (ETC) system. This study investigated whether nobiletin regulated mitochondrial dysfunction mediated by ETC system downregulation by inhibiting complex I (CI) and complex III (CIII) in pure mitochondria and the cortical neurons of rats. The results showed that nobiletin significantly reduced mitochondrial reactive oxygen species (ROS) production, inhibited apoptotic signaling, enhanced ATP production and then restored neuronal viability under conditions of CI inhibition, but not CIII inhibition. These effects were attributed to the downregulation of translocation of apoptosis-induced factor (AIF), and the upregulation of CI activity and the expression of antioxidant enzymes such as Nrf2 and HO-1. Together with our previous study, these results indicate that the neuroprotective effects of nobiletin under mitochondrial dysfunction may be associated with its function to activate antioxidant signaling cascades. Our findings suggest the possibility that nobiletin has therapeutic potential in treating oxidative neurological and neurodegenerative diseases mediated by mitochondrial dysfunction.

中文翻译：

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Nobiletin通过调节细胞凋亡信号转导显示针对线粒体复合体I抑制的神经保护作用。

Nobiletin是一种在柑橘中发现的聚甲氧基化类黄酮，由于其在细胞信号级联反应中的调节功能，以及防止线粒体钙超载和神经元细胞死亡的作用，因此已得到研究。特别是，我们先前曾报道，诺比列汀通过K ⁺诱导线粒体膜电位的变化。通道调节，表明诺比列汀可能通过调节与电子传输链（ETC）系统相关的线粒体功能发挥神经保护作用。这项研究调查了nobiletin是否通过抑制纯线粒体和大鼠皮质神经元中的复合物I（CI）和复合物III（CIII）来调节ETC系统下调介导的线粒体功能障碍。结果表明，在CI抑制而不是CIII抑制的条件下，诺比列汀显着降低了线粒体活性氧（ROS）的产生，抑制了细胞凋亡信号，增强了ATP的产生，然后恢复了神经元的生存能力。这些作用归因于凋亡诱导因子（AIF）的转位下调，以及CI活性的上调和Nrf2和HO-1等抗氧化酶的表达。与我们以前的研究一起，这些结果表明，诺比汀在线粒体功能障碍下的神经保护作用可能与其激活抗氧化剂信号级联反应的功能有关。我们的发现表明，诺比列汀具有治疗线粒体功能障碍介导的氧化性神经系统疾病和神经退行性疾病的潜力。