Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Mol Biol Cell. 2011 Jan 15;22(2):256-65. doi: 10.1091/mbc.E10-06-0551. Epub 2010 Nov 30.
Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.
在许多神经紊乱中，神经元细胞死亡与异常的线粒体动力学和线粒体退化有关。然而，这种线粒体失调的触发因素尚不清楚。在这里，我们发现在高血压大鼠的大脑中存在过度的线粒体裂变和线粒体结构紊乱，这些大鼠患有高血压引起的脑损伤（脑病）。我们发现，蛋白激酶 Cδ（PKCδ）的激活会导致培养的 SH-SY5Y 神经元细胞和高血压诱导脑病的大鼠模型中出现异常的线粒体片段化和线粒体功能障碍。免疫沉淀研究表明，PKCδ与 Drp1 结合，Drp1 是一种主要的线粒体分裂蛋白，并使 Drp1 的丝氨酸 579 磷酸化，从而增加线粒体的片段化。此外，我们发现 PKCδ 磷酸化 Drp1 的丝氨酸 579 与 Drp1 在氧化应激下向线粒体的易位有关。重要的是，使用选择性 PKCδ 肽抑制剂（δV1-1）抑制 PKCδ 可减少线粒体分裂和片段化，并在体内和体外提供神经保护作用。我们的研究表明，PKCδ 的激活会使线粒体分裂机制失调，并导致异常的线粒体分裂，从而导致神经病理学。
