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The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway

机译:Omi蛋白酶通过GSK3 β / PGC-1 α途径调节线粒体生物发生

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Loss of the mitochondrial protease activity of Omi causes mitochondrial dysfunction, neurodegeneration with parkinsonian features and premature death in mnd2 (motor neuron degeneration 2) mice. However, the detailed mechanisms underlying this pathology remain largely unknown. Here, we report that Omi participates in the process of mitochondrial biogenesis, which has been linked to several neurodegenerative diseases. The mitochondrial biogenesis is deficit in mnd2 mice, evidenced by severe decreases of mitochondrial components, mitochondrial DNA and mitochondrial density. Omi cleaves glycogen synthase kinase 3 β (GSK3 β ), a kinase promoting PPARγ coactivator-1 α (PGC-1 α ) degradation, to regulate PGC-1 α , a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3 β abundance is increased and PGC-1 α abundance is decreased significantly. Inhibition of GSK3 β by SB216763 or overexpression of PGC-1 α can restore mitochondrial biogenesis in mnd2 mice or Omi -knockdown N2a cells. Furthermore, there is a significant improvement of the movement ability of mnd2 mice after SB216763 treatment. Thus, our study identified Omi as a novel regulator of mitochondrial biogenesis, involving in Omi protease-deficient-induced neurodegeneration.
机译:Omi的线粒体蛋白酶活性丧失会导致线粒体功能障碍,具有帕金森氏症特征的神经变性和mnd2(运动神经元变性2)小鼠过早死亡。但是,这种病理学的详细机制仍然未知。在这里,我们报道Omi参与了线粒体生物发生的过程,该过程已与几种神经退行性疾病相关。线粒体生物发生在mnd2小鼠中是缺陷的,线粒体成分,线粒体DNA和线粒体密度的严重降低证明了这一点。 Omi切割糖原合酶激酶3β(GSK3β)(一种促进PPARγ共激活因子1α(PGC-1α)降解的激酶)来调节PGC-1α(对线粒体生物发生很重要的因子)。在mnd2小鼠中,GSK3β的丰度增加,PGC-1α的丰度明显降低。 SB216763对GSK3β的抑制或PGC-1α的过表达可以恢复mnd2小鼠或Omi-nockdown N2a细胞的线粒体生物发生。此外,SB216763处理后,mnd2小鼠的运动能力有了显着改善。因此,我们的研究确定Omi为线粒体生物发生的新型调节剂,涉及Omi蛋白酶缺陷诱导的神经变性。

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