Xu R, Hu Q, Ma Q, Liu C, Wang G
Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui, China.
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Suzhou, Jiangsu, China.
Cell Death Dis. 2014 Aug 14;5(8):e1373. doi: 10.1038/cddis.2014.328.
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 3β (GSK3β), a kinase promoting PPARγ coactivator-1α (PGC-1α) degradation, to regulate PGC-1α, a factor important for the mitochondrial biogenesis. In mnd2 mice, GSK3β abundance is increased and PGC-1α abundance is decreased significantly. Inhibition of GSK3β by SB216763 or overexpression of PGC-1α 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.
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退行性变以及mnd2（运动神经元变性2）小鼠过早死亡。然而，这种病理学背后的详细机制在很大程度上仍然未知。在此，我们报告Omi参与线粒体生物发生过程，这一过程与多种神经退行性疾病有关。mnd2小鼠的线粒体生物发生存在缺陷，表现为线粒体成分、线粒体DNA和线粒体密度严重降低。Omi裂解糖原合酶激酶3β（GSK3β），一种促进PPARγ共激活因子-1α（PGC-1α）降解的激酶，从而调节PGC-1α，这是线粒体生物发生的一个重要因子。在mnd2小鼠中，GSK3β丰度增加，而PGC-1α丰度显著降低。用SB216763抑制GSK3β或过表达PGC-1α可以恢复mnd2小鼠或Omi敲低的N2a细胞中的线粒体生物发生。此外，SB216763治疗后mnd2小鼠的运动能力有显著改善。因此，我们的研究确定Omi是线粒体生物发生的一种新型调节因子，参与Omi蛋白酶缺陷诱导的神经退行性变。
