Mitoguardin通过MitoPLD调节线粒体融合及维持神经系统稳态的研究

发布时间：2018-03-23 20:51

本文选题：线粒体动态变化　切入点：线粒体融合　出处：《浙江大学》2016年博士论文

【摘要】：线粒体是一个高度动态的细胞器,时时刻刻在进行融合和分裂。线粒体融合和分裂对于细胞功能的发挥非常重要,融合和分裂的核心成员突变之后将会导致严重的神经退行性疾病的发生。目前,线粒体外膜的融合模型是：蛋白MFN将两个相互靠近的线粒体拉近,靠近的线粒体在另外一个蛋白MitoPLD的作用下将线粒体膜降解成磷脂酸,最终促进线粒体膜的融合。在前人的体外结构学研究中,发现MitoPLD的结构特点更像是一个磷酸酶而不是磷脂酶,提示MitoPLD在发挥磷脂酶活性时可能降解线粒体膜上的脂类形成PA (Phosphatidic acid磷脂酸)需要其他蛋白质的协助。在我们的研究中,我们发现MIGA蛋白是线粒体外膜的蛋白,能促进线粒体的融合过程。我们进一步的研究发现,MIGA在MFN的下游发挥作用,并能和MitoPLD相互作用,稳定MitoPLD的稳定性和促进MitoPLD形成二聚体,进而促进磷脂酸在线粒体膜上的产生,最终促进线粒体融合。我们的发现不但促进了我们对现有的线粒体外膜融合模型的认识,而且促进了对神经退行性疾病和脂代谢的认识。综上,我们提出一个模型,在线粒体融合过程中,MFN将两个相互靠近的线粒体进行拉近,MitoPLD在MIGA蛋白的稳定下催化线粒体外膜磷脂的降解,产生磷脂酸,磷脂酸作为线粒体融合的信号,最终促进外膜的融合。从而在维持神经系统的稳定性中发挥重要作用。
[Abstract]:Mitochondria are highly dynamic organelles that fuse and divide all the time. Mitochondrial fusion and division are very important for the functioning of cells. Mutations in the core members of fusion and division can lead to severe neurodegenerative diseases. At present, the fusion model of mitochondrial outer membrane is that the protein MFN pulls two adjacent mitochondria closer together. The adjacent mitochondria degrade the mitochondrial membrane to phosphatidic acid under the action of another protein, MitoPLD, which ultimately promotes the fusion of the mitochondrial membrane. It was found that the structural characteristics of MitoPLD are more like phosphatase than phospholipase, suggesting that MitoPLD may degrade lipid on mitochondrial membrane to form PA Phosphatidic acid phosphatidic phosphatidic phosphatidic acid. We found that the MIGA protein is a mitochondrial outer membrane protein that can promote the mitochondrial fusion process. We have further found that the MIGA protein plays a role in the downstream of MFN and can interact with MitoPLD to stabilize the stability of MitoPLD and promote the formation of dimers of MitoPLD. Our findings not only contributed to our understanding of the existing models of mitochondrial outer membrane fusion, but also promoted the formation of phosphatidic acid on the mitochondrial membrane. And promote understanding of neurodegenerative diseases and lipid metabolism. In the process of mitochondrial fusion, MitoPLD catalyzes the degradation of mitochondrial outer membrane phospholipid and the production of phosphatidic acid, which is used as the signal of mitochondrial fusion. Ultimately promote the fusion of the adventitia and thus play an important role in maintaining the stability of the nervous system.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：Q42

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