Regulation of mitochondrial inheritance by Myo19

Myo19 对线粒体遗传的调节

• 批准号: 419818378
• 负责人: Professor Dr. Martin Bähler
• 金额: --
• 依托单位: Institut für Molekulare Zellbiologie (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419818378?language=en
• 关键词: Regulation; mitochondrial; inheritance; Myo19

Mitochondria contain their own DNA and cannot form de novo. This implies that at cell division mitochondria have to coordinate their inheritance during partitioning to daughter cells. They are highly dynamic and undergo fusion and fission in a cell cycle dependent manner. Blocking fission or increasing fusion leads to stochastic failure of cytokinesis. Inappropriate movement and distribution of mitochondria during mitosis blocks their faithful segregation during division. Both too low and too high mitochondria content have been associated with various cellular deficits and the development of pathogenesis. In mammalian cells mitochondrial transport is predominately microtubule-based. The motor proteins kinesin and dynein associate with the help of the adaptor protein TRAK to the outer mitochondrial membrane protein Miro, a RhoGTPase and direct bidirectional movement along microtubules. Additionally, one finds also actin-based motor proteins associated with mitochondria such as myosin XIX (Myo19). Myo19 competes with the adaptor protein TRAK for binding to Miro and this binding stabilizes the Myo19 protein. Knockdown and overexpression of Myo19 both cause a redistribution of mitochondria to the perinuclear region. These results suggest that Miro coordinates microtubule- and actin-based mitochondria movement. In cells that lack Myo19 mitochondria segregate during mitosis asymmetrically to the spindle poles and are partitioned unequally to daughter cells. In addition, Myo19-deficient cells demonstrate a stochastic failure of cytokinesis. How Myo19 regulates mitochondria segregation and cytokinesis and what the physiological consequences are of asymmetric mitochondrial inheritance, is currently not well understood. We propose to unravel the molecular mechanisms by which Myo19 regulates mitotic segregation of mitochondria using a broad spectrum of state of the art cell biological methods. Furthermore, we propose to study how cells cope with an altered content of mitochondria. For that purpose Myo19-deficient cells will be sorted according to mitochondrial content followed by analysis of various functional and metabolic parameters.

线粒体含有自己的DNA，不能从头形成。这意味着在细胞分裂时，线粒体必须在分裂到子细胞的过程中协调它们的遗传。它们是高度动态的，并以细胞周期依赖的方式进行融合和裂变。阻断裂变或增加融合会导致细胞分裂的随机失败。线粒体在有丝分裂过程中的不适当运动和分布阻碍了它们在分裂过程中的忠实分离。线粒体含量过低和过高都与各种细胞缺陷和发病机制的发展有关。在哺乳动物细胞中，线粒体运输主要以微管为基础。运动蛋白激酶（kinesin）和动力蛋白（dynein）在接头蛋白TRAK的帮助下与线粒体外膜蛋白Miro、RhoGTPase和沿着微管的直接双向运动相关联。此外，人们还发现与线粒体相关的基于肌动蛋白的运动蛋白，如肌球蛋白XIX （Myo19）。Myo19与接头蛋白TRAK竞争与Miro的结合，这种结合稳定了Myo19蛋白。Myo19的敲低和过表达都会导致线粒体重新分布到核周区域。这些结果表明，Miro协调微管和肌动蛋白为基础的线粒体运动。在缺乏Myo19的细胞中，线粒体在有丝分裂过程中不对称地与纺锤极分离，并不均匀地分裂成子细胞。此外，myo19缺陷细胞表现为细胞分裂的随机失败。Myo19如何调节线粒体分离和细胞分裂，以及线粒体不对称遗传的生理后果，目前尚不清楚。我们建议利用广泛的细胞生物学方法来揭示Myo19调节线粒体有丝分裂分离的分子机制。此外，我们建议研究细胞如何应对线粒体含量的改变。为此，将根据线粒体含量对myo19缺陷细胞进行分类，然后分析各种功能和代谢参数。