Regulation of mitochondrial inheritance by Myo19

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，以依赖于细胞周期的方式进行融合和分裂。阻止分裂或增加融合会导致细胞质分裂的随机失败。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多种细胞缺陷和发病机制有关。在哺乳动物细胞中，线粒体的运输主要是基于微管的。运动蛋白Kinesin和Dynein与线粒体膜外膜蛋白MIRO的接头蛋白TRAK、RhoGTP酶和沿微管的直接双向运动有关。此外，还发现了肌球蛋白XIX(Myo19)等与线粒体相关的肌动蛋白。Myo19与接头蛋白TRAK竞争结合Miro，这种结合稳定了Myo19蛋白。Myo19基因的敲除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协调基于微管和肌动蛋白的线粒体运动。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体极分离，并不均匀地分割为子细胞。此外，Myo19缺陷细胞表现为胞质分裂的随机失败。Myo19如何调节线粒体分离和胞质分裂，以及不对称线粒体遗传的生理后果目前尚不清楚。我们建议使用最先进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内容的变化。为此，Myo19缺陷细胞将根据线粒体含量进行分类，然后分析各种功能和代谢参数。

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.