Mitochondrial Motility and Inheritance

描述（申请人提供）：线粒体遗传是细胞分裂过程中线粒体从母细胞转移到子细胞的过程。在芽殖酵母的遗传过程中，线粒体被主动转移到细胞的两极。运输后，线粒体被锚定并保留在两极，直到分裂细胞周期结束。这些运动和保留事件的净效应是母细胞和子细胞之间的细胞器的平均分布。在酵母中，线粒体、内体、分泌囊泡、mRNA和其他货物的运动的细胞骨架轨道是肌动蛋白电缆，从一极到另一极的F-肌动蛋白束。我们发现，肌动蛋白电缆是移动的轨道，经历延长驱动延伸从芽到母细胞。这种“逆行”影响线粒体向两极的运动。对于逆行运动，线粒体与经历逆行流动的肌动蛋白电缆结合，并使用这些电缆作为“传送带”向母细胞尖端运输。线粒体向相反极的运动需要细胞器与肌动蛋白电缆的可逆结合，以及线粒体和肌动蛋白电缆之间界面处的顺行力。几种分子有助于这种顺行运动：1）线粒体介导线粒体与肌动蛋白电缆的结合，2）Arp 2/3复合物在细胞器-肌动蛋白电缆界面产生顺行力，3）2个Pumilio家族蛋白（Jsn 1 p和Puf 3 p）将Arp 2/3复合物募集到线粒体。线粒体在芽中的锚定需要V型肌球蛋白（Myo 2 p）和2个Myo 2 p结合伴侣（Ypt 11 p，Ras样G蛋白和Mmrlp）。我们的研究还揭示了一种新的调节系统，当线粒体遗传缺陷时，它会抑制胞质分裂。这个过程是由有丝分裂出口网络（MEN），一个信号转导途径，协调染色体分离，退出M期，胞质分裂。因此，我们现在能够从芽殖酵母遗传过程中线粒体运动的描述转向理解这一过程的分子基础以及线粒体遗传如何整合到整个细胞周期中。我们将研究Pumilio家族蛋白与线粒体和Arp 2/3复合物的相互作用，以更全面地了解Arp 2/3复合物靶向线粒体。我们将研究Myo 2 p，Ypt 11 p和Mmrlp在芽尖线粒体锚定中的作用。最后，我们将研究线粒体遗传是如何监测和整合信号转导的MEN。

DESCRIPTION (provided by applicant): Mitochondrial inheritance is the process whereby mitochondria are transferred from mother to daughter cell during cell division. During inheritance in budding yeast, mitochondria are actively transferred to opposite poles of the cell. After transport, mitochondria are anchored to and retained at the poles until the end of the division cell cycle. The net effect of these motility and retention events is the equal distribution of the organelle between mother and daughter cells. The cytoskeletal track for movement of mitochondria, endosomes, secretory vesicles, mRNAs, and other cargos in yeast are actin cables, bundles of F-actin that run from pole to pole. We found that actin cables are moving tracks that undergo elongation-driven extension from the bud into the mother cell. This "retrograde flow" affects movement of mitochondria toward both poles. For retrograde movement, mitochondria bind to actin cables undergoing retrograde flow and use these cables as "conveyor belts" for transport toward the mother cell tip. Movement of mitochondria to the opposite pole requires reversible binding of the organelle to actin cables, and anterograde forces at the interface between mitochondria and actin cables. Several molecules contribute to this anterograde movement: 1) the mitochore mediates binding of mitochondria with actin cables, 2) the Arp2/3 complex generates anterograde forces at the organelle-actin cable interface, and 3) 2 Pumilio family proteins (Jsn1p and Puf3p) recruit Arp2/3 complex to mitochondria. Anchorage of mitochondria in the bud requires a type V myosin (Myo2p), and 2 Myo2p binding partners (Ypt11p a Ras-like G-protein, and Mmrlp). Our studies also revealed a novel regulatory system, that inhibits cytokinesis when mitochondrial inheritance is defective. This process is regulated by the mitotic exit network (MEN), a signal transduction pathway that coordinates chromosome segregation, exit from M-phase, and cytokinesis. Thus, we are now in a position to move from a description of mitochondrial motility during inheritance in budding yeast to understanding the molecular basis for this process and how mitochondrial inheritance is integrated into the cell cycle as a whole. We will study the interaction of Pumilio family proteins with mitochondria and the Arp2/3 complex, to more fully understand Arp2/3 complex targeting to mitochondria. We will study the role of Myo2p, Ypt11p, and Mmrlp in anchorage of mitochondria in the bud tip. Finally, we will study how mitochondrial inheritance is monitored and integrated with signal transduction by the MEN.