Non-apoptotic mitochondrial functions of C. elegans CED-9 BCL2

BCL2类蛋白是I型程序性细胞死亡的关键调节因子，在线虫、秀丽线虫和哺乳动物等动物中也被称为细胞凋亡。最近，有研究表明BCL2样蛋白也具有非凋亡功能。例如，BCL2类蛋白参与了一个被称为线粒体动力学的过程。线粒体动力学描述了一个事实，即细胞内的线粒体网络经常经历融合和分裂的周期，并可以改变其整体形态以响应特定的信号。虽然线粒体动力学对细胞功能至关重要，但线粒体动力学的具体生理作用仍有待阐明。我们已经证明线虫类BCL2蛋白CED-9可以促进线粒体融合和线粒体分裂。此外，我们发现CED-9通过直接与动力蛋白相关的GTP酶FZO-1 MFN和DRP-1 Drp1相互作用来实现这一点，这两种酶分别是线粒体融合和分裂所必需的。这项拟议研究的目的是测试在健康的、非凋亡的细胞中，CED-9在融合和分裂周期中充当线粒体融合和线粒体分裂的耦合器的模型。为此，我们将结合使用细胞生物学、遗传学和生化方法。这些研究结果不仅有助于我们更好地理解bcl2样蛋白的非凋亡功能，而且有助于确定线粒体动力学的生理作用。

BCL2-like proteins are crucial regulators of programmed cell death type I, also referred to as apoptosis, in animals as diverse as the nematode Caenorhabditis elegans and mammals. Recently, it has been suggested that BCL2-like proteins also have non-apoptotic functions. For example, BCL2-like proteins have been implicated in a process referred to as mitochondrial dynamics. Mitochondrial dynamics describes the fact that the mitochondrial network within a cell frequently undergoes cycles of fusion and fission and can change its overall morphology in response to specific signals. While mitochondrial dynamics is critical for cellular function, the specific physiological roles of mitochondrial dynamics remain to be elucidated. We have demonstrated that the BCL2-like protein CED-9 of C. elegans can promote both mitochondrial fusion and mitochondrial fission. Furthermore, we found that CED-9 does so by directly interacting with the dynamin-related GTPases FZO-1 Mfn and DRP-1 Drp1, which are required for mitochondrial fusion and fission, respectively. The goal of the proposed studies is to test the model that in healthy, non-apoptotic cells, CED-9 acts as a coupler of mitochondrial fusion and mitochondrial fission during cycles of fusion and fission. To that end, we will use a combination of cell biological, genetic and biochemical approaches. Results from the proposed studies will not only improve our understanding of the non-apoptotic functions of BCL2-like proteins but help to determine the physiological roles of mitochondrial dynamics.