MTFR2 in the control of mitochondrial dynamics and mitotic spindle integrity

项目总结 PI的实验室对异常有丝分裂是如何发生的以及它与癌细胞异质性的关系有着长期的兴趣。 我们之前的工作有助于目前对主轴组件检查点的理解，这是一个关键的 防止染色体不稳定的机制。许多其他因素也有助于控制染色体的保真度。 种族隔离。与这一提议最相关的是，有一些证据表明，线粒体的缺陷 动力学影响染色体分离，但仍缺乏详细的机制分析。线粒体分裂 调控子2(MTFR2，也称为FAM54A或DUFD1)是作为一个与KEY共转录的基因被检索到的 着丝粒/着丝粒成分在我们之前的研究中。这种联系表明MTFR2在 有丝分裂。然而，尽管名为MTFR2，但人们对MTFR2的生物学功能或调控知之甚少 在细胞水平上。我们的初步结果表明，MTFR2调节DRP1-1中的线粒体分裂。 依赖的态度。我们还发现，许多发生癌症的MTFR2变体在触发过程中存在缺陷 线粒体分裂。此外，可诱导的Cas9/CRISPR有条件地敲除MTFR2导致了 有丝分裂过程中的星形微管和多极纺锤体，导致染色体错误分离。建房 根据初步数据，我们假设mtfr2在协调线粒体方面起着关键作用。 有丝分裂过程中的分裂和染色体分离。这个项目的总体目标是进一步澄清 线粒体分裂和有丝分裂过程中MTFR2的活性，以及细胞周期机制 调节MTFR2的活性。目的1实验将阐明MTFR2的活性和作用机制。 线粒体分裂，特别是在有丝分裂期间，目标2的实验将研究如何损害MTFR2 有丝分裂的活性会影响染色体的错误分离和紫杉醇的抗性。这项提议预计将扩大 我们对线粒体分裂机制的理解，并提供了关于线粒体和 染色体遗传在有丝分裂期间得到协调，以确保健康的子细胞。协作 该项目将在托莱多大学提供一个宝贵的平台来支持和培训本科生 以获得实际的研究体验。

PROJECT SUMMARY The PI’s lab has long-term interest in how aberrant mitosis occurs and its relationship to cancer cell heterogeneity. Our prior work has contributed to current understanding about the spindle assembly checkpoint, a critical mechanism to prevent chromosomal instability. Many other factors also help control the fidelity of chromosome segregation. Most relevant to this proposal, there was some evidence indicating that defects in mitochondrial dynamics affect chromosome segregation, but detailed mechanistic analysis is still lacking. Mitochondrial Fission Regulator 2 (MTFR2, also named FAM54A or DUFD1) was retrieved as a gene co-transcribed with key centromere/kinetochore components in our previous study. Such association suggested a role of MTFR2 in mitosis. However, despite the name, not much is known about the biological function or regulation of MTFR2 at the cellular level. Our preliminary results demonstrated that MTFR2 regulates mitochondrial fission in a Drp1- dependent manner. We also found that many cancer-occurring MTFR2 variants are defective in triggering mitochondrial fission. In addition, conditional MTFR2 knockout by inducible Cas9/CRISPR resulted in loss of astral microtubules and multipolar spindles during mitosis, resulting in chromosome missegregation. Building upon the preliminary data, we hypothesize that MTFR2 plays critical roles in coordinating mitochondrial fission and chromosome segregation during mitosis. The overall objective of this project is to further clarify the MTFR2 activity in mitochondrial fission and mitotic progression, and conversely how cell cycle machinery regulates MTFR2 activity. Aim 1 experiments will elucidate the activities and mechanisms of MTFR2 in mitochondrial fission especially during mitosis, and Aim 2 experiments will investigate how compromising MTFR2 activity in mitosis affects chromosome missegregation and taxol resistance. The proposal is expected to expand our understanding about mitochondrial fission mechanisms, and provide insights how mitochondria and chromosome inheritance are coordinated during mitosis to ensure healthy daughter cells. The collaborative project will provide an invaluable platform at the University of Toledo to support and train undergraduate students for hands-on research experience.