MTFR2 in the control of mitochondrial dynamics and mitotic spindle integrity

项目摘要 PI的实验室长期关注异常有丝分裂如何发生及其与癌细胞异质性的关系。 我们先前的工作有助于目前对纺锤体组装检查点的理解，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 种族隔离与这一建议最相关的是，有一些证据表明，线粒体缺陷， 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 调节子2（MTFR 2，也称为FAM 54 A或DUFD 1）作为与关键转录因子共转录的基因被检索。 着丝粒/动粒组分在我们以前的研究中。这种关联表明MTFR 2在以下方面的作用： 分裂。然而，尽管有这个名字，对MTFR 2的生物学功能或调节知之甚少， 细胞水平。我们的初步结果表明，MTFR 2调节线粒体分裂在一个Drp 1- 依赖的方式。我们还发现，许多发生癌症的MTFR 2变异体在触发肿瘤细胞凋亡方面存在缺陷。 线粒体分裂此外，通过诱导型Cas9/CRISPR的条件性MTFR 2敲除导致MTFR 2的缺失。 在有丝分裂过程中，由于星形微管和多极纺锤体，导致染色体的错误分离。建筑 根据初步的数据，我们假设MTFR 2在协调线粒体内 分裂和染色体分离。本项目的总体目标是进一步澄清 线粒体分裂和有丝分裂进程中MTFR 2活性，以及相反地细胞周期机制 调节MTFR 2活性。目的1实验将阐明MTFR 2的活性和机制， 线粒体分裂，特别是在有丝分裂期间，Aim 2实验将研究如何损害MTFR 2 有丝分裂的活性影响染色体错误分离和紫杉醇抗性。预计该提案将扩大 我们对线粒体裂变机制的理解，并提供线粒体和 染色体遗传在有丝分裂期间协调以确保健康的子细胞。合作 该项目将为托莱多大学提供一个宝贵的平台，以支持和培训本科生 来获得实际的研究经验

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.