MTFR2 in the control of mitochondrial dynamics and mitotic spindle integrity

MTFR2 控制线粒体动力学和有丝分裂纺锤体完整性

• 批准号: 10796164
• 负责人: Song-Tao Liu
• 金额: $ 9.67万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796164
• 关键词: Affect; Biological Process; CRISPR/Cas technology; Cell Cycle; Centromere; Chromosomal Instability; Chromosome Segregation; Chromosomes; Data; Defect; Ensure; Genes; Genetic Transcription; Heterogeneity; Kinetochores; Knock-out; Malignant Neoplasms; Microtubules; Mitochondria; Mitosis; Mitotic; Mitotic spindle; Names; Paclitaxel; Play; Regulation; Resistance; Role; Training; Universities; Variant; Work; cancer cell; chromosome missegregation; daughter cell; experience; experimental study; hands on research; insight; interest; novel; prevent; undergraduate student

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.

项目摘要 PI的实验室对异常有丝分裂的发生及其与癌细胞异质性的关系具有长期兴趣。 我们先前的工作有助于当前对主轴组件检查站的理解，这是一个关键的 预防染色体不稳定性的机制。许多其他因素还有助于控制染色体的保真度 隔离。与该提案最相关，有一些证据表明线粒体缺陷 动态影响染色体分离，但仍缺乏详细的机械分析。线粒体裂变 调节器2（MTFR2，也称为FAM54A或DUFD1）作为与钥匙共转录的基因 在我们先前的研究中，Centromere/Kinetochore成分。这种关联表明MTFR2在 有丝分裂。然而，尽管有名字，但对MTFR2的生物功能或调节尚不了解 细胞水平。我们的初步结果表明，MTFR2调节DRP1-中的线粒体裂变 依赖方式。我们还发现，许多癌症发生的MTFR2变体在触发方面有缺陷 线粒体裂变。此外，诱导CAS9/CRISPR的有条件MTFR2敲除导致失去 星体微管和有丝分裂过程中的多极纺锤体，导致染色体错误分析。建筑 根据初步数据，我们假设MTFR2在协调线粒体中起关键作用 有丝分裂过程中的裂变和染色体分离。该项目的总体目标是进一步澄清 线粒体裂变和有丝分裂进展的MTFR2活性，相反 调节MTFR2活性。 AIM 1实验将阐明MTFR2的活动和机制 线粒体裂变特别是在有丝分裂过程中，AIM 2实验将研究MTFR2的损害 有丝分裂的活性会影响染色体的错误分析和紫杉醇耐药性。该提议有望扩大 我们对线粒体裂变机制的理解，并提供了线粒体和线粒体的见解 染色体遗传在有丝分裂期间协调，以确保健康的子细胞。协作 项目将在托莱多大学提供一个宝贵的平台，以支持和培训本科生 实践研究经验。