CAREER: Defining novel pathways for mitochondrial dynamics in an early-diverging eukaryote

职业：定义早期分化真核生物线粒体动力学的新途径

• 批准号: 1651517
• 负责人: Megan Povelones
• 金额: $ 92.29万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1651517&HistoricalAwards=false
• 关键词: CAREER; Defining; novel; pathways; mitochondrial

In this project, the investigators will engage high school, undergraduate, and graduate students in cutting-edge cell biology research to discover how compartments within cells change shape in response to nutrient availability. Mitochondria are energy-generating compartments present in large numbers in complex cells. Mitochondria have a characteristic shape in different cell types, which is closely correlated to function. The shape of mitochondria is also highly dynamic, and can readily shift to adapt to different energy requirements. To discover shared mechanisms for establishment and maintenance of mitochondrial shape, the researchers will use model organisms from a group of single-celled parasites called the kinetoplastids. Kinetoplastids are unusual in that each cell contains only a single mitochondrion that undergoes dramatic changes in structure and function as the parasites alternate between insect and mammalian hosts. This arrangement greatly facilitates the analysis of changes in mitochondrial structure, and will reveal shared mechanisms by which cells control the number and distribution of their mitochondria. Due to their evolutionary position, kinetoplastids possess a basal set of mitochondrial shape proteins, the investigation of which will provide insight into how these processes work in a wide variety of cell types. To allow for better understanding of these complex structures, engineering students will create mitochondrial models using a 3-D printer. This interdisciplinary effort will illustrate the connections between engineering and biology, and will demonstrate how this technology may be applied for enhanced understanding and communication of fundamental questions in cell biology.Kinetoplastid parasites such as Crithidia fasciculata and Trypanosoma brucei have long been important models for basic cellular processes. Kinetoplastid mitochondria in particular have unusual features, including the fact that there is only one mitochondrion per cell. This necessitates a thus far unknown mechanism for regulation of mitochondrial biogenesis and division within the cell cycle. In addition, the shape and function of the mitochondrion are dramatically and reversibly altered in different life cycle stages of the parasite. In other organisms, mitochondrial shape is established and maintained by membrane fusion and fission events, collectively called mitochondrial dynamics. While much of the machinery for mitochondrial dynamics has been described in yeast and humans, how these processes are regulated is not well understood, and not all mitochondrial dynamics proteins are conserved. The investigators will use a variety of cellular and molecular biology techniques to identify the mechanisms controlling mitochondrial shape in kinetoplastids, providing important insight into how these processes evolved and their function in other organisms.

在这个项目中，研究人员将与高中，本科生和研究生一起参与尖端的细胞生物学研究，以发现细胞内部的隔室如何响应养分可用性而改变形状。线粒体是在复杂细胞中大量产生的能量隔室。线粒体在不同的细胞类型中具有特征形状，与功能密切相关。线粒体的形状也具有高度动态性，并且可以轻松地转移以适应不同的能量需求。为了发现用于建立和维护线粒体形状的共同机制，研究人员将使用一组称为动质塑料的单细胞寄生虫的模型生物。动力质体是不寻常的，因为每个细胞只包含一个线粒体，该线粒体在结构和功能上随着昆虫和哺乳动物宿主之间的寄生虫的交替而发生急剧变化。这种布置极大地促进了线粒体结构变化的分析，并将揭示细胞控制线粒体的数量和分布的共同机制。由于它们的进化位置，动力质体具有一组基础线粒体形状蛋白，其研究将提供有关这些过程如何在各种细胞类型中起作用的洞察力。为了更好地了解这些复杂的结构，工程专业的学生将使用3D打印机创建线粒体模型。这项跨学科的工作将说明工程与生物学之间的联系，并将证明如何将该技术应用于细胞生物学中的基本问题。金属质体寄生虫fasciculata和Brucei等Crithidia fasciculata和Brucei等长期以来一直是基本细胞过程的重要模型。动力质体线粒体特别具有异常特征，包括每个细胞只有一个线粒体。迄今为止，这需要一种未知的机制来调节细胞周期内线粒体生物发生和分裂。另外，线粒体的形状和功能在寄生虫的不同生命周期阶段发生了巨大和可逆的改变。在其他生物体中，线粒体形状是通过膜融合和裂变事件（共同称为线粒体动力学）确定和维护的。尽管已经在酵母和人类中描述了线粒体动力学的许多机械，但如何对这些过程进行调节，但并非所有线粒体动力学蛋白都保存。研究人员将使用各种细胞和分子生物学技术来确定控制线粒体形状的机制，从而为这些过程如何演变及其在其他生物体中的功能提供了重要的见解。

项目成果

Dramatic changes in gene expression in different forms of Crithidia fasciculata reveal potential mechanisms for insect-specific adhesion in kinetoplastid parasites

不同形式的束状短膜虫基因表达的巨大变化揭示了动质体寄生虫中昆虫特异性粘附的潜在机制

• DOI: 10.1371/journal.pntd.0007570
• 发表时间: 2019
• 期刊: PLOS Neglected Tropical Diseases
• 影响因子: 3.8
• 作者: Filosa, John N.;Berry, Corbett T.;Ruthel, Gordon;Beverley, Stephen M.;Warren, Wesley C.;Tomlinson, Chad;Myler, Peter J.;Dudkin, Elizabeth A.;Povelones, Megan L.;Povelones, Michael
• 通讯作者: Povelones, Michael

2,3-Diphenyl-2,3-dihydro-4H-1,3-thiaza-4-one heterocycles inhibit growth and block completion of cytokinesis in kinetoplastid parasites

• DOI: 10.1016/j.molbiopara.2021.111396
• 发表时间: 2021-07-26
• 期刊: MOLECULAR AND BIOCHEMICAL PARASITOLOGY
• 影响因子: 1.5
• 作者: Malfara, Madeline F.;Silverberg, Lee J.;Povelones, Megan L.
• 通讯作者: Povelones, Megan L.