"Rheostatic" regulation of mitchondrial volume density: evaluating the relative contributions of synthetic and degradative pathways to total organelle content.

线粒体体积密度的“变态”调节：评估合成和降解途径对总细胞器含量的相对贡献。

• 批准号: 386642-2010
• 负责人: Leary, Scot
• 金额: $ 2.4万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=463885
• 关键词: Rheostatic; regulation; mitchondrial; volume; density

Mitochondria are organelles that have numerous functions crucial to cellular homeostasis. To fulfill these varied functions, mitochondria occupy a fixed percentage of the total cell volume, a parameter known as mitochondrial content. While ~2-20 fold variations in mitochondrial content are observed across the tissues of higher eukaryotes, the developmental program that establishes these "set points" is unknown. Equally unclear is what limits the adaptive responses of the organelle in select tissues upon exposure to a given physiological stimulus. My NSERC Discovery program will address these two fundamental biological problems by testing the following hypothesis; inter-tissue differences in both total mitochondrial content and its adaptive potential are explained by the differential regulation of flux through pathways that synthesize and degrade the organelle. An integrative, multifaceted approach will be used to quantify total mitochondrial content in different tissues of C57BL/6 mice, and measure the relative contributions of organelle biogenesis and turnover in regulating these "set points", both under basal conditions and during physiological transitions. Mechanisms that regulate the activities of relevant synthetic and degradative pathways will also be investigated, first in situ in primary cultures and then in vivo in the whole animal. Initially, these studies will be focused on the their involvement in regulating mitochondrial content in the liver; however, over the long-term, they will be expanded to include other tissues of C57BL/6 mice, as well as those of transgenic mice with isolated defects in organelle biogenesis and turnover, so that the inter-tissue nature of the hypothesis can be fully addressed. Numerous training opportunities for highly qualified personnel exist within the outlined program, whose advancement will make fundamental contributions to our understanding of biology by identifying the molecular genetic mechanisms that regulate mitochondrial content and determining whether they are conserved across tissues.

线粒体是细胞器，具有许多对细胞内稳态至关重要的功能。为了实现这些不同的功能，线粒体在总细胞体积中占据固定的百分比，这一参数被称为线粒体含量。虽然在高等真核生物的组织中观察到线粒体含量的~2-20倍的变化，但建立这些“设定点”的发育程序尚不清楚。同样不清楚的是，是什么限制了选定组织中细胞器在暴露于给定生理刺激时的适应性反应。我的NSERC Discovery计划将通过测试以下假设来解决这两个基本的生物学问题：组织间线粒体总含量及其适应潜力的差异是通过合成和降解细胞器的途径对通量的不同调节来解释的。将使用一种综合的、多方面的方法来量化C57BL/6小鼠不同组织中的线粒体总含量，并测量细胞器生物发生和周转在调节这些“设定点”中的相对贡献，无论是在基础条件下还是在生理转变期间。调节相关合成和降解途径活动的机制也将被研究，首先在原代培养中原位，然后在整个动物体内。最初，这些研究将侧重于它们参与调节肝脏线粒体含量的能力；但是，从长远来看，它们将扩大到包括C57BL/6小鼠的其他组织，以及细胞器生物发生和周转方面存在孤立缺陷的转基因小鼠的组织，以便能够充分解决该假说的组织间性质。在概述的计划中，存在着许多高素质人员的培训机会，这些机会的进步将通过识别调节线粒体内容的分子遗传机制并确定它们是否在组织中保守，从而为我们理解生物学做出根本性贡献。