Mitochondrial architecture as a key determinant of cell function

线粒体结构是细胞功能的关键决定因素

• 批准号: RGPIN-2019-07197
• 负责人: Germain, Marc
• 金额: $ 3.64万
• 依托单位: Université du Québec à Trois-Rivières
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745047
• 关键词: Mitochondrial; architecture; key; determinant; cell

Mitochondria are a central metabolic hub. As a consequence, they play a crucial role in cellular functions ranging from maintenance of stem cells to cell growth and differentiation. Mitochondrial activity thus needs to be tightly controlled through the modulation of their energetic output and modification of their structure. This occurs through changes in mitochondrial length, reorganisation of mitochondrial cristae, the folds of the mitochondrial inner membrane, and interaction with the endoplasmic reticulum (ER). Mitochondria form interconnected networks that are constantly changing through mitochondrial fusion and fission. For example, amino acid starvation causes an increase in mitochondrial length which is required to maintain the levels of cellular energy and cell survival. To follow up on these studies, we recently developed a novel algorithm to measure mitochondrial length and connectivity (mitochondrial branch sites). Using this algorithm, we showed that increased in mitochondrial connectivity is a key feature of nutrient starvation, contrary to elongation which is restricted to amino acid starvation. This supports the novel idea that mitochondrial length and connectivity are two independent determinants of mitochondrial function. We thus hypothesize that mitochondrial network connectivity is a key determinant of mitochondrial function required for cellular adaptation to changes in nutrient availability. We will: Aim 1. Define the link between mitochondrial connectivity and cristae structure. Mitochondrial structure and function are linked but the underlying mechanisms poorly understood. We will thus determine how changes in mitochondrial connectivity affect cristae structure and mitochondrial activity in the context of changing nutrient availability. Aim 2. Define the role of the cytoskeleton in regulating mitochondrial connectivity and activity. We will determine the role of both microtubules and the actin cytoskeleton in the regulation of mitochondrial connectivity and cristae structure. Aim 3. Define the role of ER-mitochondria contact sites in the coordination of mitochondrial connectivity and activity. ER-mitochondria contact sites control mitochondria fission and transfer of metabolites between the two organelles. We will thus determine the effect of nutrient starvation on ER-mitochondria contact sites. We will then define role of ER-mitochondria contact sites in the regulation of mitochondrial connectivity. Mitochondrial dynamics control cell fate by regulating key cellular functions. The mechanisms controlling mitochondrial structure and activity in the context of changing nutrient conditions, and their consequences on cell fate, are only partially understood. These experiments will thus provide much needed insights into the processes regulating mitochondrial architecture and activity.

线粒体是中心代谢中心。因此，它们在细胞功能中发挥着关键作用，从维持干细胞到细胞生长和分化。因此，需要通过调节线粒体的能量输出和改变其结构来严格控制线粒体的活动。这是通过改变线粒体的长度、线粒体脊的重组、线粒体内膜的折叠以及与内质网(ER)的相互作用来实现的。线粒体形成相互连接的网络，通过线粒体融合和裂变不断变化。例如，氨基酸饥饿导致线粒体长度增加，这是维持细胞能量水平和细胞生存所必需的。为了跟进这些研究，我们最近开发了一种新的算法来测量线粒体长度和连接性(线粒体分支位置)。使用这个算法，我们证明了线粒体连接性的增加是营养饥饿的一个关键特征，而不是伸长，后者仅限于氨基酸饥饿。这支持了线粒体长度和连接性是线粒体功能的两个独立决定因素的新观点。因此，我们假设线粒体网络连通性是细胞适应营养物质供应变化所需的线粒体功能的关键决定因素。我们将：目标1.定义线粒体连接性和冠状突起结构之间的联系。线粒体的结构和功能是联系在一起的，但其潜在的机制却鲜为人知。因此，我们将确定在营养供应变化的背景下，线粒体连接性的变化如何影响冠状结构和线粒体的活动。目的2.明确细胞骨架在调节线粒体连通性和活性中的作用。我们将确定微管和肌动蛋白细胞骨架在调节线粒体连通性和嵴结构中的作用。目的3.明确内质网-线粒体接触位点在协调线粒体连通性和活性中的作用。内质网-线粒体接触部位控制着线粒体的分裂和代谢产物在两个细胞器之间的转移。因此，我们将确定营养饥饿对内质网-线粒体接触部位的影响。然后，我们将确定内质网-线粒体接触位点在线粒体连通性调节中的作用。线粒体动力学通过调节细胞的关键功能来控制细胞的命运。在营养条件变化的背景下控制线粒体结构和活动的机制，以及它们对细胞命运的影响，目前还只有部分了解。因此，这些实验将为调控线粒体结构和活动的过程提供亟需的见解。