Mitochondrial architecture as a key determinant of cell function

线粒体是一个中心代谢枢纽。因此，它们在从维持干细胞到细胞生长和分化的细胞功能中起着至关重要的作用。因此，线粒体的活动需要通过调节其能量输出和修改其结构来严格控制。这通过线粒体长度的变化、线粒体嵴的重组、线粒体内膜的折叠以及与内质网（ER）的相互作用而发生。线粒体形成相互连接的网络，通过线粒体融合和分裂不断变化。例如，氨基酸饥饿导致线粒体长度增加，这是维持细胞能量和细胞存活水平所必需的。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（线粒体分支位点）。使用该算法，我们发现线粒体连接性的增加是营养饥饿的一个关键特征，与仅限于氨基酸饥饿的延伸相反。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接是细胞适应营养物质可用性变化所需的线粒体功能的关键决定因素。我们将：目标1。定义线粒体连接和嵴结构之间的联系。线粒体的结构和功能是相互联系的，但其潜在的机制却知之甚少。因此，我们将确定线粒体连接的变化如何影响嵴结构和线粒体活性的背景下，不断变化的营养物质的可用性。目标二。定义细胞骨架在调节线粒体连接和活性中的作用。我们将确定微管和肌动蛋白细胞骨架在调节线粒体连接和嵴结构中的作用。 目标3。确定ER-线粒体接触位点在线粒体连接和活性协调中的作用。ER-线粒体接触位点控制线粒体分裂和两个细胞器之间的代谢物转移。因此，我们将确定营养饥饿对ER-线粒体接触位点的影响。然后，我们将定义ER-线粒体接触位点在线粒体连接调节中的作用。线粒体动力学通过调节关键细胞功能来控制细胞命运。在不断变化的营养条件下，控制线粒体结构和活性的机制及其对细胞命运的影响，只有部分了解。因此，这些实验将为调节线粒体结构和活性的过程提供急需的见解。

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.