Mechanisms of selection against cells with mitochondrial dysfunction during mammalian development

线粒体是细胞器(细胞的器官)，产生细胞运作所需的能量。线粒体功能障碍或功能障碍会导致从心力衰竭到癌症等一系列疾病。在胚胎发育过程中，线粒体功能障碍会导致线粒体疾病，从而导致生长不良、肌肉无力、神经疾病和心脏、肝脏或肾脏疾病等症状。这些疾病影响每4,300人中的1人。然而，尽管了解人类线粒体功能障碍的重要性，我们仍然对这些疾病是如何产生的知之甚少。人们已经描述了许多不同的机制来移除胚胎中功能失调的线粒体，但这些机制如何在分子水平上发挥作用也鲜为人知。我们最近发现，在小鼠早期胚胎中，具有不同线粒体活性的细胞之间的竞争作为一种质量控制机制，消除了具有功能障碍的线粒体的细胞。在这项提案中，我们的目标是研究这种质量控制，以确定在哺乳动物发育过程中为线粒体功能障碍的细胞选择的分子途径。为此，我们将做三件事：首先，我们将分析在早期胚胎发育过程中线粒体功能障碍的细胞的哪些最重要的特性。为了实现这一目标，我们将使用小鼠胚胎和干细胞作为我们的模型系统，因为它们的发育概括了人类发育的许多特征。利用这些系统，我们将在细胞和胚胎中诱导线粒体功能障碍，并分析在这些细胞中激活了哪些类型的应激途径。一旦确定了由线粒体功能障碍诱导的特定应激途径，这些途径将被操纵，以测试它们的激活是否会复制线粒体功能障碍的不利影响。我们还将测试抑制这些压力是否可以阻止线粒体功能障碍的细胞的消除。我们要研究线粒体功能障碍的细胞在发育过程中会发生什么，我们将做的第二件事是分析哪些信号通路被受损的线粒体激活或抑制，并导致这些细胞的死亡。我们之前的工作已经发现，mTOR途径是细胞生长的关键调节因子，对于消除胚胎发育过程中的异常细胞非常重要。在这里，我们将通过询问mTOR途径的抑制如何有助于消除线粒体功能障碍的细胞来测试mTOR途径对于消除线粒体功能障碍的细胞的重要性。我们将做的第三件事是研究线粒体功能障碍的细胞在胚胎发育期间的命运，是分析如果这些细胞没有被上述竞争淘汰会发生什么。为此，我们将研究如何防止它们的消除影响早期胚胎不同组织的形成和代谢性能。同时，我们预计我们的研究将提供一个全面的概述，在胚胎发育期间有线粒体功能障碍的细胞的命运，以及通常导致这些细胞消除的途径。

Mitochondria are organelles (organs of the cell) that produce the energy required for the cell to function. The dysfunction or malfunction of mitochondria contribute to a wide range of diseases, from heart failure to cancer. During the development of the embryo, mitochondrial dysfunction causes mitochondrial diseases, that lead to poor growth, muscle weakness, neurological disorders and heart, liver or kidney disease amongst other symptoms. These disorders affect ~1 in 4,300 of the population. However, in spite of the importance of understanding mitochondrial dysfunction in humans, we still know little about how these disorders arise. A number of different mechanisms have been described that remove dysfunctional mitochondria in the embryo, but how these mechanisms act at the molecular level is also poorly understood. We have recently found that in the early mouse embryo the competition between cells with different mitochondrial activity acts as a quality control mechanism that eliminates cells with dysfunctional mitochondria. In this proposal we aim to study this quality control to identify the molecular pathways that select for cells with mitochondrial dysfunction during mammalian development. For this we will do three things:First, we will analyse which are the most important properties of cells with mitochondrial dysfunction during early embryo development. To achieve this, we will use the mouse embryo and stem cells as our model systems as their development recapitulates many features of human development. Using these systems we will induce mitochondrial dysfunction in cells and embryos and analyse what types of stress pathways are activated in these cells. Once the specific stress pathways that are induced by mitochondrial dysfunction are identified, these will manipulated to test if their activation reproduces the adverse effects of mitochondrial dysfunction. We will also test if inhibiting these stresses prevents the elimination of cells with mitochondrial dysfunction.The second thing that we will do to study what happens to cells with mitochondrial dysfunction during development is to analyse what signalling pathways are activated or repressed by damaged mitochondria and cause the death of these cells. Our previous work has identified the mTOR pathway, that is a key regulator of cell growth, as important for the elimination of abnormal cells during embryonic development. Here we will test the importance of the mTOR pathway for the elimination of cells with mitochondrial dysfunction by asking how its repression contributes to the elimination of cells with dysfunctional mitochondria.The third thing that we will do to study the fate of cells with dysfunctional mitochondria during embryogenesis is to analyse what happens to these cells if they are not eliminated by the competition described above. For this we will study how preventing their elimination affects the formation and metabolic performance of the different tissues of the early embryo.Together we anticipate that our studies will provide a comprehensive overview of the fate of cells with mitochondrial dysfunction during embryonic development and what pathways normally lead to the elimination of these cells.