Mechanisms of selection against cells with mitochondrial dysfunction during mammalian development

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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.