Mitochondrial DNA mutations disrupt the energy supply of cells in early human embryos, and this project will trace exactly how that happens. Mitochondrial diseases affect roughly 1 in 4,300 people, often damaging the nervous system, yet scientists do not understand how these mutations alter the earliest stages of human development. The researchers have already shown that in mouse embryos, cells with faulty mitochondria are actively eliminated. Using human embryonic stem cells carrying different mitochondrial mutations, they found that disease-linked mutations reduce oxygen consumption and disrupt how embryonic cell types form. This project will identify the specific metabolic and signalling pathways that go wrong, and then test how those defects affect the development of motor neurons—the cell type most vulnerable in mitochondrial disorders. If successful, this work will reveal the molecular mechanisms that allow harmful mitochondrial DNA to persist or be removed during early development. That knowledge could eventually lead to therapies that reduce the transmission of mitochondrial disease from mother to child, or that protect vulnerable tissues like the nervous system. For now, the research is fundamental science: it asks how energy metabolism shapes the earliest decisions an embryo makes about which cells become what.
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Mitochondria are cellular organelles that produce most of the energy of the cell. The dysfunction of mitochondria contributes to a wide range of diseases, from heart failure to cancer, and is a hallmark of ageing. Mitochondria, have their own DNA (mtDNA) that encodes key components of the bioenergetic and mitochondrial translation machinery. Mutations in the mtDNA causes mitochondrial diseases that affect ~1 in 4,300 of the population, and have variable phenotypes, with the most predominant involving the nervous system. How these mutations affect development of the embryo is poorly understood. During early mammalian development there are multiple mechanisms that reduce the mtDNA mutation load. These promote tissue fitness as well as reduce the contribution of mutant mtDNAs to the germline. In humans, these mechanisms include the bottleneck effect, that results in a reduction in mtDNA copy number and the asymmetric segregation of mutant and wild-type mtDNAs, and purifying selection against pathogenic mtDNA mutations. How these mechanisms act at the molecular and cellular level is still poorly understood. We have shown that in the early mouse embryo a novel form of purifying selection eliminates cells with dysfunctional mitochondria and mtDNA mutations. To model this elimination in humans we have generated human embryonic stem cell (hESC) lines carrying different types of mtDNA mutations. Importantly, we have found that those mutations associated with pathogenic phenotypes in humans, reduce oxygen consumption rates and disrupt the patterning of the embryonic lineages in stem cells models of early human embryogenesis. In this proposal we aim to determine how these mtDNA mutation cause these bioenergetic and patterning defects observed. For this we will do three things. First, we will characterise the impact of different types of mtDNA mutations on the metabolic and signalling pathways that regulate pluripotent stem cell fitness. Second, we will study how those metabolic and signalling pathways that are affected by mtDNA mutations cause aberrant embryonic patterning. Finally, given that the nervous system is frequently affected in mitochondrial disorders, we will differentiate our mutant mtDNA hESCs into motor neurons and study the phenotypes arising and their causes. Our work will provide an understanding of the impact of mtDNA mutations on early human development. We anticipate that this knowledge will help us in the to develop therapeutic targets for reducing the transmission of heteroplasmic mtDNA disease.
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