Investigating the biology of mitochondrial DNA disease transmission to enable affected families to have healthy children

线粒体对于产生生命所必需的能量至关重要。尽管线粒体很重要，但每400人中就有一人在线粒体DNA(MtDNA)上存在母系遗传突变，线粒体DNA是一些重要线粒体成分的蓝图。虽然大多数传递这些mtDNA突变的女性的孩子只会出现轻微的症状，比如老年时耳聋，但她们可能会受到严重影响。线粒体DNA突变会导致一系列疾病，包括耳聋、失明、糖尿病、技能丧失、心脏和肝脏衰竭，目前还没有治愈的方法。一些中心正在开发用健康线粒体取代受损线粒体的技术。在这项技术(所谓的“核移植”)中，有可能生下受影响孩子的夫妇的胚胎是在体外产生的。在早期阶段，包含除线粒体以外的所有遗传物质的核被从卵子(卵母细胞)中移除，并被放入健康的卵子或胚胎中，在那里核已经被去除。由此产生的胚胎可以放入母亲的子宫中，在那里它变成一个婴儿。虽然在猴子和老鼠身上的实验表明，这样的婴儿可能是健康的，但它们还没有在人类身上做过。替换细胞核并不能阻止婴儿的发育，但它会造成损害，这可能需要细胞的彻底重组。由于胚胎在这个阶段已经高度组织化，这种操纵可能会在以后的生命中产生后果。我们的目标是使用不那么激进的技术来改善这些疾病的基因管理。目前的方法由于我们对基本机制的理解不足而受到阻碍。线粒体DNA只能通过雌性系遗传。携带mtDNA突变的妇女将这些基因遗传给她的孩子，并让孩子出现症状的可能性，是非常难以预测的。这是因为在同一个体中发现了突变和正常的线粒体DNA。疾病的严重程度取决于体内特定细胞中异常线粒体DNA的比例。然而，这一比例在一代又一代人中有所不同，无法预测。线粒体遗传异常数量的变化是由发生在女性生殖系中的线粒体瓶颈事件引起的。我们计划研究的生物过程决定了医学干预的有效性。这些治疗包括植入前遗传诊断，即卵子在试管中受精，进行测试，以及选择低风险胚胎开始怀孕。我们将研究现有的细胞机制，这些机制可能能够消除不健康的线粒体，而不需要如此激烈的干预。从长远来看，我们可能会确定核移植是否会损害维持健康线粒体的细胞过程。我们还可以开发不那么激进的程序，以产生具有健康线粒体的胚胎，而不会对细胞造成损害。我们的最终目标是使受影响的家庭有更健康的孩子。

Mitochondria are critically important for generating the energy that is essential for life. Despite the importance of mitochondria, one in 400 people has a maternally-inherited mutation in mitochondrial DNA (mtDNA), the blue print for some vital mitochondrial components. While most women transmitting these mtDNA mutations will have children who only develop mild symptoms, such as deafness in old age, they may be severely affected. The mtDNA mutations can cause a range of illnesses, including deafness, blindness, diabetes, loss of skills, heart and liver failure and there are no curative treatments. Some centres are developing techniques for replacing disabled mitochondria with healthy ones. In this technique (so-called "nuclear transfer"), embryos of the couple at risk of having an affected child are generated in vitro. At an early stage, the nucleus that contains all of the genetic material apart from the mitochondria is removed from the egg (oocyte) and placed into a healthy egg or embryo from which the nucleus has been removed. The resulting embryo can then be placed in the mother's womb where it becomes a baby. While experiments on monkeys and mice suggest that such babies will probably be healthy, they have not been done in humans. Replacing the nucleus does not prevent development into a baby, but it causes damage that probably requires radical re-organisation of the cell. Because the embryo is already highly organised at this stage, such manipulations could have consequences later in life.We aim to improve the genetic management of these diseases using less radical techniques. Current approaches are hampered by our poor understanding of the underlying mechanisms. MtDNA is inherited via the female line only. The chances that a woman carrying mtDNA mutations will pass them on to her child, and that child develops symptoms, are exceptionally difficult to predict. This is because both mutant and normal mtDNA are found in the same individual. The severity of the disease depends on the proportion of abnormal mtDNAs in particular cells of the body. However, this proportion varies from one generation to the next and cannot be predicted. The variability in the number of abnormal mtDNAs inherited is caused by an event known as the mitochondrial bottleneck which takes place in the female germline.The biological processes that we plan to study determine the effectiveness of medical interventions. These treatments include preimplantation genetic diagnosis where eggs are fertilized in a test tube, tested, and low risk embryos selected to start a pregnancy. We will investigate existing cellular mechanisms that might be able to eliminate the unhealthy mitochondria, without such drastic interventions. In the long term we may determine whether nuclear transfer damages the cellular processes for maintaining healthy mitochondria. We may also develop less radical procedures, to generate embryos that have healthy mitochondria, without causing damage to the cell. Our ultimate aim is to enable affected families to have healthier children.