Genetic variation of mitochondrial complex I: its role in rare and common diseases

我们的身体在称为线粒体的微小细胞发电厂中将食物转化为能量。每年约有50名澳大利亚儿童遗传线粒体能量生成障碍。最严重的疾病会导致婴儿死亡，而其他疾病会导致晚年的退行性疾病，特别是影响大脑和肌肉。在大多数情况下，我们缺乏有效的治疗方法。线粒体疾病的遗传原因令人难以置信地多样化，已知的疾病基因超过70个。有些基因位于我们只从母亲那里继承的独特的线粒体DNA上。更多的基因等待着人们去发现。这笔赠款的重点是最常见的能量生成障碍，即复合体I缺乏症。Complex I需要将46个独立的组件组装在一起才能正常工作，但编码这些组件的46个基因的突变似乎只解释了大约一半患者的疾病。我们的目标是识别新的疾病基因，并确定一些患者是否存在两个不同基因的突变，这两个基因相互作用导致疾病，而不是单个基因。我们将使用许多方法来精确定位致病基因在基因组中的位置，然后定位导致疾病的基因的确切变化。识别这些基因将使我们能够改进未来对线粒体疾病的诊断和预防。我们还将在其中一个复杂的I基因被敲除的小鼠身上进行实验。这些小鼠将使我们能够更好地了解将基因变化与疾病联系起来的基本疾病机制。了解基础生物学可能会让我们开发新的治疗方法。小鼠模型还将有助于试验新的治疗方法，并研究较轻微的线粒体问题在糖尿病和帕金森病等常见疾病中的作用。任何新的治疗方法都可能有广泛的应用前景。

Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 46 separate components to be assembled together in order to work properly, but mutations in the 46 genes encoding these components only seem to explain disease in about half of all patients. Our aim is to identify new disease genes and to determine whether some patients have mutations in two different genes that interact to cause disease, rather than in a single gene. We will use a number of methods to pinpoint where in the genome the causative genes are located and then home in on the exact changes in the genes that cause disease. Identifying these genes will allow us to improve future diagnosis and prevention of mitochondrial disease. We will also generate mice in which one of the Complex I genes has been knocked out. These mice will allow us to better understand the basic disease mechanisms that link gene changes to disease. Understanding the basic biology may allow us to develop new methods of treatment. The mouse models will also be useful for trialling new treatments and for investigating the role of milder mitochondrial problems in common diseases such as diabetes and Parkinson disease. Any new treatments could potentially have wide application.