Molecular basis of mitochondrial Complex I deficiency, the most common energy generation disorder

人体内的每个细胞都需要氧气来燃烧燃料（即糖，脂肪和蛋白质），这些燃料在每个细胞内称为线粒体的小型发电厂中燃烧。在澳大利亚，每年约有50名新生儿患有遗传性线粒体能量生成障碍。最严重的疾病会导致婴儿死亡，而其他疾病则会在晚年引起一系列退行性疾病，特别是影响大脑、肌肉和心脏。在大多数情况下，我们没有有效的治疗方法。理解线粒体能量生成障碍的一个主要问题是遗传原因是令人难以置信的多样性。到目前为止，已经有20多个基因被证明会导致线粒体疾病，很可能还有100多个基因有待发现。除了导致这些和其他遗传疾病的常规基因外，线粒体还携带37个额外的基因，这些基因位于细胞的不同部分，远离人类基因组的其余部分，并且只从母亲那里遗传。该拨款重点关注最常见的能量产生障碍，即复杂I缺乏症。复合物I需要43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43个基因中的突变在大多数患者中不存在。我们相信，最常见的问题将出现在参与组装43个组件的基因中，而不是组件本身。我们将使用多种方法来确定致病基因在基因组中的位置，然后锁定致病基因的确切变化。识别这些基因将使我们能够改善未来对线粒体疾病的诊断和预防。了解基本的生物学也可以让我们开发新的治疗方法。最近的研究表明，较轻的线粒体问题也会导致一系列更常见的疾病，如糖尿病和帕金森病，因此任何新的治疗方法都可能具有广泛的应用。

Oxygen is needed by every cell in the body to burn fuels (ie sugar, fat and protein) in small power plants inside each cell called mitochondria. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause a range of degenerative diseases later in life, particularly affecting brain, muscle and heart. In most cases we do not have any effective treatments. A major problem in understanding mitochondrial energy generation disorders is that the genetic causes are incredibly diverse. So far more than 20 genes have been shown to cause mitochondrial disorders, and it is likely that over one hundred more genes remain to be discovered. In addition to the regular genes that cause these and other genetic disorders, mitochondria are unique in carrying 37 extra genes located in a different part of the cell away from the rest of the human genome, and inherited only from the mother. This grant focuses on the most common energy generation disorder, known as Complex I deficiency. Complex I requires 43 separate components to be assembled together in order to work properly, but mutations in the 43 genes encoding these components are not present in most patients. We believe that the most common problems will be in genes involved in assembling the 43 components rather than in the components themselves. 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. Understanding the basic biology may also allow us to develop new methods of treatment. Recent studies suggest that milder mitochondrial problems also contribute to a range of more common diseases such as diabetes and Parkinson disease, so any new treatments could potentially have wide application.