Mitochondrial Disorders: Nuclear Gene Mutations

In addition to mutations of mitochondrial deoxyribonucleic acid (mtDNA), many mitochondrial syndromes are due to abnormalities in nuclear genes related to oxidative phosphorylation (OXPHOS). Nuclear genes encode hundreds of proteins directly involved in mitochondrial OXPHOS or linked to other metabolic pathways that are related to OXPHOS, such as the tricarboxylic acid (TCA) cycle and fatty acids b-oxidation, cell signalling and apoptosis. Although the identification of mutations in mtDNA has become relatively easy because its small size and the nearly complete elucidation of its sequence polymorphisms, the analysis of nuclear disease genes is still a formidable challenge. However, with the recent improvement in technology throughput and bio-computational power, this scenario is rapidly changing. The discovery of several OXPHOS-related human genes and the identification of mutations responsible for different clinical syndromes indicate that the majority, but not all, of the inherited mitochondrial disorders are due to nuclear genes encoding proteins targeted to mitochondria.