Mitochondrial Disorders: Nuclear Gene Mutations

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Abstract 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 β‐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. Key Concepts: Mitochondria are the principal intracellular source of energy through the production of ATP by oxidative phosphorylation (OXPHOS). Mitochondria contain their own genome, a small, circular double‐stranded DNA (mtDNA). mtDNA contains 13 genes encoding subunits of the respiratory chain complexes and 24 genes encoding 2 ribosomal and 22 transfer RNAs, which are necessary to carry out intramitochondrial translation. Mitochondria depend on the nucleus for the supply of all of the other OXPHOS proteins as well as the factors necessary for replication, repair, transcription, translation, maintenance of mtDNA and for the biogenesis, shaping, fusion and fission of the organelles. Mitochondrial‐inherited diseases may present with a vast range of symptoms, severity, age of onset and outcome. Because of its dual genetic control, OXPHOS disorders can be due to mutations in mtDNA or nuclear DNA genes. Recent epidemiological studies show that mitochondrial disorders have a minimal prevalence of 1:5 000.