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Mitochondria are small, membrane-bound organelles. They provide the adenosine triphosphate (ATP) that is required for all active cellular processes. ATP is produced by a cluster of five enzyme complexes that form the mitochondrial respiratory chain on the inner mitochondrial membrane. Each complex is composed of multiple subunits. The majority of the >70 respiratory chain subunits are the products of nuclear genes, but 13 are synthesized within mitochondria from multiple small circles of DNA that are present within the mitochondrial matrix—the mitochondrial genome (mtDNA). MtDNA is a relatively small molecule of only 16,569 base pairs, and therefore particularly amenable to genetic analysis. The complete sequence of human mtDNA was published in 1981,1 and the first pathogenic mtDNA mutations were identified 7 years later.2,3⇓ Most patients with chronic progressive external ophthalmoplegia (CPEO) and the Kearns-Sayre syndrome were found to have a single deletion of mtDNA in skeletal muscle,4 and point mutations were found in patients with other well-defined clinical syndromes such as Leber hereditary optic neuropathy (LHON)2 and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).5 The 1990s saw a profusion of articles published describing new mutations and novel phenotypes, but mitochondria and mtDNA do not exist in isolation, and toward the end of the decade clinical scientists started to look beyond the magic circle of mtDNA6 for further insights into mitochondrial biology.
MtDNA is almost exclusively transmitted down the maternal line, and as a result, mtDNA mutations cause maternally inherited diseases or isolated cases. However, in 1990, Zeviani et al described large families where the affected individuals had CPEO, but in these pedigrees there was clear evidence of autosomal dominant transmission (adPEO), and the skeletal muscle contained a wide range of different mtDNA deletions.7 The nuclear gene defects have been identified in …
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