The most relevant contribution to the elucidation of the molecular basis of mitochondrial disorders has come from the discovery of an impressive and ever expanding number of mutations of mitochondrial DNA. However, known mutations of mtDNA only account for a fraction of all the mitochondrial disorders in both infants and adults. A number of recent clinical and molecular observations indicate that many syndromes are caused by abnormalities in nuclear genes related to oxidative phosphorylation. Nuclear genes encode hundreds of proteins involved in mitochondrial biogenesis and oxidative phosphorylation. Nevertheless, the identification of the nuclear genes responsible for oxidative phosphorylation-related disorders has proceeded at a much slower pace, compared with the discovery and characterization of mtDNA mutations. The reasons for such a gap are numerous, including the rarity of the syndromes, their genetic heterogeneity, and our ignorance of this nuclear gene repertoire in humans. This scenario is rapidly changing, thanks to the discovery of several oxidative phosphorylation-related human genes, and to the identification in some of them of mutations responsible for different clinical syndromes. In addition, animal models have recently been generated, which will offer the opportunity to understand better the pathogenesis of specific oxidative phosphorylation defects, and to test in a rational and controlled fashion therapeutic strategies for the treatment of these disorders.
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