Nuclear genetic defects of oxidative phosphorylation.

ATP generated by oxidative phosphorylation is necessary for the normal function of most cells in the body. Partial deficiencies in this system are an important cause of a large and diverse group of multisystem disorders. As both the nuclear and mitochondrial genomes encode structural components of the enzyme complexes of the oxidative phosphorylation system, the disorders can be transmitted either in a Mendelian fashion or maternally, or can occur as sporadic cases. Over the last 12 years more than 100 mutations have been uncovered in mtDNA, mostly associated with disease in the adult population. Recently, much attention has turned to the investigation of the nuclear oxidative phosphorylation gene defects. The majority of these are inherited as autosomal recessive traits, producing severe, and usually fatal disease in infants. Adult-onset Mendelian oxidative phosphorylation diseases, which can be inherited as autosomal recessive or dominant traits, have a milder phenotype, and most are associated with multiple mtDNA deletions. Approximately 20 different nuclear gene defects have now been identified in genes coding for structural components of the complexes, assembly/maintenance factors and factors necessary for the maintenance of mtDNA integrity. Some clear genotype-phenotype associations have emerged, and there is an unexpected link between some structural gene mutations and rare cancers, implicating mitochondria as oxygen sensors in the hypoxia response.