Nuclear genetic defects of oxidative phosphorylation

ATP generated by oxidative phosphorylation is necessary for the normal func tion 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 b oth the nuclear and mitochondrial genomes encode structural components of t he enzyme complexes of the oxidative phosphorylation system, the disorders can be transmitted either in a Mendelian fashion or maternally, or can occu r as sporadic cases. Over the last 12 years more than 100 mutations have be en uncovered in mtDNA, mostly associated with disease in the adult populati on. Recently, much attention has turned to the investigation of the nuclear oxidative phosphorylation gene defects. The majority of these are inherite d as autosomal recessive traits, producing severe, and usually fatal diseas e in infants. Adult-onset Mendelian oxidative phosphorylation diseases, whi ch can be inherited as autosomal recessive or dominant traits, have a milde r phenotype, and most are associated with multiple mtDNA deletions. Approxi mately 20 different nuclear gene defects have now been identified in genes coding for structural components of the complexes, assembly/maintenance fac tors and factors necessary for the maintenance of mtDNA integrity. Some cle ar 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.