Biogenesis of mitochondria and genetics of mitochondrial defects

Mitochondria are formed by the concerted action of two genetic systems: the nucleocytoplasmic system and the intrinsic mitochondrial system. The genetic contribution of the mitochondria is modest because the genetic potential of mtDNA of mammals is restricted to the equivalent of about 16 000 base pairs. For various animals and man the complete base sequence of mtDNA is known and all possible polypeptide genes have now been assigned to subunits of the respiratory enzymes. The mtDNA sequences are not present on the nuclear genome. From a genetic point of view it is important that the inheritance of mtDNA is strictly maternal. Mutations of mtDNA primarily lead to impairments of energy metabolism. In view of the indispensability of oxidative phosphorylation for obligatory aerobic organisms, such mutations should be lethal. However, there are various inborn errors of metabolism with tissue-specific manifestations, which are maternally inherited. The question discussed is whether these diseases can be explained on the basis of mutations of mitochondrial gene products. Tissue specificity poses a special problem, since it is not very attractive to assume that there is a heterogenous population of mtDNA molecules in the fertilized egg. Therefore, one should rather think in terms of a double mutational event, one tissue-specific cytoplasmic and the other general mitochondrial. These mutations only give rise to metabolic disturbances if they are expressed together in the same cel