Vertebrate mitochondrial DNA-a circle of surprises

Evidence for the existence of a vertebrate mitochondrial genome first arose over 30 years ago. Application of emerging techniques of molecular biology established the structure of vertebrate mitochondrial DNA (mtDNA) as a small closed-circular species. The ability to purify these mtDNAs to a high degree facilitated studies on the overall replication and expression pattern of the genome. With the acquisition of the genomic sequences of human and mouse mtDNAs, it was possible to infer the genetic organization and some of the genes contained therein, as well as providing a basis for developing strategies to assign important regulatory elements involved in mtDNA replication and transcription. This, in turn, presented the opportunity to identify nucleus-encoded proteins that target to mtDNA and, in doing so, determine the replication and expression modes of the genome. Vertebrate cells, in general, need mtDNA due to the requirements for maintaining a functional oxidative phosphorylation pathway. Depression of mtDNA content or mutations in mtDNA can result in metabolic dysfunction severe enough, in some cases, to result in human lethality. The emergence of mouse models for human mitochondrial diseases should provide the experimental context to understand the full role of mtDNA in different cells, tissues, and organs; the control of organelle biogenesis; and the development of therapeutic strategies for treatment of mitochondrial disorders.