Mitochondrial dna recombination, repair and segregation, recent scientific data and perspectives

Dynamics, maintenance and transmission of the mitochondrial DNA (mtDNA) are at the forefront of organellar genetics. Recombination plays a major role in these processes in many organisms and has mostly been documented at the genetic and molecular level in yeast and plant mitochondria. In these organisms, repeat-mediated recombination generates subgenomes and alternative mtDNA configurations. On the other hand, recombination takes part in mtDNA repair pathways, including error-prone mechanisms like break-induced replication. In plants, minor alternative configurations can segregate from the heteroplasmic state and become predominant through substoichiometric shifting. Ectopic recombination and recombination-mediated repair are major contributors to the evolution and transmission of the plant mitochondrial genome. These mechanisms are supported by a series of nuclear-encoded and mitochondrially imported factors of prokaryotic origin. The situation differs in mammals, where mitochondria essentially lack such factors. Historically, the occurrence of recombination in mammalian mitochondria has been a matter of debate and has been considered to be rare. The most recent investigations brought evidence for mtDNA recombination intermediates and active homologous recombination in heart and brain mitochondria. The issue is of importance, as mutations in the mtDNA are the cause of multiple, severe and incurable neurodegenerative diseases. Mutations are usually heteroplasmic and the onset of clinical symptoms is determined by the ratio of wild-type to mutant mtDNA, with a typical threshold effect. Heteroplasmy yields mitotic segregation, i.e. the proportion of mutated mtDNA copies may shift in daughter cells. In post-mitotic tissues, mutated mtDNA copies are often preferentially amplified, leading to clonal expansion. Finally, mtDNA genotypes may segregate between generations. The mechanisms underlying all these fundamental processes are little understood in mammals. Knowledge gained in plants and introduction of plant factors into mammalian model systems might shed new light into the field.