MAMMALIAN MITOCHONDRIAL GENETICS - HEREDITY, HETEROPLASMY AND DISEASE

Mammalian mitochondrial DNA (mtDNA) is present at high copy number (10 (3)-10(4) copies) in virtually all cells of the bony. The mitochondria l genome shows strict maternal inheritance and the vast majority of co pies are identical nt birth (homoplasmy). Occasionally, a subpopulatio n of mtDNA molecules carry a pathogenic mutation When this heteroplasm ic mtDNA is present during embryogenesis, it can lead to a variety of clinical symptoms predominantly affecting muscle and nerve, but also a ffecting other tissues. While the importance of mitochondrial heteropl asmy in human disease is unquestioned, we remain largely ignorant of m any fundamental aspects of mitochondrial genetics. How do mutations ar ise and can they be repaired, what influences the segregation and fixa tion of heteroplasmic mtDNA, no levels of heteroplasmy fluctuate durin g life, is it possible to modulate these levels by external interventi on and, finally, can we predict the segregation and transmission of a mutant genome? The aim of this article is to summarize and discuss rec ent observations that have addressed several of these fundamental issu es and to reiterate how much we still have to learn about mitochondria l genetics.