Mammalian mitochondrial genetics: heredity, heteroplasmy and disease

Abstract

Mammalian mitochondrial DNA (mtDNA) is present at high copy number (10(3)-10(4) copies) in virtually all cells of the body. The mitochondrial genome shows strict maternal inheritance and the vast majority of copies are identical at birth (homoplasmy). Occasionally, a subpopulation of mtDNA molecules carry a pathogenic mutation. When this heteroplasmic mtDNA is present during embryogenesis, it can lead to a variety of clinical symptoms predominantly affecting muscle and nerve, but also affecting other tissues. While the importance of mitochodrial heteroplasmy in human disease is unquestioned, we remain largely ignorant of many fundamental aspects of mitochondrial genetics. How do mutations arise and can they be repaired, what influences the segregation and fixation of heteroplasmic mtDNA, do levels of heteroplasmy fluctuate during life, is it possible to modulate these levels by external intervention and, finally, can we predict the segregation and transmission of a mutant genome? The aim of this article is to summarize and discuss recent observations that have addressed several of these fundamental issues and to reiterate how much we still have to learn about mitochondrial genetics.