Chapter 5 - Mitochondrial DNA: Structure, Genetics, Replication and Defects

Abstract

Since the discovery of DNA in mitochondria in 1963, our knowledge of the structure, function, and cellular mechanisms involved in the replication and transmission of this mitochondrial DNA (mtDNA) has progressed spectacularly. We now know that human mtDNA is a circular duplex molecule of 16,569 base pairs that is present in multiple copies in the cell, contains genes indispensable for the biosynthesis of the oxidative phosphorylation enzymes, and shows maternal inheritance. With the advance of molecular genetic techniques in the late 1980s, it became clear that mutations in mtDNA are a common cause of a number of genetic diseases with variable clinical expression. Most often, both mutant and wild-type mtDNA copies co-exist within the same cell, a phenomenon known as heteroplasmy. Symptoms manifest only when the proportion of mutated mtDNA in a tissue passes a critical threshold. Women carrying heteroplasmic mutations will pass on different mutation loads to their offspring, leading to substantial phenotypic heterogeneity among siblings. Because mtDNA diseases have no cure, the current focus of research is on risk reduction strategies for women to prevent germline transmission of mtDNA mutations.