Defects of Mitochondrial DNA

Abstract

Human mitochondrial DNA is small (16.5 kb compared to 3 million kb of nuclear DNA). Each mitochondrion contains multiple genomes. Per cell there are hundreds or thousands of copies of mitochondrial DNA. In normal persons all mitochondrial DNA molecules are identical (homoplasmy). If there is a mutation in the mitochondrial DNA, this may affect all genomes (homoplasmy), or part of the genomes, resulting in the presence of two types of mitochondrial DNA, normal and mutant (heteroplasmy). In most cases of mitochondrial genomic defects, heteroplasmy is present. At cell division mitochondria (and mitochondrial DNA) distribute haphazardly between daughter cells. As a consequence, the proportion of mutant genomes may shift in daughter cells. The percentage of mutant DNA versus normal DNA may, therefore, be very different in different tissues and may shift in the course of time. Whether or not the mitochondrial DNA mutation is actually expressed, is largely determined by the relative proportion of normal versus mutant genomes in a given tissue. A minimum critical number of mutant DNAs is necessary to impair energy metabolism severely enough to cause dysfunction of that particular organ or tissue. This phenomenon is known as the threshold effect. The number of mutant genomes needed to cause cell dysfunction varies from tissue to tissue depending on the vulnerability of any given tissue to impairments of oxidative phosphorylation. The relative reliance of tissues on oxidative phosphorylation energy decreases in the following order: CNS, skeletal muscle, heart, kidney and liver. The presence of a mutation in a particular percentage of mitochondrial genomes may lead to signs of encephalopathy and/or myopathy, without any sign of dysfunction of other organs. The metabolic vulnerability may also vary in the same tissue with time and according to functional demands. As the proportion of mutant mitochondrial genomes may shift in daughter cells, this may also be the cause of a change in phenotype. Finally, there is a decline in oxidative phosphorylation capacity with age. The most likely mechanism for this phenomenon is the accumulation of damage to mitochondrial DNA in the face of insufficient ability to repair DNA alterations. This phenomenon may explain the late age of onset of clinical signs and symptoms in some patients, and the increase in severity of the disease with age.