DNA, mitochondrial: Mitochondrial DNA (mtDNA) is the DNA of the mitochondrion, a structure situated in the cytoplasm of the cell rather than in the nucleus (where all the other chromosomes are located).
mtDNA is a double-stranded, circular molecule. It is very small relative to the chromosomes in the nucleus and so contains only a limited number of genes. It is specialized in the information it carries and encodes a number of the subunits in the mitochondrial respiratory-chain complex that the cell needs to make energy from oxygen. (It also contains genes for some ribosomal RNAs and transfer RNAs).
Mutations (changes) in mtDNA can cause disease. The mutations often impair the function of oxidative-phosphorylation enzymes in the respiratory chain. This is especially manifest in tissues with a high energy expenditure such as brain and muscle.
Point mutations in mtDNA, for example, are associated with:
- NARP -- which stands for Neuropathy, Ataxia and Retinitis Pigmentosa: a disease with proximal muscle weakness, wobbliness, retinal disease, seizures and developmental delay;
- MELAS -- which stands for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke: a disease with migraine-like attacks of headache & vomiting, hemiplegia (weakness on one side of the body), visual defect, hearing loss, exercise intolerance and weakness, loss of consciousness, seizures, mental retardation or dementia, and elevated lactic acid in blood;
- MERRF -- which stands for Myoclonic Epilepsy and Ragged Red Fibers: a disease with epilepsy, myoclonus (shock-like contraction of muscle), dysfunction of the cerebellar portion of the brain, hearing loss and dementia;
- Leber's hereditary optic atrophy -- the onset in midlife (average age 30) of painless central visual loss that progresses over a period averaging 4 months, affecting both eyes; and
- Leigh's syndrome -- a disease starting usually in the 1st year of life with hypotonia (floppiness), episodes of vomiting, ataxia (wobbliness), choreoathetosis (abnormal involuntary writhing movements), hyperventilation, loss of motor and verbal milestones, spasticity, hearing loss, visual loss, carbohydrate intolerance, high lactic acid, and death often within 2 years of onset.
All mtDNA at fertilization comes from the oocyte. Therefore, inherited mtDNA mutations are transmitted from the mother to all offspring, male and female alike. The higher the level of mutant mtDNA in the mother's blood, the higher is the frequency of clinically affected offspring and the more severely the children tend to be affected.
Each cell in the body contains different mtDNA populations. Due to presence of multiple mitochondria in cells, each cell contains several mtDNA copies. This produces tissue variation so that a mutation in mtDNA vs normal mtDNA can vary widely among tissues in an individual.
There is thus a threshold effect. The percent of mutant mtDNAs must be above a certain threshold to produce clinical disease. This threshold varies from tissue to tissue because the percent of mutant mDNAs needed to cause cell dysfunction varies according to the oxidative requirements of the tissue, affecting particularly organs with a high energy needs such as brain and muscle.