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mtDNA mutations

Wednesday 28 September 2005

More than 75 human diseases have been associated with mitochondrial dysfunction, and many of these are directly caused by overtly pathogenic mutations in the mitochondrial genome (mtDNA). In addition, there have been a number of reports that posit a different, subtler role for mtDNA substitutions in the disease process.

Each mitochondrion contains thousands of mtDNA molecules, and, typically, deleterious mutations of the mtDNA affect some but not all of these genes. Thus, tissues and, indeed, whole individuals may harbor both wild-type and mutant mtDNA, a situation called heteroplasmy.

It should be evident that a minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease. This is called the "threshold effect." Not surprisingly, the threshold is reached most easily in the metabolically active tissues listed earlier.

During cell division, mitochondria and their contained DNA are randomly distributed to the daughter cells. Thus, when a cell containing normal and mutant mtDNA divides, the proportion of the normal and mutant mtDNA in daughter cells is extremely variable. Therefore, the expression of disorders resulting from mutations in mtDNA is quite variable.

Diseases associated with mitochondrial inheritance are rare and, as mentioned earlier, many of them affect the neuromuscular system. Leber hereditary optic neuropathy is a prototype of this disorder.

See also

- mtDNA deletions


- Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005 May;6(5):389-402. PMID: 15861210

- Howell N, Elson JL, Chinnery PF, Turnbull DM. mtDNA mutations and common neurodegenerative disorders. Trends Genet. 2005 Nov;21(11):583-6. PMID: 16154228

- Herrnstadt C, Howell N. An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion. 2004 Sep;4(5-6):791-8. PMID: 16120433